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  • 1.
    Al Dabbagh, Z.
    et al.
    Department of Molecular Medicine and Surgery, Section of Orthopaedics and Sports Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Jansson, K. Å.
    Department of Molecular Medicine and Surgery, Section of Orthopaedics and Sports Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Stiller, C. O.
    Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Weiss, R. J.
    Department of Molecular Medicine and Surgery, Section of Orthopaedics and Sports Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Long-term pattern of opioid prescriptions after femoral shaft fractures2016In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 60, no 5, p. 634-641Article in journal (Refereed)
    Abstract [en]

    Background: The use of opioids in non-cancer-related pain following skeletal trauma is controversial due to the presumed risk of dose escalation and dependence. We therefore examined the pattern of opioid prescriptions, that is, those actually dispensed, in patients with femoral shaft fractures.

    Methods: We analysed data from the Swedish National Hospital Discharge Register and the Swedish Prescribed Drug Register between 2005 and 2008.

    Results: We identified 1471 patients with isolated femoral shaft fractures. The median age was 75 (16-102) years and 56% were female. In this cohort, 891 patients (61%) received dispensed opioid prescriptions during a median follow-up of 20 months (interquartile range 11-32). In the age- and sex-matched comparison cohort (7339 individuals) without fracture, 25% had opioid prescriptions dispensed during the same period. The proportions of patients receiving opioid analgesics at 6 and 12 months after the fracture were 45% (95% CI 42-49) and 36% (32-39), respectively. The median daily morphine equivalent dose (MED) was between 15 and 17 mg 1-12 months post-fracture. After 3 months, less than 5% used prescription doses higher than 20 mg MED per day. Older age (≥ 70 compared with < 70 years) was a significant predictor of earlier discontinuation of opioid use (Hazard ratio [HR] 1.9).

    Conclusion: A notable proportion of patients continued to receive dispensed prescriptions for opioids for over 6 months (45%) and more than a third of them (36%) continued treatment for at least 12 months. However, the risk of dose escalation seems to be small in opioid-naïve patients.

  • 2.
    Al Dabbagh, Zewar
    et al.
    Dept Mol Med & Surg, Sect Orthopaed & Sports Med, Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden.
    Jansson, Karl-Åke
    Dept Mol Med & Surg, Sect Orthopaed & Sports Med, Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden.
    Stiller, Carl-Olav
    Dept Med, Clin Pharmacol Unit, Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept Med, Clin Epidemiol Unit, Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden; Dept Epidemiol & Publ Hlth, University College London (UCL), London, England .
    Weiss, Rudiger J.
    Dept Mol Med & Surg, Sect Orthopaed & Sports Med, Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden.
    No signs of dose escalations of potent opioids prescribed after tibial shaft fractures: a study of Swedish National Registries2014In: BMC Anesthesiology, ISSN 1471-2253, E-ISSN 1471-2253, Vol. 14, p. 4-Article in journal (Refereed)
    Abstract [en]

    Background: The pattern of opioid use after skeletal trauma is a neglected topic in pain medicine. The purpose of this study was to analyse the long-term prescriptions of potent opioids among patients with tibial shaft fractures.

    Methods: Data were extracted from the Swedish National Hospital Discharge Register, the National Pharmacy Register, and the Total Population Register, and analysed accordingly. The study period was 2005-2008.

    Results: We identified 2,571 patients with isolated tibial shaft fractures. Of these, 639 (25%) collected a prescription for opioids after the fracture. The median follow-up time was 17 (interquartile range [IQR] 7-27) months. Most patients with opioid prescriptions after fracture were male (61%) and the median age was 45 (16-97) years. The leading mechanism of injury was fall on the same level (41%). At 6 and 12 months after fracture, 21% (95% CI 17-24) and 14% (11-17) were still being treated with opioids. Multiple Cox regression-analysis (adjusted for age, sex, type of treatment, and mechanism of injury) revealed that older patients (age >50 years) were more likely to end opioid prescriptions (Hazard ratio 1.5 [95% CI 1.3-1.9]). During follow-up, the frequency of patients on moderate and high doses declined. Comparison of the daily morphine equivalent dose among individuals who both had prescriptions during the first 3 months and the 6th month indicated that the majority of these patients (11/14) did not have dose escalations.

    Conclusions: We did not see any signs in registry-data of major dose escalations over time in patients on potent opioids after tibial shaft fractures.

  • 3. Ali, Magdi M. M.
    et al.
    ElGhazali, Gehad
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Farouk, Salah E.
    Nasr, Amre
    Noori, Suzan I. A.
    Shamad, Mahdi M.
    Fadlelseed, Omar E.
    Berzins, Klavs
    Fc gamma RIIa (CD32) polymorphism and onchocercal skin disease: implications for the development of severe reactive onchodermatitis (ROD)2007In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 77, no 6, p. 1074-8Article in journal (Refereed)
    Abstract [en]

    The pathologic manifestations of Onchocerca volvulus infection depend on the interplay between the host and the parasite. A genetic single nucleotide polymorphism in the Fc gamma RIIa gene, resulting in arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses and may influence the clinical variations seen in onchocerciasis. This study investigated the relationship between this polymorphism and disease outcome. Fc gamma RIIa genotyping was performed on clinically characterized onchocerciasis patients (N = 100) and healthy controls (N = 74). Fc gamma RIIa genotype R/R131 frequencies were significantly higher among patients with severe dermatopathology (P < 0.001). Increased risk of developing this form was mostly associated with one tribe (Masalit) (OR = 3.2, 95% CI 1-9.9, P = 0.042). The H131 allele was found to be significantly associated with a reduced risk of having the severe form of the disease (adjusted OR = 0.26, 95% CI = 0.13-0.46, P < 0.001). Our findings suggest that the polymorphism influences the clinical outcome of onchocerciasis.

  • 4. Amoudruz, Petra
    et al.
    Holmlund, Ulrika
    Schollin, Jens
    Örebro University, School of Health and Medical Sciences.
    Sverremark-Ekström, Eva
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Maternal country of birth and previous pregnancies are associated with breast milk characteristics2009In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 20, no 1, p. 19-29Article in journal (Refereed)
    Abstract [en]

    Populations in high infectious exposure countries are at low risk of some immune-mediated diseases such as Crohn's disease and allergy. This low risk is maintained upon immigration to an industrialized country, but the offspring of such immigrants have a higher immune-mediated disease risk than the indigenous population. We hypothesize that early life exposures in a developing country shape the maternal immune system, which could have implications for the offspring born in a developed country with a low infectious load. The aim of this study was to investigate if exposures in childhood (indicated by country of origin) and subsequent exposures influence immunologic characteristics relevant to stimulation of offspring. Breast milk components among 64 mothers resident in Sweden, 32 of whom immigrated from a developing country, were examined using the ELISA and Cytometric Bead Array methods. Immigrants from a developing country had statistically significantly higher levels of breast milk interleukin-6 (IL-6), IL-8 and transforming growth factor-beta1. A larger number of previous pregnancies were associated with down-regulation of several substances, statistically significant for soluble CD14 and IL-8. The results suggest that maternal country of birth may influence adult immune characteristics, potentially relevant to disease risk in offspring. Such a mechanism may explain the higher immune-mediated disease risk among children of migrants from a developing to developed country. Older siblings may influence disease risk through the action of previous pregnancies on maternal immune characteristics.

  • 5.
    Arribas, Christina
    et al.
    Department of Pediatrics, Neonatal Intensive Care Unit, Clínica Universidad de Navarra, Madrid, Spain.
    Cavallaro, Giacomo
    Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy.
    Gonzalez, Juan-Luis
    Department of Statistics and Operations Research, Faculty of Medicine, University of Cadiz, Cádiz, Spain.
    Lagares, Carolina
    Department of Statistics and Operations Research, Faculty of Medicine, University of Cadiz, Cádiz, Spain.
    Raffaeli, Genny
    Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy .
    Smits, Anne
    Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium.
    Simons, Sinno H. P.
    Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center—Sophia Children’s Hospital, Rotterdam, The Netherlands.
    Villamor, Eduardo
    MosaKids Children’s Hospital, Maastricht University Medical Center (MUMC + ), School for Oncology and Reproduction (GROW), Maastricht University, Maastricht, The Netherlands.
    Allegaert, Karel
    Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium .
    Garrido, Felipe
    Department of Pediatrics, Neonatal Intensive Care Unit, Clínica Universidad de Navarra, Madrid, Spain.
    Ullsten, Alexandra (Contributor)
    Örebro University, School of Health Sciences.
    Olsson, Emma (Contributor)
    Örebro University, School of Health Sciences.
    Gradin, Maria (Contributor)
    Örebro University, School of Health Sciences. Örebro University Hospital.
    Carlsen Misic, Martina (Contributor)
    Örebro University, School of Health Sciences. Örebro University Hospital.
    Montgomery, Scott (Contributor)
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Global cross-sectional survey on neonatal pharmacologic sedation and analgesia practices and pain assessment tools: impact of the sociodemographic index (SDI)2024In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447Article in journal (Refereed)
    Abstract [en]

    Background: There is variability in the use of sedatives and analgesics in neonatal intensive care units (NICUs). We aimed to investigate the use of analgesics and sedatives and the management of neonatal pain and distress.

    Methods: This was a global, prospective, cross-sectional study. A survey was distributed May–November 2022. The primary outcome of this research was to compare results between countries depending on their socio-sanitary level using the sociodemographic index (SDI). We organized results based on geographical location.

    Results: The survey collected 1304 responses, but we analyzed 924 responses after database cleaning. Responses from 98 different countries were analyzed. More than 60% of NICUs reported having an analgosedation guideline, and one-third of respondents used neonatal pain scales in more than 80% of neonates. We found differences in the management of sedation and analgesia between NICUs on different continents, but especially between countries with different SDIs. Countries with a higher SDI had greater availability of and adherence to analgosedation guidelines, as well as higher rates of analgosedation for painful or distressing procedures. Countries with different SDIs reported differences in analgosedation for neonatal intubation, invasive ventilation, and therapeutic hypothermia, among others.

    Conclusions: Socio-economic status of countries impacts on neonatal analgosedation management.

  • 6.
    Athlin, Åsa
    et al.
    Örebro University, School of Medical Sciences.
    Giezeman, Maaike
    Örebro University, School of Medical Sciences. Centre foClinical Research, Region Värmland, Karlstad, Sweden.
    Hasselgren, Mikael
    Örebro University, School of Medical Sciences.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College, London, UK.
    Lisspers, Karin
    Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.
    Ställberg, Björn
    Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.
    Janson, Christer
    Department of Medical Sciences, Respiratory, Allergy & Sleep Research, Uppsala University, Uppsala, Sweden.
    Sundh, Josefin
    Örebro University, School of Medical Sciences. Department of Respiratory Medicine.
    Prediction of Mortality Using Different COPD Risk Assessments: A 12-Year Follow-Up2021In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 16, p. 665-675Article in journal (Refereed)
    Abstract [en]

    Purpose: A multidimensional approach in the risk assessment of chronic obstructive pulmonary disease (COPD) is preferable. The aim of this study is to compare the prognostic ability for mortality by different COPD assessment systems; spirometric staging, classification by GOLD 2011, GOLD 2017, the age, dyspnea, obstruction (ADO) and the dyspnea, obstruction, smoking, exacerbation (DOSE) indices.

    Patients and Methods: A total of 490 patients diagnosed with COPD were recruited from primary and secondary care in central Sweden in 2005. The cohort was followed until 2017. Data for categorization using the different assessment systems were obtained through questionnaire data from 2005 and medical record reviews between 2000 and 2003. Kaplan-Meier survival analyses and Cox proportional hazard models were used to assess mortality risk. Receiver operating characteristic curves estimated areas under the curve (AUC) to evaluate each assessment systems´ ability to predict mortality.

    Results: By the end of follow-up, 49% of the patients were deceased. The mortality rate was higher for patients categorized as stage 3-4, GOLD D in both GOLD classifications and those with a DOSE score above 4 and ADO score above 8. The ADO index was most accurate for predicting mortality, AUC 0.79 (95% CI 0.75-0.83) for all-cause mortality and 0.80 (95% CI 0.75-0.85) for respiratory mortality. The AUC values for stages 1-4, GOLD 2011, GOLD 2017 and DOSE index were 0.73, 0.66, 0.63 and 0.69, respectively, for all-cause mortality.

    Conclusion: All of the risk assessment systems predict mortality. The ADO index was in this study the best predictor and could be a helpful tool in COPD risk assessment.

