To Örebro University

Cognitive difficulties are known to persist after remission of symptoms and to affect psychosocial functioning and quality of life. Cognitive function, measured with the Cambridge Neuro-psychological Test Automated Battery (CANTAB), is a reliable approach to measure cognitive function in major depression. This systematic review and meta-analysis appraise cross-sectional and longitudinal studies that used specific CANTAB tests to measure cognitive function in major depression and the effect of treatment (PROSPERO ID: CRD42022355903). 1212 studies were identified and 41 were included, 1793 patients and 1445 healthy controls. Deficits in executive functions were detected with the Stocking Of Cambridge (SOC) 'number of problems solved with minimal number of moves' and 'subsequent thinking time', Intra-Extra Dimensional Set Shift 'number of trials to complete the test', Spatial Working Memory 'strategy score' and 'between errors score', Spatial Span. Memory deficits were detected with Paired Associates Learning 'number of total errors', Pattern Recognition Memory (PRM) '% of correct answers' and 'response latency', Spatial Recognition Memory '% of correct answers', Delayed Matching To Sample (DMS) '% of total responses'. Impaired attention was detected by Rapid Visual Information Processing 'response latency' and probability to detect target'. Mental and motor responses increased when Reaction Time was measured. SOC 'number of problems solved with minimal number of moves', PRM 'response latency' and DMS '% of total responses' improved after a course of treatment. A range of variables including year of publication, age, IQ, severity and duration of illness influenced cognitive changes. The presence of significant cognitive deficits requires novel targeted interventions.

INTRODUCTION: In the Middle East and North Africa (MENA) region, changing demographic and epidemiological profiles have resulted in a diverse and shifting burden of disease (BoD). Disability-adjusted life years (DALYs), which combine years of life lost (YLL) due to premature mortality and years lived with disability (YLD), offer a valuable metric for assessing disease burden at the national level. While global burden of disease (GBD) estimates provide broad insights, national burden of disease (NBD) estimates offer country-specific data that can better inform tailored health policies and resource allocation. This systematic review protocol outlines our methodology for collating and analysing the NBD estimates in the MENA region using DALYs as the primary outcome measure.

METHODS AND ANALYSIS: This review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We will systematically search PubMed, Scopus, Web of Science and EMBASE for studies published from 1993 to 2024 that report national-level DALY estimates for diseases, injuries or risk factors in MENA countries. Eligible studies must report DALY estimates using national methodologies, while studies using exclusively GBD estimates will be excluded. Two independent reviewers will conduct title/abstract and full-text screening, data extraction and quality assessment using Standardised Reporting of Burden of Disease Studies (STROBOD), with disagreements resolved by a third reviewer when necessary.

ETHICS AND DISSEMINATION: Ethical approval is not required for this review as it involves analysis of previously published data. The findings will be disseminated through publication in a peer-reviewed journal and presented at relevant academic and policy forums.

PROSPERO REGISTRATION NUMBER: PROSPERO CRD42024498688.

Background/Objectives: Lamotrigine has been widely investigated in the treatment and prevention of the emergence of symptoms of depression in unipolar and bipolar depression. This work systematically appraises published and unpublished double-blind randomised controlled trials of lamotrigine to provide up-to-date guidance on the use of lamotrigine in the presence of depressive symptoms.

Methods: Systematic searches identified 32 randomised controlled trials, of which 24 were included in the meta-analysis, involving 2257 patients and 2320 controls.

Results: Evidence supports the use of lamotrigine in the acute phase of bipolar depression in monotherapy vs. placebo (SMD: 0.155; CI: 0.005-0.305) in the absence of significant heterogeneity and small study effects. In the prophylaxis of bipolar depression, lamotrigine reduced the risk of the emergence of depressive symptoms (RR: 0.78; CI: 0.63, 0.98) and prolonged the duration of symptoms survival (RR: 1.59; CI: 1.19, 2.11) compared to placebo, with no evidence of publication and small study bias. Lamotrigine was not found to be superior to lithium in the acute treatment and prophylaxis of bipolar depression. In the treatment of unipolar depressive episodes, with the inclusion in the analyses of three unpublished studies, lamotrigine was not superior to placebo in monotherapy and as adjunct treatment. There were no maintenance studies in unipolar depression.