  • 7.
    Athlin, Åsa
    et al.
    Örebro University, School of Medical Sciences.
    Lisspers, Karin
    Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.
    Hasselgren, Mikael
    Örebro University, School of Medical Sciences. Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden.
    Ställberg, Björn
    Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.
    Janson, Christer
    Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden; Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Giezeman, Maaike
    Örebro University, School of Medical Sciences. Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden.
    Kisiel, Marta
    Department of Medical Sciences, Occupational and Environment Medicine, Uppsala University, Uppsala, Sweden.
    Nager, Anna
    Division of Family Medicine and Primary Care, Inst NVS, Karolinska Institutet, Stockholm, Sweden.
    Sandelowsky, Hanna
    Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Division of Family Medicine and Primary Care, Inst NVS, Karolinska Institutet, Stockholm, Sweden; Academic Primary Health Care Centre, Region Stockholm, Stockholm, Sweden.
    Arne, Mats
    Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden; Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.
    Sundh, Josefin
    Örebro University, School of Medical Sciences. Department of Respiratory Medicine.
    Diagnostic spirometry in COPD is increasing, a comparison of two Swedish cohorts2023In: npj Primary Care Respiratory Medicine, E-ISSN 2055-1010, Vol. 33, no 1, article id 23Article in journal (Refereed)
    Abstract [en]

    Spirometry should be used to confirm a diagnosis of chronic obstructive pulmonary disease (COPD). This test is not always performed, leading to possible misdiagnosis. We investigated whether the proportion of patients with diagnostic spirometry has increased over time as well as factors associated with omitted or incorrectly interpreted spirometry. Data from medical reviews and a questionnaire from primary and secondary care patients with a doctors' diagnosis of COPD between 2004 and 2010 were collected. Data were compared with a COPD cohort diagnosed between 2000 and 2003. Among 703 patients with a first diagnosis of COPD between 2004 and 2010, 88% had a diagnostic spirometry, compared with 59% (p < 0.001) in the previous cohort. Factors associated with not having diagnostic spirometry were current smoking (OR 2.21; 95% CI 1.36-3.60), low educational level (OR 1.81; 1.09-3.02) and management in primary care (OR 2.28; 1.02-5.14). The correct interpretation of spirometry results increased (75% vs 82%; p = 0.010). Among patients with a repeated spirometry, 94% had a persistent FEV1/FVC or FEV1/VC ratio <0.70.

  • 8. Bahmanyar, S.
    et al.
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Hillert, J.
    Ekbom, A.
    Olsson, T.
    Cancer risk among patients with multiple sclerosis and their parents2009In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 72, no 13, p. 1170-1177Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We investigated cancer risk among patients with multiple sclerosis (MS) and whether variation by age at MS diagnosis helps to elucidate mechanisms underlying the previously reported reduced cancer risk. We also studied cancer risk among parents to ascertain if MS susceptibility genes may confer protection against cancer in relatives. METHODS: Cox proportional hazards regression, adjusted for age, sex, area, and socioeconomic index, estimated cancer risk among 20,276 patients with MS and 203,951 individuals without MS, using Swedish general population register data. Similar analyses were conducted among 11,284 fathers and 12,006 mothers of patients with MS, compared with 123,158 fathers and 129,409 mothers of controls. RESULTS: With an average of 35 years of follow-up, there was a decreased overall cancer risk among patients with MS (hazard ratio = 0.91, 0.87-0.95). Increased risks were observed for brain tumors (1.44, 1.21-1.72) and urinary organ cancer (1.27, 1.05-1.53). Parents of patients with MS did not have a notably increased or decreased overall cancer risk. CONCLUSIONS: The reduction in cancer risk in patients with multiple sclerosis (MS) may result from behavioral change, treatment, or we speculate that some immunologic characteristics of MS disease activity improve antitumor surveillance. The lack of association among parents indicates that a simple inherited characteristic is unlikely to explain the reduced cancer risk among patients with MS. MS is associated with increased risk for some cancers, such as of urinary organs and brain tumors (although surveillance bias may be responsible).

  • 9.
    Bahmanyar, Shahram
    et al.
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital, Stockholm, Sweden; Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
    Ekbom, Anders
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital, Stockholm, Sweden.
    Askling, Johan
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital, Stockholm, Sweden.
    Johannesson, Marie
    Department, Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital, Stockholm, Sweden; Department of Primary Care and Social Medicine, Charing Cross Hospital, Imperial College, London, United Kingdom.
    Cystic fibrosis gene mutations and gastrointestinal diseases2010In: Journal of Cystic Fibrosis, ISSN 1569-1993, E-ISSN 1873-5010, Vol. 9, no 4, p. 288-291Article in journal (Refereed)
    Abstract [en]

    Background: This study examined if CF mutation heterozygosity is associated with diseases of gastrointestinal epithelial barrier function. Design and methods: Swedish registers identified 865 patients with a diagnosis of CF between 1968 and 2003 and matched with 8101 individuals without CF. Gastrointestinal disease risk was examined among 1534 biological parents and 1396 siblings of CF patients, compared with 15,526 parents and 15,542 siblings of individuals without CF. Results: First-degree relatives of CF patients were not at lower risk of the gastrointestinal diseases, in contrast with a raised risk among CF patients. Conclusion: Heterozygosity for CF gene mutations does not protect against gastrointestinal diseases where impaired barrier function may be relevant. (C) 2010 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  • 10. Bahmanyar, Shahram
    et al.
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Weiss, Rüdiger J.
    Ekbom, Anders
    Maternal smoking during pregnancy, other prenatal and perinatal factors, and the risk of Legg-Calvé-Perthes disease2008In: Pediatrics, ISSN 0031-4005, E-ISSN 1098-4275, Vol. 122, no 2, p. e459-e464Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The causes of Legg-Calvé-Perthes disease are largely unknown, but this pediatric disease seems to result from interruption of the blood supply to the proximal femur and is considered a vascular disease. Because maternal smoking during pregnancy influences fetal development and is associated with cardiovascular diseases in offspring, we hypothesized that this exposure is a risk for Legg-Calvé-Perthes disease and also investigated other markers of impaired fetal development and early-life exposures.

    MATERIALS AND METHODS: The Swedish Inpatient Register identified 852 individuals with a diagnosis of Legg-Calvé-Perthes disease from 1983 to 2005, individually matched by year of birth, age, sex, and region of residence with 4432 randomly selected control subjects. Linkage with the Swedish Medical Birth Register provided information on prenatal factors, including maternal smoking. Conditional logistic regression examined associations of maternal smoking during pregnancy and the other measures with the risk of Legg-Calvé-Perthes disease in offspring, adjusted for socioeconomic index and other potential confounding factors.

    RESULTS: Maternal smoking during pregnancy was associated with an increased Legg-Calvé-Perthes disease risk, and heavy smoking was associated with a risk increase of almost 100%. Very low birth weight and cesarean section were independently associated with approximately 240% and 36% increases in the risk of Legg-Calvé-Perthes disease, respectively.

    CONCLUSION: Maternal smoking during pregnancy and other factors indicated by impaired fetal development may be associated with an increased risk of Legg-Calvé-Perthes disease. 

  • 11.
    Batyrbekova, Nurgul
    et al.
    Department of Biostatistics, Scandinavian Development Services AB.
    Aleman, Soo
    Karolinska Institute, Stockholm, Sweden.
    Lybeck, Charlotte
    Örebro University, School of Medical Sciences. Infectious Diseases.
    Montgomery, Scott
    Örebro University, School of Medical Sciences.
    Duberg, Ann-Sofi
    Örebro University, School of Medical Sciences.
    Hepatitis C virus infection and the temporal trends in the risk of liver cancer: a national register-based cohort study in Sweden2020In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 29, no 1, p. 63-70Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In many countries, including Sweden, the birth cohorts with the highest prevalence of hepatitis C virus (HCV) infection have now reached the ages with high risk of primary liver cancer (PLC). The aims were to investigate the temporal trends in PLC incidence and the relative risks of PLC among people diagnosed with HCV-infection between 1990 and 2015.

    METHODS: The HCV-cohort (n: 52,853) was compared with a matched non-HCV comparison-cohort (n: 523,649). Both the Cancer (CR) and Death registers (DR) were used for follow-up. The crude and age-standardised PLC incidence rates were calculated. The relative risk was estimated as standardized incidence ratios (SIR) and as hazard ratios (HR) using stratified Cox hazards regression.

    RESULTS: There were 1,609 with PLC-diagnosis in the HCV-cohort, the annual number increased continuously with the crude incidence rate reaching 4.56 per 1,000 person-years in 2013, while remaining low and stable in the comparison-cohort. In the HCV-cohort, the age-standardised PLC incidence rates per 1,000 person-years remained relatively constant at 2.64 (95% CI: 1.54, 3.75) in 2000 and 3.31 (2.51, 4.12) in 2014. The highest SIR was 73 (65.9, 79.5) among those infected for 35-40 years; and the highest HR was 65.9 (55.9, 77.6) for men and 62.2 (31.9, 121.1) for women.

    CONCLUSIONS: There was a considerable increase in PLC-incidence over time and an extremely high relative risk in the population with HCV-infection for more than 35 years.

    IMPACT: The national HCV-associated PLC-incidence should be monitored in future studies to evaluate the effect of DAA-treatment.

  • 12.
    Bejerot, Susanne
    et al.
    Örebro University, School of Medical Sciences. Faculty of Health and Medical Sciences, University Health Care Research Centre, Örebro University, Örebro, Sweden.
    Eklund, Daniel
    Örebro University, School of Medical Sciences.
    Hesser, Hugo
    Örebro University, School of Behavioural, Social and Legal Sciences.
    Hietala, Max Albert
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Kariis, Tarmo
    Karlstad Central Hospital, Region Värmland, Karlstad, Sweden.
    Lange, Niclas
    Örebro University, School of Medical Sciences.
    Lebedev, Alexander
    Center for Psychiatry Research (CPF), Center for Cognitive and Computational Neuropsychiatry (CCNP), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Nordenskjöld, Axel
    Örebro University, School of Medical Sciences.
    Petrovic, Predrag
    Center for Psychiatry Research (CPF), Center for Cognitive and Computational Neuropsychiatry (CCNP), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Söderbergh, Annika
    Department of Rheumatology, Örebro University Hospital, Örebro, Sweden.
    Thunberg, Per
    Örebro University, School of Medical Sciences. Department of Radiology and Medical Physics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Center for Experimental and Biomedical Imaging in Örebro (CEBIO), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Wikström, Sverre
    Örebro University, School of Medical Sciences. Centre for Clinical Research, County Council of Värmland, Karlstad, Sweden.
    Humble, Mats B.
    Örebro University, School of Medical Sciences.
    Study protocol for a randomized controlled trial with rituximab for psychotic disorder in adults (RCT-Rits)2023In: BMC Psychiatry, E-ISSN 1471-244X, Vol. 23, no 1, article id 771Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The role of inflammation in the aetiology of schizophrenia has gained wide attention and research on the association shows an exponential growth in the last 15 years. Autoimmune diseases and severe infections are risk factors for the later development of schizophrenia, elevated inflammatory markers in childhood or adolescence are associated with a greater risk of schizophrenia in adulthood, individuals with schizophrenia have increased levels of pro-inflammatory cytokines compared to healthy controls, and autoimmune diseases are overrepresented in schizophrenia. However, treatments with anti-inflammatory agents are so far of doubtful clinical relevance. The primary objective of this study is to test whether the monoclonal antibody rituximab, directed against the B-cell antigen CD20 ameliorates psychotic symptoms in adults with schizophrenia or schizoaffective disorder and to examine potential mechanisms. A secondary objective is to examine characteristics of inflammation-associated psychosis and to identify pre-treatment biochemical characteristics of rituximab responders. A third objective is to interview a subset of patients and informants on their experiences of the trial to obtain insights that rating scales may not capture.

    METHODS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of B-cell depletion in patients with psychosis. 120 participants with a diagnosis of schizophrenia spectrum disorders (SSD) (ICD-10 codes F20, F25) will receive either one intravenous infusion of rituximab (1000 mg) or saline. Psychiatric measures and blood samples will be collected at baseline, week 12, and week 24 post-infusion. Brief assessments will also be made in weeks 2 and 7. Neuroimaging and lumbar puncture, both optional, will be performed at baseline and endpoints. Approximately 40 of the patients and their informants will be interviewed for qualitative analyses on the perceived changes in well-being and emotional qualities, in addition to their views on the research.

    DISCUSSION: This is the first RCT investigating add-on treatment with rituximab in unselected SSD patients. If the treatment is helpful, it may transform the treatment of patients with psychotic disorders. It may also heighten the awareness of immune-psychiatric disorders and reduce stigma.

    TRIAL REGISTRATION: NCT05622201, EudraCT-nr 2022-000220-37 version 2.1. registered 14th of October 2022.

  • 13. Bereczky, S.
    et al.
    Dolo, A.
    Maiga, B.
    Hayano, M.
    Granath, F.
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Daou, M.
    Arama, C.
    Troye-Blomberg, M.
    Doumbo, O. K.
    Färnert, A.
    Spleen enlargement and genetic diversity of Plasmodium falciparum infection in two ethnic groups with different malaria susceptibility in Mali, West Africa2006In: Transactions of the Royal Society of Tropical Medicine and Hygiene, ISSN 0035-9203, E-ISSN 1878-3503, Vol. 100, no 3, p. 248-257Article in journal (Refereed)
    Abstract [en]

    The high resistance to malaria in the nomadic Fulani population needs further understanding. The ability to cope with multiclonal Plasmodium falciparum infections was assessed in a cross-sectional survey in the Fulani and the Dogon, their sympatric ethnic group in Mali. The Fulani had lower parasite prevalence and densities and more prominent spleen enlargement. Spleen rates in children aged 2–9 years were 75% in the Fulani and 44% in the Dogon (P < 0.001). There was no difference in number of P. falciparum genotypes, defined by merozoite surface protein 2 polymorphism, with mean values of 2.25 and 2.11 (P = 0.503) in the Dogon and Fulani, respectively. Spleen rate increased with parasite prevalence, density and number of co-infecting clones in asymptomatic Dogon. Moreover, splenomegaly was increased in individuals with clinical malaria in the Dogon, odds ratio 3.67 (95% CI 1.65–8.15, P = 0.003), but not found in the Fulani, 1.36 (95% CI 0.53–3.48, P = 0.633). The more susceptible Dogon population thus appear to respond with pronounced spleen enlargement to asymptomatic multiclonal infections and acute disease whereas the Fulani have generally enlarged spleens already functional for protection. The results emphasize the importance of spleen function in protective immunity to the polymorphic malaria parasite.

  • 14. Bereczky, Sándor
    et al.
    Liljander, Anne
    Rooth, Ingegerd
    Faraja, Lea
    Granath, Fredrik
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Färnert, Anna
    Multiclonal asymptomatic Plasmodium falciparum infections predict a reduced risk of malaria disease in a Tanzanian population2007In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 9, no 1, p. 103-110Article in journal (Refereed)
    Abstract [en]

    Protective immunity to malaria is acquired after repeated exposure to the polymorphic Plasmodium falciparum parasite. Whether the number of concurrent antigenically diverse clones in asymptomatic infections predicts the risk of subsequent clinical malaria needs further understanding. We assessed the diversity of P. falciparum infections by merozoite surface protein 2 genotyping in a longitudinal population based study in Tanzania. The number of clones was highest in children 6–10 years and in individuals with long time to previous anti-malarial treatment. Individual exposure, analysed by circumsporozoite protein antibody levels, was associated with parasite prevalence but not with the number of clones. The risk of subsequent clinical malaria in children free of acute disease or recent treatment was, compared to one clone, reduced in individuals with multiclonal infections or without detectable parasites, with the lowest hazard ratio 0.28 (95% confidence interval 0.10–0.78 Cox regression) for 2–3 clones. The number of clones was not associated with haemoglobin levels. A reduced risk of malaria in asymptomatic individuals with multiclonal persistent P. falciparum infections suggests that controlled maintenance of diverse infections is important for clinical protection in continuously exposed individuals, and needs to be considered in the design and evaluation of new malaria control strategies.

  • 15.
    Bergh, Cecilia
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Fall, Katja
    Örebro University, School of Medical Sciences.
    Udumyan, Ruzan
    Örebro University, School of Medical Sciences.
    Sjöqvist, Hugo
    Örebro University, Örebro University School of Business.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Department of Cardiology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Severe infections and subsequent delayed cardiovascular disease2017In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 24, no 18, p. 1958-1966Article in journal (Refereed)
    Abstract [en]

    Background: Severe infections in adulthood are associated with subsequent short-term cardiovascular disease. Whether hospital admission for sepsis or pneumonia is associated with persistent increased risk (over a year after infection) is less well established.

    Design: The design of this study was as a register-based cohort study.

    Methods: Some 236,739 men born between 1952-1956 were followed from conscription assessments in adolescence to 2010. All-cause cardiovascular disease ( n = 46,754), including coronary heart disease ( n = 10,279) and stroke ( n = 3438), was identified through national registers 1970-2010 (at ages 18-58 years).

    Results: Sepsis or pneumonia in adulthood (resulting in hospital admission) are associated with increased risk of cardiovascular disease in the years following infection. The risk is highest during the first year after the infection, with an adjusted hazard ratio (and 95% confidence intervals) of 6.33 (5.65-7.09) and a notably increased risk persisted with hazard ratios of 2.47 (2.04-3.00) for the second and 2.12 (1.71-2.62) for the third year after infection. The risk attenuated with time, but remained raised for at least five years after infection; 1.87 (1.47-2.38). The results are adjusted for characteristics in childhood, cardiovascular risk factors and medical history in adolescence. Similar statistically significant associations were found for coronary heart disease and stroke.

    Conclusions: Raised risks of cardiovascular disease following hospital admission for sepsis or pneumonia were increased for more than five years after the infection, but with the highest magnitude during the first three years following infection, suggesting a period of vulnerability when health professionals and patients should be aware of the heightened risk for cardiovascular disease.

  • 16.
    Bergh, Cecilia
    et al.
    Örebro University, School of Health Sciences.
    Hiyoshi, Ayako
    Örebro University, School of Medical Sciences. Department of Public Health Sciences, Stockholm University, Stockholm, Sweden.
    Eriksson, Mats
    Örebro University, School of Health Sciences.
    Fall, Katja
    Örebro University, School of Medical Sciences.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, UK.
    Shared unmeasured characteristics among siblings confound the association of Apgar score with stress resilience in adolescence2019In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 108, no 11, p. 2001-2007Article in journal (Refereed)
    Abstract [en]

    AIM: We investigated the association between low Apgar score, other perinatal characteristics and low stress resilience in adolescence. A within-siblings analysis was used to tackle unmeasured shared familial confounding.

    METHODS: We used a national cohort of 527,763 males born in Sweden between 1973 and 1992 who undertook military conscription assessments at mean age 18 years (17-20). Conscription examinations included a measure of stress resilience. Information on Apgar score and other perinatal characteristics was obtained through linkage with the Medical Birth Register. Analyses were conducted using ordinary least squares and fixed-effects linear regression models adjusted for potential confounding factors.

    RESULTS: Infants with a prolonged low Apgar score at five minutes had an increased risk of low stress resilience in adolescence compared to those with highest scores at one minute, with an adjusted coefficient and 95% confidence interval of -0.26 (-0.39, -0.13). The associations were no longer statistically significant when using within-siblings models. However, the associations with stress resilience and birthweight remained statistically significant in all analyses.

    CONCLUSION: The association with low Apgar score seems to be explained by confounding due to shared childhood circumstances among siblings from the same family, while low birthweight is independently associated with low stress resilience.

  • 17.
    Bergh, Cecilia
    et al.
    Örebro University, School of Health Sciences.
    Oasti, Zahra
    Örebro University, Örebro, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences.
    Non-psychotic mental disorders in adolescent men and risk of myocardial infarction: A national cohort study2020In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 41, no Suppl. 2, p. 2812-2812Article in journal (Other academic)
    Abstract [en]

    Background/Purpose: Recent studies show that early life stress is associated with later risk of cardiovascular disease (CVD) and stress may also increase the risk of psychiatric disease. We investigated the association between non-psychotic mental disorders in adolescence and subsequent myocardial infarction, and the role of stress resilience and physical fitness in this association.

    Method: This is a register-based cohort study with 238 013 males born between 1952 and 1956 followed from 1987 to 2010 using information from Swedish registers. Stress resilience was measured at a compulsory military conscription examination using a semi-structured interview with a psychologist. Physical fitness was measured at conscription examination with a cycle ergometer test. A total of 34 503 men were diagnosed with a non-psychotic mental disorder at conscription. Using Cox regression, we estimated the association of mental disorders with myocardial infarction after adjustment for other established CVD risk factors in adolescence. Stress resilience and physical fitness were included in the adjusted model in a second set of analyses.

    Results: A total of 5891 diagnoses of first myocardial infarction were identified. Non-psychotic mental disorders were associated with an increased risk of myocardial infarction, with a hazard ratio (HR) and confidence interval (CI) of 1.51 (1.41–1.62). The association remained statistically significant after adjustment for other important potential confounders in adolescence such as systolic and diastolic blood pressure, body mass index, inflammation, cognitive function, parental socioeconomic index and a summary disease score (HR 1.24 (CI 1.13–1.35)). The association was further explained by stress resilience and lifestyle factors assessed with a cardiovascular fitness test in adolescence, as the association attenuated but remained statistically significant when further adjusting for stress resilience and physical fitness (HR 1.18 (CI 1.08–1.29)).

    Conclusion: A non-psychotic mental disorder in adolescences may increase the risk of developing myocardial infarction later in life. This association was partly but not completely explained by poorer stress resilience and physical fitness. Effective prevention might focus on behaviour/lifestyle and psychosocial stress in early life.

  • 18.
    Bergh, Cecilia
    et al.
    Örebro University, School of Medical Sciences.
    Udumyan, Ruzan
    Örebro University, School of Medical Sciences.
    Appelros, Peter
    Department of Neurology, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Fall, Katja
    Örebro University, School of Medical Sciences.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Determinants in adolescence of stroke-related hospital stay duration in men: a national cohort study2016In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 47, no 9, p. 2416-2418Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Physical and psychological characteristics in adolescence are associated with subsequent stroke risk. Our aim is to investigate their relevance to length of hospital stay and risk of second stroke.

    Methods: Swedish men born between 1952 and 1956 (n=237 879) were followed from 1987 to 2010 using information from population-based national registers. Stress resilience, body mass index, cognitive function, physical fitness, and blood pressure were measured at compulsory military conscription examinations in late adolescence. Joint Cox proportional hazards models estimated the associations of these characteristics with long compared with short duration of stroke-related hospital stay and with second stroke compared with first.

    Results: Some 3000 men were diagnosed with nonfatal stroke between ages 31 and 58 years. Low stress resilience, underweight, and higher systolic blood pressure (per 1-mm Hg increase) during adolescence were associated with longer hospital stay (compared with shorter) in ischemic stroke, with adjusted relative hazard ratios (and 95% confidence intervals) of 1.46 (1.08-1.89), 1.41 (1.04-1.91), and 1.01 (1.00-1.02), respectively. Elevated systolic and diastolic blood pressures during adolescence were associated with longer hospital stay in men with intracerebral hemorrhage: 1.01 (1.00-1.03) and 1.02 (1.00-1.04), respectively. Among both stroke types, obesity in adolescence conferred an increased risk of second stroke: 2.06 (1.21-3.45).

    Conclusions: Some characteristics relevant to length of stroke-related hospital stay and risk of second stroke are already present in adolescence. Early lifestyle influences are of importance not only to stroke risk by middle age but also to recurrence and use of healthcare resources among stroke survivors.

  • 19.
    Bergh, Cecilia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Udumyan, Ruzan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Almroth, Henrik
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom .
    Stress resilience and physical fitness in adolescence and risk of coronary heart disease in middle age2015In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 101, no 8, p. 623-629Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Psychosocial stress is a suggested risk for coronary heart disease (CHD). The relationship of stress resilience in adolescence with subsequent CHD risk is underinvestigated, so our objective was to assess this and investigate the possible mediating role of physical fitness.

    METHODS: In this register-based study, 237 980 men born between 1952 and 1956 were followed from 1987 to 2010 using information from Swedish registers. Stress resilience was measured at a compulsory military conscription examination using a semistructured interview with a psychologist. Some 10 581 diagnoses of CHD were identified. Cox regression estimated the association of stress resilience with CHD, with adjustment for established cardiovascular risk factors.

    RESULTS: Low-stress resilience was associated with increased CHD risk. The association remained after adjustment for physical fitness and other potential confounding and mediating factors, with adjusted HRs (and 95% CIs) of 1.17 (1.10 to 1.25), with some evidence of mediation by physical fitness. CHD incidence rates per 1000 person-years (and 95% CIs) for low-stress, medium-stress and high-stress resilience were 2.61 (2.52 to 2.70), 1.97 (1.92 to 2.03) and 1.59 (1.53 to 1.67) respectively. Higher physical fitness was inversely associated with CHD risk; however, this was attenuated by low-stress resilience, shown by interaction testing (p<0.001).

    CONCLUSIONS: Low-stress resilience in adolescence was associated with increased risk of CHD in middle age and may diminish the benefit of physical fitness. This represents new evidence of the role of stress resilience in determining risk of CHD and its interrelationship with physical fitness.

  • 20.
    Bergh, Cecilia
    et al.
    Örebro University Hospital. Örebro University, School of Medical Sciences.
    Udumyan, Ruzan
    Örebro University, School of Medical Sciences.
    Fall, Katja
    Örebro University, School of Medical Sciences.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Pre-stroke characteristics and stroke severity after first stroke in middle-aged men2015In: Nordic Stroke 2015: 18th Nordic Congress of Cerebrovascular Diseases, 2015Conference paper (Refereed)
  • 21.
    Bergh, Cecilia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Physiotherapy, Örebro University Hospital, Örebro, Sweden.
    Udumyan, Ruzan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nilsagård, Ylva
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Centre for Health Care Sciences, Örebro University Hospital, Örebro, Sweden.
    Appelros, Peter
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Neurology, Örebro University Hospital, Örebro, Sweden.
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Departnment of Epidemiology and Public Health, University College London, London, UK; Cinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Stress resilience in male adolescents and subsequent stroke risk: cohort study2014In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 85, no 12, p. 1331-1336Article in journal (Refereed)
    Abstract [en]

    Objective Exposure to psychosocial stress has been identified as a possible stroke risk, but the role of stress resilience which may be relevant to chronic exposure is uncertain. We investigated the association of stress resilience in adolescence with subsequent stroke risk.

    Methods Register-based cohort study. Some 237 879 males born between 1952 and 1956 were followed from 1987 to 2010 using information from Swedish registers. Cox regression estimated the association of stress resilience with stroke, after adjustment for established stroke risk factors.

    Results Some 3411 diagnoses of first stroke were identified. Lowest stress resilience (21.8%) compared with the highest (23.7%) was associated with increased stroke risk, producing unadjusted HR (with 95% CIs) of 1.54 (1.40 to 1.70). The association attenuated slightly to 1.48 (1.34 to 1.63) after adjustment for markers of socioeconomic circumstances in childhood; and after further adjustment for markers of development and disease in adolescence (blood pressure, cognitive function and pre-existing cardiovascular disease) to 1.30 (1.18 to 1.45). The greatest reduction followed further adjustment for markers of physical fitness (BMI and physical working capacity) in adolescence to 1.16 (1.04 to 1.29). The results were consistent when stroke was subdivided into fatal, ischaemic and haemorrhagic, with higher magnitude associations for fatal rather than non-fatal, and for haemorrhagic rather than ischaemic stroke.

    Conclusions Stress susceptibility and, therefore, psychosocial stress may be implicated in the aetiology of stroke. This association may be explained, in part, by poorer physical fitness. Effective prevention might focus on behaviour/lifestyle and psychosocial stress.

  • 22. Bergquist, Annika
    et al.
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Bahmanyar, Shahram
    Olsson, Rolf
    Danielsson, Åke
    Lindgren, Stefan
    Prytz, Hanne
    Hultcrantz, Rolf
    Lööf, Lars
    Sandberg-Gertzén, Hanna
    Almer, Sven
    Askling, Johan
    Ehlin, Anna
    Ekbom, Anders
    Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis2008In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 6, no 8, p. 939-943Article in journal (Refereed)
    Abstract [en]

    Background & Aims: The importance of genetic factors for the development of primary sclerosing cholangitis (PSC) is incompletely understood. This study assessed the risk of PSC and inflammatory bowel disease (IBD) among first-degree relatives of patients with PSC, compared with the first-degree relatives of a cohort without PSC. Methods: Subjects from the national Swedish cohort of PSC patients (n = 678) were matched for date of birth, sex, and region to up to 10 subjects without a diagnosis of PSC (n = 6347). Linkage through general population registers identified first-degree relatives of subjects in both the PSC and comparison cohorts (n = 34,092). Diagnoses among first-degree relatives were identified by using the Inpatient Register. Results: The risk of cholangitis was statistically significantly increased in offspring, siblings, and parents of the PSC patient cohort, compared with relatives of the comparison cohort, with the hazard ratios and 95% confidence intervals, 11.5 (1.6–84.4), 11.1 (3.3–37.8), and 2.3 (0.9–6.1), respectively. The hazard ratios for ulcerative colitis (UC) among first-degree relatives of all PSC patients was 3.3 (2.3–4.9) and for Crohn's disease 1.4 (0.8–2.5). The risk of UC for relatives of PSC patients without IBD was also increased, 7.4 (2.9–18.9). Conclusions: First-degree relatives of patients with PSC run an increased risk of PSC, indicating the importance of genetic factors in the etiology of PSC. First-degree relatives of PSC patients without IBD are also at an increased risk of UC, which might indicate shared genetic susceptibility factors for PSC and UC. 

  • 23. Bergquist, Annika
    et al.
    Montgomery, Scott M.
    Örebro University, Department of Clinical Medicine.
    Lund, Ulrika
    Ekbom, Anders
    Olsson, Rolf
    Lindgren, Stefan
    Prytz, Hanne
    Hultcrantz, Rolf
    Broomé, Ulrika
    Perinatal events and the risk of developing primary sclerosing cholangitis2006In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 12, no 37, p. 6037-6040Article in journal (Refereed)
    Abstract [en]

    AIM: To investigate whether perinatal events, intrauterine or postpartum, are associated with the development of primary sclerosing cholangitis (PSC) later in life.

    METHODS: Birth records from 97 patients with adult PSC in Sweden were reviewed. Information on perinatal events including medications and complications during pregnancy, gestation length, birth weight and length were collected. Two control children of the same sex were selected for each subject. Conditional multiple logistic regression was used to assess associations of the perinatal measures with development of PSC.

    RESULTS: No significant associations were found between gestational age, birth length, breastfeeding, and the majority of medical complications including infections or medication during pregnancy for the mothers or postpartum for the children. Vaginal bleeding and peripheral oedema showed associations with PSC, with matched odds ratios of 5.70 (95% CI, 1.13-28.83) and 2.28 (95% CI, 1.04-5.03), respectively.

     

    CONCLUSION: The associations of vaginal bleeding and oedema with subsequent PSC cannot readily be explained, so our findings do not strongly support the hypothesis of a significant role of perinatal events as a risk for the development of PSC later in life.

  • 24.
    Bergsten, Elisabet
    et al.
    Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden; Theme of Children’s and Women’s Health, Karolinska University Hospital, Stockholm, Sweden.
    Horne, AnnaCarin
    Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden; Theme of Children’s and Women’s Health, Karolinska University Hospital, Stockholm, Sweden.
    Aricó, Maurizio
    Direzione Generale, Azienda Sanitaria Provinciale, Ragusa, Italy.
    Astigarraga, Itziar
    Servicio de Pediatria, BioCruces Health Research Institute, Hospital Universitario Cruces, Universidad del Pais Vasco–Euskal Herriko Unibertsitatea (UPV/EHU), Barakaldo, Spain.
    Egeler, R. Maarten
    Division of Hematology & Oncology, The Hospital for Sick Children, Toronto ON, Canada.
    Filipovich, Alexandra H.
    Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati OH, USA.
    Ishii, Eiichi
    Department of Pediatrics, Graduate School of Medicine, Ehime University, Ehime, Japan.
    Janka, Gritta
    Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany.
    Ladisch, Stephan
    Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Washington DC, USA.
    Lehmberg, Kai
    Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany.
    McClain, Kenneth L.
    Texas Children’s Cancer Center, Baylor College of Medicine, Houston TX, USA.
    Minkov, Milen
    University Clinic of Pediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Nanduri, Vasanta
    Department of Pediatrics, Watford General Hospital, Watford, United Kingdom.
    Rosso, Diego
    Department of Pediatric Hematology and Oncology, Hospital de Niños Dr Pedro De Elizalde, Buenos Aires, Argentina; Department of Pediatrics, Hospital de Clinicas Jose de San Martin, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
    Henter, Jan-Inge
    Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden; Theme of Children’s and Women’s Health, Karolinska University Hospital, Stockholm, Sweden.
    Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study2017In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 130, no 25, p. 2728-2738Article in journal (Refereed)
    Abstract [en]

    Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. From 2004 to 2011, 369 children aged <18 years fulfilled HLH-2004 inclusion criteria (5 of 8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n = 168) and without (n = 201) family history/genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n = 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P = .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 (P =020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL, 70% [63%-78%]). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly.

  • 25. Bhattarai, Achuyt
    et al.
    Ali, Abdullah S.
    Kachur, S. Patrick
    Mårtensson, Andreas
    Abbas, Ali K.
    Khatib, Rashid
    Al-Mafazy, Abdul-Wahiyd
    Ramsan, Mahdi
    Rotllant, Guida
    Gerstenmaier, Jan F.
    Molteni, Fabrizio
    Abdulla, Salim
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Kaneko, Akira
    Björkman, Anders
    Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar2007In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 4, no 11, p. e309-Article in journal (Refereed)
    Abstract [en]

    Background

    The Roll Back Malaria strategy recommends a combination of interventions for malaria control. Zanzibar implemented artemisinin-based combination therapy (ACT) for uncomplicated malaria in late 2003 and long-lasting insecticidal nets (LLINs) from early 2006. ACT is provided free of charge to all malaria patients, while LLINs are distributed free to children under age 5 y (“under five”) and pregnant women. We investigated temporal trends in Plasmodium falciparum prevalence and malaria-related health parameters following the implementation of these two malaria control interventions in Zanzibar.

    Methods and Findings

    Cross-sectional clinical and parasitological surveys in children under the age of 14 y were conducted in North A District in May 2003, 2005, and 2006. Survey data were analyzed in a logistic regression model and adjusted for complex sampling design and potential confounders. Records from all 13 public health facilities in North A District were analyzed for malaria-related outpatient visits and admissions. Mortality and demographic data were obtained from District Commissioner's Office. P. falciparum prevalence decreased in children under five between 2003 and 2006; using 2003 as the reference year, odds ratios (ORs) and 95% confidence intervals (CIs) were, for 2005, 0.55 (0.28–1.08), and for 2006, 0.03 (0.00–0.27); p for trend < 0.001. Between 2002 and 2005 crude under-five, infant (under age 1 y), and child (aged 1–4 y) mortality decreased by 52%, 33%, and 71%, respectively. Similarly, malaria-related admissions, blood transfusions, and malaria-attributed mortality decreased significantly by 77%, 67% and 75%, respectively, between 2002 and 2005 in children under five. Climatic conditions favorable for malaria transmission persisted throughout the observational period.

    Conclusions

    Following deployment of ACT in Zanzibar 2003, malaria-associated morbidity and mortality decreased dramatically within two years. Additional distribution of LLINs in early 2006 resulted in a 10-fold reduction of malaria parasite prevalence. The results indicate that the Millennium Development Goals of reducing mortality in children under five and alleviating the burden of malaria are achievable in tropical Africa with high coverage of combined malaria control interventions.

  • 26.
    Björk, Tabita
    et al.
    Psychiatric Research Centre, Örebro County Council, Örebro, Sweden; Department of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    Brus, Ole
    Örebro University Hospital, Örebro, Sweden.
    Osika, Walter
    Stress Research Institute, Stockholm University, Stockholm, Sweden.
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden; Department of Primary Care and Public Health, Charing Cross Hospital, Imperial College, London, UK.
    Laterality, hand control and scholastic performance: a British birth cohort study2012In: BMJ Open, E-ISSN 2044-6055, Vol. 2, no 2, article id e000314Article in journal (Refereed)
    Abstract [en]

    Objectives: To use simple measures of laterality and hand control that can identify a greater risk of poorer scholastic ability, potentially signalling suboptimal hemispheric lateralisation.

    Design: Analysis of material from a birth cohort study.

    Setting: Members of the National Child Development Study, a British birth cohort study following people born in 1958.

    Participants: 10 612 children who undertook tests at age 11 years.

    Primary outcome measures: Teacher-administered tests of non-verbal general ability, verbal general ability, reading comprehension and mathematics.

    Results: Linear regression produced associations (and 95% CIs) with tests of verbal general ability, non-verbal general ability, reading comprehension and mathematics scores for the lowest third (compared with highest) of a left-hand control test involving picking up matches of -1.21 (-1.73 to -0.68; p<0.001), -0.72 (-1.14 to -0.29; p=0.001), -0.70 (-1.06 to -0.35; p<0.001) and -1.32 (-1.90 to -0.73; p<0.001). Among those in the lowest third of the right-hand control test score, mixed-handedness compared with right-handedness was associated with poorer scholastic performance, with regression coefficients (and 95% CIs; p values) of 1.90 (-3.01 to -0.80; p=0.001), -1.25 (-2.15 to -0.35; p=0.007), -1.28 (2.04 to -0.53; p=0.001) and -1.33 (-2.53 to -0.13; p=0.030). The estimates are for a point change in the scholastic test scores, after adjustment for sex, left-hand motor function and social class. Statistically significant associations with mixed-handedness were only observed for the lowest third of right-hand motor function.

    Conclusions: Measures involving poorer left-hand motor function may represent useful markers of reduced cognitive function possibly reflecting suboptimal hemispheric lateralisation. Crude measures of laterality such as reported non-right-handedness may be more useful for research when combined with measures of motor function.

  • 27.
    Blane, David
    et al.
    Imperial College, London, UK.
    Kelly-Irving, Michelle
    INSERM U1027, Toulouse, France.
    d'Errico, Angelo
    University of Torino, Torino, Italy.
    Bartley, Melanie
    University College London, London, UK.
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden; Örebro University, Örebro, Sweden.
    Social-biological transitions: how does the social become biological2013In: Longitudinal and Life Course Studies, E-ISSN 1757-9597, Vol. 4, no 2Article in journal (Refereed)
    Abstract [en]

    The present discussion paper sets forward a model within the life course perspective of how the social becomes biological.  The model is intended to provide a framework for thinking about such questions as how does social class get into the molecules, cells and tissues of the body to produce social class differences in life expectancy and cause of death?  A categorisation of social exposures and biological processes is suggested; and some principles governing their inter-relations proposed.  The paper ends by suggesting two public health applications of this approach.

  • 28. Blane, David
    et al.
    Netuveli, Gopalakrishnan
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Quality of life, health and physiological status and change at older ages2008In: Social Science and Medicine, ISSN 0277-9536, E-ISSN 1873-5347, Vol. 66, no 7, p. 1579-1587Article in journal (Refereed)
    Abstract [en]

    The relationship between self-reported health status and quality of life at older ages is well established. The present paper investigates this relationship further, using objective measures of health and their change over time in the English Longitudinal Study of Ageing, where positive quality of life at older ages was measured as CASP-19. Cross-sectionally, lung function and obesity, but not blood pressure, were associated with quality of life; these relationships in path analysis were transmitted primarily via functional limitation and more modestly, and only for lung function, via clinical depression. Longitudinally, the results suggest a stable and long-term influence on quality of life of lung function and, among women, body mass index, to which the influence of change may be cumulative; longer follow-up is required to clarify these processes. Overall, the results show that the relationship between health and quality of life is independent of potential psychological confounders, that functional limitation is the key dimension of health in its relationship with quality of life and that clinical depression may be an important mediator between functional limitation and quality of life.

  • 29.
    Bouhuis, Dennis
    et al.
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Giezeman, Maaike
    Örebro University, School of Medical Sciences. Centre for Clinical Research and Education, Karlstad, Sweden.
    Hasselgren, Mikael
    Örebro University, School of Medical Sciences. Centre for Clinical Research and Education, Karlstad, Sweden.
    Janson, Christer
    Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.
    Kisiel, Marta A.
    Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, Uppsala, Sweden.
    Lisspers, Karin
    Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Faculty of Medicine and Health, Örebro, Sweden; Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College, London, UK.
    Nager, Anna
    Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.
    Sandelowsky, Hanna
    Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden; Academic Primary Health Care Centre, Stockholm, Sweden.
    Ställberg, Björn
    Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.
    Sundh, Josefin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Respiratory Medicine.
    Factors Associated with the Non-Exacerbator Phenotype of Chronic Obstructive Pulmonary Disease2023In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 18, p. 483-492Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) and no exacerbations may need less maintenance treatment and follow-up. The aim was to identify factors associated with a non-exacerbator COPD phenotype.

    METHODS: Cross-sectional analysis of 1354 patients from primary and secondary care, with a doctor's diagnosis of COPD. In 2014, data on demographics, exacerbation frequency and symptoms using COPD Assessment Test (CAT) were collected using questionnaires and on spirometry and comorbid conditions by record review. The non-exacerbator phenotype was defined as having reported no exacerbations the previous six months. Multivariable logistic regression with the non-exacerbator phenotype as dependent variable was performed, including stratification and interaction analyses by sex.

    RESULTS: The non-exacerbator phenotype was found in 891 (66%) patients and was independently associated with COPD stage 1 (OR [95% CI] 5.72 [3.30-9.92]), stage 2 (3.42 [2.13-5.51]) and stage 3 (2.38 [1.46-3.88]) compared with stage 4, and with CAT score <10 (3.35 [2.34-4.80]). Chronic bronchitis and underweight were inversely associated with the non-exacerbator phenotype (0.47 [0.28-0.79]) and (0.68 [0.48-0.97]), respectively. The proportion of non-exacerbators was higher among patients with no maintenance treatment or a single bronchodilator. The association of COPD stage 1 compared with stage 4 with the non-exacerbator phenotype was stronger in men (p for interaction 0.048). In women, underweight and obesity were both inversely associated with the non-exacerbator phenotype (p for interaction 0.033 and 0.046 respectively), and in men heart failure was inversely associated with the non-exacerbator phenotype (p for interaction 0.030).

    CONCLUSION: The non-exacerbator phenotype is common, especially in patients with no maintenance treatment or a single bronchodilator, and is characterized by preserved lung function, low symptom burden, and by absence of chronic bronchitis, underweight and obesity and heart failure. We suggest these patients may need less treatment and follow-up, but that management of comorbid conditions is important to avoid exacerbations.

  • 30.
    Bouhuis, Dennis
    et al.
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Giezeman, Maaike
    Örebro University, School of Medical Sciences.
    Janson, Christer
    Department of Medical Sciences, Respiratory, Allergy & Sleep Research, Uppsala University, Uppsala, Sweden.
    Kisiel, Marta Alina
    Department of Medical Sciences, Environmental and Occupational Medicine, Uppsala University, Uppsala, Sweden.
    Lisspers, Karin
    Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Nager, Anna
    Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.
    Sandelowsky, Hanna
    Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.
    Ställberg, Björn
    Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.
    Sundh, Josefin
    Örebro University, School of Medical Sciences. Department of Respiratory Medicine.
    Factors associated with self-assessed asthma severity2022In: Journal of Asthma, ISSN 0277-0903, E-ISSN 1532-4303, Vol. 59, no 4, p. 691-696Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Asthma severity can be estimated as the level of medication needed to achieve asthma control or by the patient's subjective assessment. Factors associated with self-assessed asthma severity are still incompletely explored.

    AIM: The aim was to study factors associated with self-assessed moderate or severe asthma.

    METHOD: In total, 1828 randomly selected asthma patients from primary (69%) and secondary (31%) care, completed a questionnaire including items about patient characteristics, comorbidity, the Asthma Control Test (ACT), emergency care visits and a scale for self-assessed asthma severity. Logistic regression was used to analyze associations with the dependent variable, self-assessed moderate or severe asthma in the entire study population and stratified by sex.

    RESULTS: Of the patients, 883 (45%) reported having moderate or severe asthma. Factors independently associated with self-assessed moderate or severe asthma were age >60 years (OR [95% CI] 1.98 [1.37-2.85]), allergic rhino-conjunctivitis (1.43 [1.05-1.95]), sinusitis (1.45 [1.09-1.93]), poor asthma control as measured by ACT <20 (5.64 [4.45-7.16]) and emergency care visits the previous year (2.52 [1.90-3.34]). Lower level of education was associated with self-assessed moderate/severe asthma in women (1.16 [1.05-2.43]) but not in men (0.90 [0.65-1.25]), p for interaction = .012.

    CONCLUSION: Poor asthma control, allergic rhino-conjunctivitis, recent sinusitis and older age were independently associated with self-assessed moderate or severe asthma. Important implications are that comorbid conditions of the upper airways should always be considered as part of asthma management, and that elderly patients may need extra attention.

  • 31.
    Brand, Judith
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, Bristol, UK.
    Hiyoshi, Ayako
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Public Health Sciences, Stockholm University, Stockholm, Sweden.
    Cao, Yang
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Lawlor, Deborah A.
    MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, Bristol, UK.
    Cnattingius, Sven
    Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Solna, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Solna, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Maternal smoking during pregnancy and fractures in offspring: national register based sibling comparison study2020In: The BMJ, E-ISSN 1756-1833, Vol. 368, article id l7057Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the impact of maternal smoking during pregnancy on fractures in offspring during different developmental stages of life.

    DESIGN: National register based birth cohort study with a sibling comparison design.

    SETTING: Sweden.

    PARTICIPANTS: 1 680 307 people born in Sweden between 1983 and 2000 to women who smoked (n=377 367, 22.5%) and did not smoke (n=1 302 940) in early pregnancy. Follow-up was until 31 December 2014.

    MAIN OUTCOME MEASURE: Fractures by attained age up to 32 years.

    RESULTS: During a median follow-up of 21.1 years, 377 970 fractures were observed (the overall incidence rate for fracture standardised by calendar year of birth was 11.8 per 1000 person years). The association between maternal smoking during pregnancy and risk of fracture in offspring differed by attained age. Maternal smoking was associated with a higher rate of fractures in offspring before 1 year of age in the entire cohort (birth year standardised fracture rates in those exposed and unexposed to maternal smoking were 1.59 and 1.28 per 1000 person years, respectively). After adjustment for potential confounders the hazard ratio for maternal smoking compared with no smoking was 1.27 (95% confidence interval 1.12 to 1.45). This association followed a dose dependent pattern (compared with no smoking, hazard ratios for 1-9 cigarettes/day and >= 10 cigarettes/day were 1.20 (95% confidence interval 1.03 to 1.39) and 1.41 (1.18 to 1.69), respectively) and persisted in within-sibship comparisons although with wider confidence intervals (compared with no smoking, 1.58 (1.01 to 2.46)). Maternal smoking during pregnancy was also associated with an increased fracture incidence in offspring from age 5 to 32 years in whole cohort analyses, but these associations did not follow a dose dependent gradient. In within-sibship analyses, which controls for confounding by measured and unmeasured shared familial factors, corresponding point estimates were all close to null. Maternal smoking was not associated with risk of fracture in offspring between the ages of 1 and 5 years in any of the models.

    CONCLUSION: Prenatal exposure to maternal smoking is associated with an increased rate of fracture during the first year of life but does not seem to have a long lasting biological influence on fractures later in childhood and up to early adulthood.

  • 32.
    Brand, Judith
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Population Health Sciences, Bristol Medical School, Bristol, United Kingdom.
    Lawlor, Deborah A.
    Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Population Health Sciences, Bristol Medical School, Bristol, United Kingdom.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Association Between Hypertensive Disorders of Pregnancy and Neurodevelopmental Outcomes Among Offspring2021In: JAMA pediatrics, ISSN 2168-6203, E-ISSN 2168-6211, Vol. 175, no 6, p. 577-585Article in journal (Refereed)
    Abstract [en]

    Importance: Hypertensive disorders of pregnancy (HDP) have been associated with poorer neurodevelopmental outcomes in offspring, but the role of familial confounding in these associations is unclear.

    Objective: To investigate associations of maternal HDP with risks in offspring of autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), as well as variation in overall cognitive performance in offspring.

    Design, Setting, and Participants: This Swedish register-based study used data from a birth cohort divided into 1 085 024 individuals born between 1987 and 1996 and followed up until December 31, 2014, and 285 901 men born between 1982 and 1992 who attended assessments for military conscription, including a cognitive function test. Statistical analysis was performed from April 1, 2019, to June 1, 2020.

    Exposures: Diagnoses of HDP, which were provided by the Medical Birth Register.

    Main Outcomes and Measures: Diagnoses of ASDs, ADHD, and ID were extracted from the National Patient Register. Cognitive function was assessed using written tests and summarized as a single 9-point score. Whole-cohort and within-sibship analyses were performed; the latter accounted for unmeasured familial confounding factors shared by siblings.

    Results: The study included 1 085 024 individuals (556 912 male participants [51.3%]) born between 1987 and 1996 and 285 901 men born between 1982 and 1992 who attended assessments for military conscription. The prevalence of maternal HDP was 4.0% in the 1987-1996 birth cohort (n = 42 980) and 5.1% in the military conscription cohort (n = 14 515). A total of 15 858 participants received a diagnosis of ASD, 36 852 received a diagnosis of ADHD, and 8454 received a diagnosis of ID. The mean (SD) cognitive score among the men in the conscription cohort was 5.1 (1.9). In whole-cohort analyses with multivariable adjustment, HDP were associated with offspring ASDs (hazard ratio [HR], 1.22; 95% CI, 1.13-1.31), ADHD (HR, 1.10; 95% CI, 1.05-1.16), and ID (HR, 1.39; 95% CI, 1.27-1.53). Analyses comparing siblings discordant for HDP were less statistically powered but indicated estimates of similar magnitude for ASDs (HR, 1.19; 95% CI, 1.00-1.42) and possibly ADHD (HR, 1.09; 95% CI, 0.95-1.24), but not for ID (HR, 1.04; 95% CI, 0.83-1.29). Hypertensive disorders of pregnancy were associated with somewhat lower cognitive scores in whole-cohort analysis (mean difference comparing offspring exposed with those unexposed, -0.10; 95% CI, -0.13 to -0.07), but in within-sibship analysis, the association was null (mean difference, 0.00; 95% CI, -0.09 to 0.08).

    Conclusions and Relevance: The study results suggest that HDP are associated with small increased risks of ASDs and possibly ADHD in offspring, whereas associations with ID and cognitive performance are likely confounded by shared familial (environmental or genetic) factors.

  • 33.
    Brand, Judith
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Lawlor, Deborah A.
    MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.
    Montgomery, Scott
    Örebro University, School of Medical Sciences.
    Additional Counseling Support for Mothers With Gestational Hypertensive Disorders Regarding Neurodevelopmental Outcomes in Their Children—Reply2021In: JAMA pediatrics, ISSN 2168-6203, E-ISSN 2168-6211, Vol. 175, no 10, article id 1082Article in journal (Refereed)
  • 34.
    Brand, Judith S
    et al.
    School of Medical Sciences, Örebro University, Sweden.
    Smith, Kelsi A.
    Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden.
    Piehl, Fredrik
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, UK.
    Risk of serious infections in multiple sclerosis patients by disease course and disability status: Results from a Swedish register-based study2022In: Brain, behavior, & immunity - health, E-ISSN 2666-3546, Vol. 22, article id 100470Article in journal (Refereed)
    Abstract [en]

    Background and objectives: Serious infections are an emerging concern with increasing use of potent immunomodulation in multiple sclerosis (MS), but the extent to which MS disease features influence infectious susceptibility is poorly characterized. The objective of this study was to assess the associations of MS disease course and disability status with risk of serious infections.

    Methods: A cohort of 8660 MS patients was individually matched on age, sex and region of residence with 86,600 people without MS from the general population using national registers in Sweden. The study period was from 1996 to 2012, with follow-up until December 31, 2014. The main outcomes were infection as the underlying or contributory cause of death or infection-related hospital admission identified in the Cause of Death and Patient registers. MS disease course (relapsing-remitting or progressive disease) and Expanded Disability Status Scale (EDSS) score (six and over or below six) were extracted from the MS Register Hazard ratios (HRs) for any serious infection were estimated using flexible parametric models.

    Results: During a median follow-up of 9.6 years (interquartile range = 5.5-13.5 years), 1337 MS patients experienced a serious infection. Compared with individually matched people without MS, risk of serious infection was greater for progressive disease (HR = 3.80; 95% CI 3.52: 4.09) than relapsing-remitting disease (HR = 1.77; 95% CI: 1.62:1.93). A similar pattern of risk was seen for dichotomised EDSS score (HR = 4.26; 95% CI 3.87: 4.70 for EDSS 6.0-9.5 and HR = 1.30; 95% CI 1.1853: 1.43 for EDSS 0.0-5.5). Overall, associations with greater disability did not notably differ by immunomodulatory therapy use, but associations with lower disability were more pronounced in patients receiving these therapies.

    Conclusions: Disease course or EDSS score (which may be more readily available than MS course in some patients) should be considered in individual management and monitoring of MS patients, including assessing benefit-risk of therapies that influence general immune function.

  • 35.
    Brenner, P.
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Burkill, S.
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Jokinen, J.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Sciences, Umeå University, Umeå, Sweden.
    Hillert, J.
    Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Bahmanyar, S.
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Multiple sclerosis and risk of attempted and completed suicide: a cohort study2016In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 23, no 8, p. 1329-1336Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Patients with multiple sclerosis (MS) are known to have an elevated suicide risk, but attempted suicide is incompletely investigated. The relation between education level and suicidality has not been investigated in MS patients. Our objective was to estimate attempted suicide and completed suicide risks amongst MS patients.

    Methods: A total of 29 617 Swedish MS patients were identified through the Swedish Patient Register and matched with 296 164 people without MS from the general population. Cox regression analysis estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of MS with attempted and completed suicide, with adjustment for age, sex, education and calendar period.

    Results: The adjusted HR for attempted suicide amongst MS patients is 2.18 (95% CI 1.97-2.43) compared with the general population cohort. For completed suicide the HR is 1.87 (95% CI 1.53-2.30). In both groups women are at higher risk of attempting suicide, whilst men are at higher risk of completing suicide. Education level is inversely associated with completed suicide amongst the non-MS cohort (0.68, 0.51-0.91), but not amongst MS patients (1.10, 0.60-2.04).

    Conclusion: Multiple sclerosis patients are at higher risk of both attempted and completed suicide. No evidence was found of an inverse association between educational level and risk of completed suicide amongst MS patients.

  • 36.
    Brenner, P.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Burkill, S.
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Jokinen, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Sciences, Umeå University, Umeå, Sweden.
    Moore, A.
    Quantitative Safety & Epidemiology, Novartis Pharma AG, Basel, Switzerland.
    Geissbuehler, Y.
    Quantitative Safety & Epidemiology, Novartis Pharma AG, Basel, Switzerland.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Bahmanyar, S.
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medicine, Örebro University, Sweden. DepDepartment of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Multiple sclerosis and risk of completed and attempted suicide - a national cohort study2015In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 21, no Suppl. 11, p. 23-24Article in journal (Other academic)
    Abstract [en]

    Introduction: Patients with multiple sclerosis (MS) are known to have an elevated suicide risk, but attempted suicide is incompletely investigated.

    Objectives: To estimate attempted suicide and completed suicide risks among MS patients using national registers and to assess if the inverse association of higher-level education with completed suicide is affected by MS.

    Methods: A total of 29,617 Swedish MS patients were identified through the Swedish Patient Register and matched (by birth year, sex, vital status at diagnosis and region) with 296,164 people without MS from the general population. Cox regression estimated hazard ratios (HR) (with 95% confidence intervals) for the association of MS with attempted and completed suicide, with adjustment for age, sex, education level, decade of study entry, and previous suicide attempts.

    Results: The adjusted HR for attempted suicide among MS patients is 2.18 (1.97-2.43) compared with the general population cohort. For completed suicide the HR is 1.87 (1.53-2.30). Overall, men were at higher risk of completing suicide, while women were at higher risk of attempting suicide. Higher education is inversely associated with completed suicide among the non-MS cohort with an HR of 0.68, (0.51-0.91), but not among MS patients, where the HR is 1.10, (0.60-2.04). MS patients were less likely to use a violent method than the non-MS cohort.

    Conclusion: MS patients are at higher risk of both attempted and completed suicide, and the risk increase is present in both men and women. Possibly the stress and perceived prognosis associated with an MS diagnosis increases the risk of suicide. MS appears to eliminate the protective association of higher education with completed suicide.

  • 37.
    Burkill, S.
    et al.
    Centre for Pharmacoepidemiology, Karolinska Institute, Stockholm, Sweden.
    Smith, K. A.
    Clinical Epidemiology Division, Karolinska Institute, Stockholm, Sweden.
    Stridh, P.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Kockum, I.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Alfredsson, L.
    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology and Biostatistics.
    Bahmanyar, S.
    Centre for Pharmacoepidemiology, Karolinska Institute, Stockholm, Sweden.
    MS and the association of the DQB1*0302 allele with pain2019In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, no Suppl. 2, p. 437-438Article in journal (Other academic)
    Abstract [en]

    Introduction: There is an established association between multiple sclerosis (MS) and pain treatment, in particular neuropathic pain. Murine models have confirmed an association between carriage of the DQB1*0302 allele and development of neuropathic pain-like behavior after peripheral nerve injury. Observational studies in patients with spinal disc herniation identified an association between the DQB1*0302 allele and pain, indicating a possible link in humans. This HLA allele has not been previously investigated for its influence on susceptibility to pain in MS patients.

    Aim: To determine whether the DQB1*0302 genotype is associated with pain in MS patients or member of the general population without MS.

    Methods: Three Swedish studies (EIMS, GEMS and IMSE) were combined in which enrolled MS patients were matched with 1-2 randomly selected individuals without MS by sex, age and region of residence. Register data was obtained and prescriptions for pain and neuropathic pain were identified as proxy measures for pain. Blood samples were collected and genotyped. Individuals were included if genotype data were available (MS=3877, non-MS=4548). Logistic regression had pain medication use as the outcome, to examine associations with genotype, stratified by MS status.

    Results: Homo- or heterozygous MS patients with the DQB1*0302 allele had no significantly increased risk of pain (adjusted OR 1.02, 95% CI 0.85-1.23) or neuropathic pain (OR 1.14, 0.97-1.34) compared with MS patients without the allele. Non-MS comparators carrying at least one allele had an increased risk of pain (OR 1.18, 1.03-1.35). Additionally, a zygosity effect appeared present particularly for women in the non-MS cohort, as homozygous individuals had a higher risk of pain compared with heterozygotes. No association was observed for MS patients.

    Conclusions: The DQB1*0302 allele was associated with increased risk of pain among the non-MS cohort. Zygocity also impacted on pain risk in this cohort, particularly for women. The same was not observed in MS patients, for which no increased risk was detected. In view of previous data, immune functions seem to be involved in the development of pain and the observed associa-tion is likely due to peripheral nerve injuries or peripheral neu-ropathies. The allele was not associated with pain in the MS population, which often stems from CNS lesions.

  • 38.
    Burkill, Sarah
    et al.
    Centre for Pharmocoepodemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Iacobaeus, Ellen
    Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
    Bahmanyar, Shahram
    Centre for Pharmocoepodemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Brundin, Lou
    Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
    Fored, Michael
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Olsson, Tomas
    Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Pharmacological Treatments Preceding Diagnosis Of Progressive Multifocal Leukencephalopathy2016In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 25, no Suppl. 3, p. 496-497Article in journal (Other academic)
    Abstract [en]

    Background: Progressive multifocal leukencephalopathy (PML) is a rare, often fatal viral disease, which affects the white matter of the brain. It is caused by John Cunningham (JC) polyomavirus, which is present in most people and is usually harm-less. For immunocompromised persons, such as those who are taking immunosuppressive treatments, the risk of JC virus causing PML is increased, although still rare. As PML diagnosis is not always accurate, epidemiology of PML, including the true incidence and patient characteristics, is incompletely described.

    Objectives: To identify pharmacological treatments preceding diagnosis of definitive, probable and possible PML, after excluding incorrect PML diagnoses by medical record review.

    Methods: Patients with a PML diagnosis in Sweden between 1988 and 2013 were identified through the Patient register using ICD 9 code 046D and ICD 10code A81.2 (n = 281). Medical records were reviewed and information on clinical characteristics and pharmacological treatments were collected. Each of the diagnoses was determined as definite PML, possible PML, probable PML or non-PML based on the consensus statement for the AAN neuroinfectious disease section published in 2013. (PMCID: 3662270).

    Results: Medical records for 251 patients (89%) were available and examined. In total, 84 (33%) of the 251 PML diagnoses were confirmed. For those with a record of being exposed to immunosuppressant drugs, 60 (65%) of the 92 records were confirmed as being definite PML. Among 12 patients exposed to rituximab 11 (92%) had definite and 1 (8%) had probable PML. For the 9 natalizumab users, 8 (89%) had definite PML and 1 (11%) was diagnosed incorrectly.

    Conclusions: A substantial proportion of PML diagnoses recorded in Sweden are incorrect, however amongst those exposed to immunosuppressants such as rituximab and natalizumab the majority of diagnoses are correct. Assessing immunosuppressive drug history could be an important part of the diagnostic processes for PML.

  • 39.
    Burkill, Sarah M.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences.
    Lofling, Lukas
    Karolinska Institutet, Stockholm, Sweden.
    Kockum, Ingrid
    Karolinska Institutet, Stockholm, Sweden.
    Piehl, Fredrik
    Karolinska Institutet, Stockholm, Sweden.
    Strid, Pernilla
    Karolinska Institutet, Stockholm, Sweden.
    Olsson, Tomas
    Karolinska Institutet, Stockholm, Sweden.
    Hillert, Jan
    Karolinska Institutet, Stockholm, Sweden.
    Alfredsson, Lars
    Karolinska Institutet, Stockholm, Sweden.
    Bahmanyar, Shahram
    Karolinska Institutet, Stockholm, Sweden.
    Pain and Painkiller Use Among Multiple Sclerosis Patients in Sweden2017In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 26, no Suppl. 2, p. 634-634Article in journal (Other academic)
    Abstract [en]

    Background: Multiple sclerosis is an autoimmune disease which leads to demyelination and subsequent damage of axons and neurons. Pain is known to commonly affect MS patients, however the clinical characteristics of this pain are not fully described. Prescribed pain medication identifies more severe and chronic pain and different drug types can be used to identify other pain characteristics.

    Objectives: To assess whether MS patients in Sweden are at increased risk of receiving medication for pain relative to non-MS comparators. We aim to study overall pain, neuropathic pain, musculoskeletal pain and migraine.

    Methods: This cohort study using data on 5,555 MS patients in Sweden individually matched to 5,555 non-MS Swedish residents on sex, year of birth and place of residence at the time of MS diagnosis. We used Cox PH models using date of entry or 1stJuly 2006 as the beginning of follow up, whichever occurred later, and end of study was date of death, date of prescription of a painkiller or December 31st 2014, whichever occurred first. Painkillers were identified through relevant ATC codes. For neuropathic pain, pregabalin, gabapentin, amitriptyline, capsaicin or nortriptyline were used for identification, and for migraine prescriptions of anti-migraine preparations were included in the outcome. Musculoskeletal pain was identified primarily through topical products for joint and muscular pain.

    Results: Cox PH models showed MS patients to be at a 2.43 (CI 2.31–2.55) times increased risk of being prescribed any painkiller. The risk increased to 5.63 (CI 5.03–6.31) for neuropathic painkillers, however there was no significant difference for musculoskeletal painkillers (RR = 0.92 (CI 0.79–1.07)). MS patients were at a 1.28 (CI 1.10-1.50) times increased risk of being prescribed anti-migraine preparations. Restricting the data to MS patients showed that exposure to neuropathic painkillers was present in 32.8% of MS patients, and is associated with lower educational attainment and female sex.  

    Conclusions: MS patients are at significantly increased risk of pain overall, with a particularly elevated risk for neuropathic pain. It seems that lower educational attainment and female sex are risk factors of neuropathic pain. However, the reason for this is not fully understood.*We would like to acknowledge the funding from the Science for Life - Astra Zeneca collaborative grant that supported this research

  • 40.
    Burkill, Sarah
    et al.
    Clinical Epidemiology Unit, Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institute, Sweden.
    Hajiebrahimi, Mohammad Hossein
    Clinical Epidemiology Unit, Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden; Biostatistics and Epidemiology Unit, Health Faculty, Golestan University of Medical Sciences, Golestan, Iran.
    Hillert, Jan
    Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Olsson, Tomas
    Division of Neurology and Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Bahmanyar, Shahram
    Clinical Epidemiology Unit, Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Mortality trends for multiple sclerosis patients in Sweden from 1968 to 20122017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 89, no 6, p. 555-562Article in journal (Refereed)
    Abstract [en]

    Objective: To assess trends in mortality and causes of death for patients with multiple sclerosis (MS) relative to those without MS in Sweden.

    Methods: Patients with an MS diagnosis in Sweden between 1964 and 2012 were identified with the Patient Register and the Multiple Sclerosis Register. For this cohort study, each patient with MS (n = 29,617) was matched with 10 individuals without MS (n = 296,164) on sex, year of birth, vital status, and region of residence at the time of MS diagnosis with the Total Population Register. The Causes of Death Register was used to identify causes of death. Cox proportional hazard models were constructed to assess whether risk of mortality was increased for patients with MS.

    Results: The hazard ratio (HR) for patients with MS was 2.92 (95% confidence interval [CI] 2.86-2.99) for all-cause mortality over the entire study period. The largest differences between the cohorts were death resulting from respiratory (HR 5.07, 95% CI 4.87-5.26) and infectious (HR 4.07, 95% CI 3.70-4.47) diseases. Overall and for each specific cause, there have been improvements for the MS group and a subsequent reduction in the HR. The HR decreased from 6.52 (95% CI 5.79-7.34) for the period of 1968 to 1980 to 2.08 (95% CI 1.95-2.22) for the time period of 2001 to 2012. An interaction between time period and MS exposure showed that the decrease in mortality over time was statistically significant, with a larger decrease for patients with MS than their matched comparators.

    Conclusions: There has been a substantial improvement in mortality overall and for each specified cause of death for patients with MS compared with individuals without MS; however, large differences still remain.

  • 41.
    Burkill, Sarah
    et al.
    Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Sweden; Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Sweden; Department of Epidemiology and Public Health, University College London, UK.
    Kockum, Ingrid
    Department of Clinical Neuroscience, Karolinska Institutet, Sweden; Centre for Molecular Medicine, Karolinska University Hospital Solna, Sweden.
    Piehl, Fredrik
    Department of Clinical Neuroscience, Karolinska Institutet, Sweden; Centre for Molecular Medicine, Karolinska University Hospital Solna, Sweden.
    Strid, Pernilla
    Department of Clinical Neuroscience, Karolinska Institutet, Sweden; Centre for Molecular Medicine, Karolinska University Hospital Solna, Sweden.
    Hillert, Jan
    Department of Clinical Neuroscience, Karolinska Institutet, Sweden.
    Alfredsson, Lars
    Institute of Environmental Medicine, Karolinska Institutet, Sweden; Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, Sweden; Centre for Molecular Medicine, Karolinska University Hospital Solna, Sweden.
    Bahmanyar, Shahram
    Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Sweden; Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Sweden.
    The association between multiple sclerosis and pain medications2019In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 160, no 2, p. 424-432Article in journal (Refereed)
    Abstract [en]

    Patients with multiple sclerosis (MS) are at greater risk of pain than people without the disease; however, the occurrence and characteristics of pain among these patients are incompletely described. We aimed to assess characteristics of pain amongst MS patients using MS patients who were recruited to participate in 3 studies in Sweden (n = 3877) and were matched with individuals without MS (n = 4548) by sex, year of birth, and region of residence. The Prescribed Drugs Register identified prescribed pain medication, overall and restricted to those given 4 or more prescriptions in 1 year to assess chronic pain. Anatomical therapeutic chemical codes classified whether pain was neuropathic, musculoskeletal, or migraine. Cox-proportional hazard models were used to estimate associations. Our findings showed patients with MS were at increased risk of pain treatment, with a hazard ratio (HR) of 2.52 (95% confidence interval 2.38-2.66). The largest magnitude HR was for neuropathic pain (5.73, 5.07-6.47) for which 34.2% (n = 1326) of the MS and 7.15% (n = 325) of the non-MS cohort were prescribed a treatment. The HR for chronic pain treatment was 3.55 (3.27-3.84), indicating an increased effect size relative to any pain treatment. Chronic neuropathic pain showed the largest HR at 7.43 (6.21-8.89). Neuropathic pain was shown to be the primary mechanism leading to increased risk of pain in patients with MS.

  • 42.
    Burkill, Sarah
    et al.
    Department of Medicine Solna, Centre for Pharmacoepidemiology, Karolinska Institutet, Solna, Sweden; Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
    Smith, Kelsi A.
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden.
    Stridh, Pernilla
    Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden; Centre for Molecular Medicine, Karolinska University Hospital Solna, Solna, Sweden.
    Kockum, Ingrid
    Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden; Centre for Molecular Medicine, Karolinska University Hospital Solna, Solna, Sweden.
    Hillert, Jan
    Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden.
    Lindahl, Hannes
    Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden; Centre for Molecular Medicine, Karolinska University Hospital Solna, Solna, Sweden.
    Alfredsson, Lars
    Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden; Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden; Centre for Molecular Medicine, Karolinska University Hospital Solna, Solna, Sweden.
    Piehl, Fredrik
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Bahmanyar, Shahram
    Department of Medicine Solna, Centre for Pharmacoepidemiology, Karolinska Institutet, Solna, Sweden; Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden.
    The DQB1* 03:02 Genotype and Treatment for Pain in People With and Without Multiple Sclerosis2020In: Frontiers in Neurology, E-ISSN 1664-2295, Vol. 11, article id 993Article in journal (Refereed)
    Abstract [en]

    Murine models have demonstrated that the major histocompatibility complex (MHC) is associated with pain-like behavior in peripheral nerve injury, however, the same association has not been shown when considering injury to the central nervous system (CNS), which more closely mimics the damage to the CNS experienced by MS patients. Previous research has indicated the DQB1*03:02 allele of the class II HLA genes as being associated with development of neuropathic pain in persons undergoing inguinal hernia surgery or with lumbar spinal disk herniation. Whether this HLA allele plays a part in susceptibility to pain, has not, as far as we are aware, been previously investigated. This study utilizes information on DQB1*03:02 alleles as part of the EIMS, GEMS, and IMSE studies in Sweden. It also uses register data for 3,877 MS patients, and 4,548 matched comparators without MS, to assess whether the DQB1*03:02 allele is associated with prescribed pain medication use, and whether associations with this genotype differ depending on MS status. Our results showed no association between the DQB1*03:02 genotype and pain medication in MS patients, with an adjusted odds ratio (OR) of 1.02 (95% CI 0.85-1.24). In contrast, there was a statistically significant association of low magnitude in individuals without MS [adjusted OR 1.18 (95% CI 1.03-1.35)], which provides support for HLA influence on susceptibility to pain in the general population. Additionally, the effect of zygosity was evident for the non-MS cohort, but not among MS patients, suggesting the DQB1*03:02 allele effect is modified by the presence of MS.

  • 43.
    Burkill, Sarah
    et al.
    Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden; Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Vattulainen, Pia
    EPID research, Helsinki, Finland.
    Geissbuehler, Yvonne
    Novartis Pharma AG, Basel, Switzerland.
    Sabido Espin, Meritxell
    Merck group, Darmstadt, Germany.
    Popescu, Catrinel
    Biogen, Maidenhead, United Kingdom.
    Suzart-Woischnik, Kiliana
    Bayer AG, Berlin, Germany.
    Hillert, Jan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Artama, Miia
    National Institute for Health and Welfare, Helsinki, Finland.
    Verkkoniemi-Ahola, Auli
    Department of Neurology, Helsinki University, Helsinki, Finland.
    Myhr, Kjell-Morten
    Department of Clinical Medicine, University of Bergen, Bergen, Norway.
    Cnattingius, Sven
    Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Korhonen, Pasi
    EPID research, Helsinki, Finland.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Bahmanyar, Shahram
    Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden; Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    The association between exposure to interferon-beta during pregnancy and birth measurements in offspring of women with multiple sclerosis2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 12, article id e0227120Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Interferon-beta (IFN-beta) is a commonly used treatment for multiple sclerosis (MS). Current guidelines recommend cessation of treatment during pregnancy, however the results of past studies on the safety of prenatal exposure to IFN-beta have been conflicting. A large scale study of a population of MS women is therefore warranted.

    OBJECTIVES: To assess whether, among those born to women with MS, infants prenatally exposed to IFN-beta show evidence of smaller size at birth relative to infants which were not prenatally exposed to any MS disease modifying drugs.

    METHODS: Swedish and Finnish register data was used. Births to women with MS in Sweden and Finland between 2005-2014 for which a birth measurement for weight, height, and head circumference was available were included. The exposure window was from 6 months prior to LMP to the end of pregnancy.

    RESULTS: In Sweden, 411 pregnancies were identified as exposed to IFN-beta during the exposure window, and 835 pregnancies were counted as unexposed to any MS DMD. The corresponding numbers for Finland were 232 and 331 respectively. Infants prenatally exposed to interferon-beta were on average 28 grams heavier (p = 0.17), 0.01 cm longer (p = 0.95), and had head circumferences 0.14 cm larger (p = 0.13) in Sweden. In Finland, infants were 50 grams lighter (p = 0.27), 0.02 cm shorter (p = 0.92) and had head circumferences 0.22 cm smaller (p = 0.15) relative to those unexposed.

    CONCLUSIONS: This study provides evidence that exposure to IFN-beta during pregnancy does not influence birth weight, length, or head circumference.

  • 44.
    Burkill, Sarah
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Vattulainen, Pia
    EPID research, Helsinki, Finland.
    Geissbuehler, Yvonne
    Novartis Pharma AG, Basel, Switzerland.
    Sabido, Meritxell
    Merck Group, Darmstadt, Germany.
    Popescu, Catrinel
    Biogen, Maidenhead, UK.
    Suzart-Woischnik, Kiliana
    Bayer AG, Berlin, Germany.
    Hillert, Jan
    Karolinska Institute, Stockholm, Sweden.
    Cnattingus, Sven
    Karolinska Institute, Stockholm, Sweden.
    Artama, Miia
    National Institute for Health and Welfare Finland, Helsinki, Finland.
    Verkkoiemi-Ahola, Auli
    University of Helsinki, Helsinki, Finland.
    Myhr, Kjell-Morten
    University of Bergen,Bergen, Norway.
    Korhonen, Pasi
    EPID research, Helsinki, Finland.
    Montgomery, Scott
    Örebro University, School of Medical Sciences.
    Bahmanyar, Shahram
    Karolinska Institute, Stockholm, Sweden.
    The association between exposure to interferon-beta during pregnancy and birth measurements in offspring of women with multiple sclerosis2019In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 28, no Suppl. 2, p. 371-372Article in journal (Other academic)
  • 45.
    Bécares, Laia
    et al.
    University of Manchester, Manchester, United Kingdom.
    Kelly, Yvonne
    University College London, London, United Kingdom.
    Montgomery, Scott
    Örebro University, School of Medical Sciences.
    Sacker, Amanda
    University College London, London, United Kingdom.
    Bi-directional relationships between body mass index and height from three to seven years of age: an analysis of children in the United Kingdom Millennium Cohort Study2016In: Longitudinal and Life Course Studies, E-ISSN 1757-9597, Vol. 7, no 1, p. 41-52Article in journal (Refereed)
    Abstract [en]

    Adiposity and height are known to correlate in childhood but it is less clear whether height and weight gain occur in synergy. We investigate the bidirectional relationships between measures of height and body mass index (BMI) - an indicator of adiposity - and their rates of change. The sample comprises singleton children in the Millennium Cohort Study (N = 11,357). Child anthropometrics measured by trained interviewers at ages three, five and seven years (2003-2009) were transformed to standardised scores based on 1990 British Growth Reference data from which piecewise linear models for height and BMI were jointly fitted. At three years of age, zHeight was positively related to subsequent zBMI velocities, whereas zBMI at three years was positively related to zHeight velocity to age five but inversely related to zHeight velocity from five to seven years of age. Age three zBMI predicted zHeight velocity from three to five years more strongly than age three zHeight predicted zBMI velocity over the same period. The rate of change in zHeight was positively correlated with subsequent zBMI velocity and vice versa. This new evidence on the bidirectional relationships between height and BMI velocities sheds light on the early childhood origins of obesity in adulthood and the need to monitor growth as well as weight gain.

  • 46.
    Cao, Yang
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Bass, G. A.
    Örebro University, School of Medical Sciences. Faculty of Medicine and Health, School of Medical Sciences, Department of Surgery, Örebro University, Örebro, Sweden; Department of Surgery, Tallaght University Hospital, Dublin, Ireland.
    Ahl, Rebecka
    Örebro University, School of Medical Sciences. Faculty of Medicine and Health, School of Medical Sciences, Department of Surgery, Örebro University, Örebro, Sweden; Department of General Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Pourlotfi, Arvid
    Örebro University, School of Medical Sciences. Department of General Surgery, Örebro University Hospital, Örebro, Sweden.
    Geijer, Håkan
    Örebro University, School of Medical Sciences. Department of Radiology.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK..
    Mohseni, Shahin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of General Surgery, Örebro University Hospital, Örebro, Sweden.
    The statistical importance of P-POSSUM scores for predicting mortality after emergency laparotomy in geriatric patients2020In: BMC Medical Informatics and Decision Making, E-ISSN 1472-6947, Vol. 20, no 1, article id 86Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Geriatric patients frequently undergo emergency general surgery and accrue a greater risk of postoperative complications and fatal outcomes than the general population. It is highly relevant to develop the most appropriate care measures and to guide patient-centered decision-making around end-of-life care. Portsmouth - Physiological and Operative Severity Score for the enumeration of Mortality and morbidity (P-POSSUM) has been used to predict mortality in patients undergoing different types of surgery. In the present study, we aimed to evaluate the relative importance of the P-POSSUM score for predicting 90-day mortality in the elderly subjected to emergency laparotomy from statistical aspects.

    METHODS: One hundred and fifty-seven geriatric patients aged ≥65 years undergoing emergency laparotomy between January 1st, 2015 and December 31st, 2016 were included in the study. Mortality and 27 other patient characteristics were retrieved from the computerized records of Örebro University Hospital in Örebro, Sweden. Two supervised classification machine methods (logistic regression and random forest) were used to predict the 90-day mortality risk. Three scalers (Standard scaler, Robust scaler and Min-Max scaler) were used for variable engineering. The performance of the models was evaluated using accuracy, sensitivity, specificity and area under the receiver operating characteristic curve (AUC). Importance of the predictors were evaluated using permutation variable importance and Gini importance.

    RESULTS: The mean age of the included patients was 75.4 years (standard deviation =7.3 years) and the 90-day mortality rate was 29.3%. The most common indication for surgery was bowel obstruction occurring in 92 (58.6%) patients. Types of post-operative complications ranged between 7.0-36.9% with infection being the most common type. Both the logistic regression and random forest models showed satisfactory performance for predicting 90-day mortality risk in geriatric patients after emergency laparotomy, with AUCs of 0.88 and 0.93, respectively. Both models had an accuracy > 0.8 and a specificity ≥0.9. P-POSSUM had the greatest relative importance for predicting 90-day mortality in the logistic regression model and was the fifth important predictor in the random forest model. No notable change was found in sensitivity analysis using different variable engineering methods with P-POSSUM being among the five most accurate variables for mortality prediction.

    CONCLUSION: P-POSSUM is important for predicting 90-day mortality after emergency laparotomy in geriatric patients. The logistic regression model and random forest model may have an accuracy of > 0.8 and an AUC around 0.9 for predicting 90-day mortality. Further validation of the variables' importance and the models' robustness is needed by use of larger dataset.

  • 47.
    Cao, Yang
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Forssten, Maximilian Peter
    Örebro University, School of Medical Sciences. Department of Orthopedic Surgery, Örebro University Hospital, Örebro, Sweden.
    Mohammad Ismail, Ahmad
    Örebro University, School of Medical Sciences. Department of Orthopedic Surgery, Örebro University Hospital, Örebro, Sweden.
    Borg, Tomas
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Orthopedic Surgery, Örebro University Hospital, Örebro, Sweden.
    Ioannidis, Ioannis
    Örebro University, School of Medical Sciences. Department of Orthopedic Surgery, Örebro University Hospital, Örebro, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Mohseni, Shahin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Division of Trauma and Emergency Surgery, Department of Surgery, Örebro University Hospital, Örebro, Sweden.
    Predictive Values of Preoperative Characteristics for 30-Day Mortality in Traumatic Hip Fracture Patients2021In: Journal of Personalized Medicine, E-ISSN 2075-4426, Vol. 11, no 5, article id 353Article in journal (Refereed)
    Abstract [en]

    Hip fracture patients have a high risk of mortality after surgery, with 30-day postoperative rates as high as 10%. This study aimed to explore the predictive ability of preoperative characteristics in traumatic hip fracture patients as they relate to 30-day postoperative mortality using readily available variables in clinical practice. All adult patients who underwent primary emergency hip fracture surgery in Sweden between 2008 and 2017 were included in the analysis. Associations between the possible predictors and 30-day mortality was performed using a multivariate logistic regression (LR) model; the bidirectional stepwise method was used for variable selection. An LR model and convolutional neural network (CNN) were then fitted for prediction. The relative importance of individual predictors was evaluated using the permutation importance and Gini importance. A total of 134,915 traumatic hip fracture patients were included in the study. The CNN and LR models displayed an acceptable predictive ability for predicting 30-day postoperative mortality using a test dataset, displaying an area under the ROC curve (AUC) of as high as 0.76. The variables with the highest importance in prediction were age, sex, hypertension, dementia, American Society of Anesthesiologists (ASA) classification, and the Revised Cardiac Risk Index (RCRI). Both the CNN and LR models achieved an acceptable performance in identifying patients at risk of mortality 30 days after hip fracture surgery. The most important variables for prediction, based on the variables used in the current study are age, hypertension, dementia, sex, ASA classification, and RCRI.

  • 48.
    Cao, Yang
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Forssten, Maximilian Peter
    Örebro University, School of Medical Sciences. Department of Orthopedic Surgery, Örebro University Hospital, Örebro, Sweden.
    Sarani, Babak
    Center of Trauma and Critical Care, George Washington University, Washington, DC 20037, USA.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London WC1E 7HB, UK.
    Mohseni, Shahin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Division of Trauma, Critical Care & Acute Care Surgery, Department of Surgery, Sheikh Shakhbout Medical City, Mayo Clinic, Abu Dhabi P.O. Box 11001, United Arab Emirates.
    Development and Validation of an XGBoost-Algorithm-Powered Survival Model for Predicting In-Hospital Mortality Based on 545,388 Isolated Severe Traumatic Brain Injury Patients from the TQIP Database2023In: Journal of Personalized Medicine, E-ISSN 2075-4426, Vol. 13, no 9, article id 1401Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Traumatic brain injury (TBI) represents a significant global health issue; the traditional tools such as the Glasgow Coma Scale (GCS) and Abbreviated Injury Scale (AIS) which have been used for injury severity grading, struggle to capture outcomes after TBI.

    AIM AND METHODS: This paper aims to implement extreme gradient boosting (XGBoost), a powerful machine learning algorithm that combines the predictions of multiple weak models to create a strong predictive model with high accuracy and efficiency, in order to develop and validate a predictive model for in-hospital mortality in patients with isolated severe traumatic brain injury and to identify the most influential predictors. In total, 545,388 patients from the 2013-2021 American College of Surgeons Trauma Quality Improvement Program (TQIP) database were included in the current study, with 80% of the patients used for model training and 20% of the patients for the final model test. The primary outcome of the study was in-hospital mortality. Predictors were patients' demographics, admission status, as well as comorbidities, and clinical characteristics. Penalized Cox regression models were used to investigate the associations between the survival outcomes and the predictors and select the best predictors. An extreme gradient boosting (XGBoost)-powered Cox regression model was then used to predict the survival outcome. The performance of the models was evaluated using the Harrell's concordance index (C-index). The time-dependent area under the receiver operating characteristic curve (AUC) was used to evaluate the dynamic cumulative performance of the models. The importance of the predictors in the final prediction model was evaluated using the Shapley additive explanations (SHAP) value.

    RESULTS: On average, the final XGBoost-powered Cox regression model performed at an acceptable level for patients with a length of stay up to 250 days (mean time-dependent AUC = 0.713) in the test dataset. However, for patients with a length of stay between 20 and 213 days, the performance of the model was relatively poor (time-dependent AUC < 0.7). When limited to patients with a length of stay ≤20 days, which accounts for 95.4% of all the patients, the model achieved an excellent performance (mean time-dependent AUC = 0.813). When further limited to patients with a length of stay ≤5 days, which accounts for two-thirds of all the patients, the model achieved an outstanding performance (mean time-dependent AUC = 0.917).

    CONCLUSION: The XGBoost-powered Cox regression model can achieve an outstanding predictive ability for in-hospital mortality during the first 5 days, primarily based on the severity of the injury, the GCS on admission, and the patient's age. These variables continue to demonstrate an excellent predictive ability up to 20 days after admission, a period of care that accounts for over 95% of severe TBI patients. Past 20 days of care, other factors appear to be the primary drivers of in-hospital mortality, indicating a potential window of opportunity for improving outcomes.

  • 49.
    Cao, Yang
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Hiyoshi, Ayako
    Örebro University, School of Medical Sciences. Department of Public Health Sciences, Stockholm University, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    COVID-19 case-fatality rate and demographic and socioeconomic influencers: worldwide spatial regression analysis based on country-level data2020In: BMJ Open, E-ISSN 2044-6055, Vol. 10, no 11, article id e043560Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the influence of demographic and socioeconomic factors on the COVID-19 case-fatality rate (CFR) globally.

    DESIGN: Publicly available register-based ecological study.

    SETTING: Two hundred and nine countries/territories in the world.

    PARTICIPANTS: Aggregated data including 10 445 656 confirmed COVID-19 cases.

    PRIMARY AND SECONDARY OUTCOME MEASURES: COVID-19 CFR and crude cause-specific death rate were calculated using country-level data from the Our World in Data website.

    RESULTS: The average of country/territory-specific COVID-19 CFR is about 2%-3% worldwide and higher than previously reported at 0.7%-1.3%. A doubling in size of a population is associated with a 0.48% (95% CI 0.25% to 0.70%) increase in COVID-19 CFR, and a doubling in the proportion of female smokers is associated with a 0.55% (95% CI 0.09% to 1.02%) increase in COVID-19 CFR. The open testing policies are associated with a 2.23% (95% CI 0.21% to 4.25%) decrease in CFR. The strictness of anti-COVID-19 measures was not statistically significantly associated with CFR overall, but the higher Stringency Index was associated with higher CFR in higher-income countries with active testing policies (regression coefficient beta=0.14, 95% CI 0.01 to 0.27). Inverse associations were found between cardiovascular disease death rate and diabetes prevalence and CFR.

    CONCLUSION: The association between population size and COVID-19 CFR may imply the healthcare strain and lower treatment efficiency in countries with large populations. The observed association between smoking in women and COVID-19 CFR might be due to the finding that the proportion of female smokers reflected broadly the income level of a country. When testing is warranted and healthcare resources are sufficient, strict quarantine and/or lockdown measures might result in excess deaths in underprivileged populations. Spatial dependence and temporal trends in the data should be taken into account in global joint strategy and/or policy making against the COVID-19 pandemic.

  • 50.
    Cao, Yang
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Örebro University Hospital. Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Ottosson, Johan
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Surgery.
    Näslund, Erik
    Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Stenberg, Erik
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Surgery.
    Deep Learning Neural Networks to Predict Serious Complications After Bariatric Surgery: Analysis of Scandinavian Obesity Surgery Registry Data2020In: JMIR Medical Informatics, E-ISSN 2291-9694, Vol. 8, no 5, article id e15992Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Obesity is one of today's most visible public health problems worldwide. Although modern bariatric surgery is ostensibly considered safe, serious complications and mortality still occur in some patients.

    OBJECTIVE: This study aimed to explore whether serious postoperative complications of bariatric surgery recorded in a national quality registry can be predicted preoperatively using deep learning methods.

    METHODS: Patients who were registered in the Scandinavian Obesity Surgery Registry (SOReg) between 2010 and 2015 were included in this study. The patients who underwent a bariatric procedure between 2010 and 2014 were used as training data, and those who underwent a bariatric procedure in 2015 were used as test data. Postoperative complications were graded according to the Clavien-Dindo classification, and complications requiring intervention under general anesthesia or resulting in organ failure or death were considered serious. Three supervised deep learning neural networks were applied and compared in our study: multilayer perceptron (MLP), convolutional neural network (CNN), and recurrent neural network (RNN). The synthetic minority oversampling technique (SMOTE) was used to artificially augment the patients with serious complications. The performances of the neural networks were evaluated using accuracy, sensitivity, specificity, Matthews correlation coefficient, and area under the receiver operating characteristic curve.

    RESULTS: In total, 37,811 and 6250 patients were used as the training data and test data, with incidence rates of serious complication of 3.2% (1220/37,811) and 3.0% (188/6250), respectively. When trained using the SMOTE data, the MLP appeared to have a desirable performance, with an area under curve (AUC) of 0.84 (95% CI 0.83-0.85). However, its performance was low for the test data, with an AUC of 0.54 (95% CI 0.53-0.55). The performance of CNN was similar to that of MLP. It generated AUCs of 0.79 (95% CI 0.78-0.80) and 0.57 (95% CI 0.59-0.61) for the SMOTE data and test data, respectively. Compared with the MLP and CNN, the RNN showed worse performance, with AUCs of 0.65 (95% CI 0.64-0.66) and 0.55 (95% CI 0.53-0.57) for the SMOTE data and test data, respectively.

    CONCLUSIONS: MLP and CNN showed improved, but limited, ability for predicting the postoperative serious complications after bariatric surgery in the Scandinavian Obesity Surgery Registry data. However, the overfitting issue is still apparent and needs to be overcome by incorporating intra- and perioperative information.

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