Conclusions: There is evidence supporting the use of lamotrigine in monotherapy as acute and prophylactic treatment of bipolar depression. Evidence of the use of lamotrigine in unipolar disorders is lacking.

PROSPERO registration ID: CRD42025633709.

INTRODUCTION: Reversal treatment is commonly used for managing oral anticoagulant (OAC)-associated intracranial haemorrhages. Its effects on mortality are still understudied, particularly in various subtypes of intracranial haemorrhages. This systematic review and meta-analysis aims to synthesise the available data to study the impact of reversal therapies on mortality following various OAC-associated acute intracranial haemorrhages.

METHODS AND ANALYSIS: This protocol follows the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Protocols, and the final review will be reported in accordance with the PRISMA reporting guidelines. This systematic review and meta-analysis will include studies that assess contemporary reversal treatment in comparison to no reversal treatment, in cases of OAC-associated intracranial haemorrhage. Stratification will be performed for the types of bleeding as well as OAC at bleeding onset. Preliminary searches to determine search term inclusions were conducted in May-August 2024 in the electronic databases Embase, PubMed, Scopus and Web of Science without language and publication date restrictions. Randomised controlled studies, non-randomised controlled trials, and observational studies will be considered for the final meta-analysis. Three reviewers (MT, JOS and AB) will screen titles and abstracts, and one reviewer (MT) will subsequently conduct full-text screening. Risks of bias will be assessed by MT using tools such as Risk of Bias 2, Risk Of Bias In Non-randomised Studies - of Interventions and the Newcastle-Ottawa Scale. Heterogeneity among the study results will be assessed using the I² statistic. If appropriate, a random-effects meta-analysis model will be performed. Subgroup analyses and meta-regression (if applicable) will be performed to assess sources of heterogeneity among (1) intracranial haemorrhage types, (2) OAC drugs and (3) study types, with randomised controlled trials being the primary focus.

ETHICS AND DISSEMINATION: Ethical approval is not needed as this project involves previously published data. We intend to publish the results in a peer-reviewed journal.

PROSPERO REGISTRATION NUMBER: CRD42024556420.

INTRODUCTION: The ketogenic diet is a very low carbohydrate diet known for its ability to reduce weight and counteract hyperglycaemia. However, ketogenic diets recommend an increased intake of fats, raising concerns about cardiometabolic risk in adults. Due to the higher intake of fats in the ketogenic diet, there is significant variability in outcomes of lipid metabolism in the population. Interventions have reported improvements in lipid profile while other studies did not find changes, and there are reports of increased low density lipoprotein (LDL) and triglyceride values. Hence, this is a protocol for a systematic review of the published literature and a summary of the effect of ketogenic diets on lipid metabolism in adults.

METHODS AND ANALYSIS: Five databases (PubMed, Embase, Scopus, Cochrane Library and Web of Science) will be searched for studies on ketogenic diets in adult populations. Studies will be included if they report results from ketogenic diet interventions among adults. Exclusion is populations with diagnosed neurological disorders. Two reviewers will independently screen retrieved citations, extract data and appraise the risk of bias. Quantitative estimates (eg, standardised mean difference) measuring the change in the total cholesterol, LDL and triglyceride concentration will be pooled using random effects meta-analysis to produce one summarised weighted estimate. Sources of heterogeneity will be explored using subgroup analysis. This protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis for Protocols (PRISMA), and the final review will be reported following the PRISMA 2020 guidelines.

ETHICS AND DISSEMINATION: The present protocol and the systematic review to be carried out do not require ethics clearance. The data source will be published studies. This review will provide estimates to inform the public about the effect of ketogenic diets on lipid metabolism and the possible peril of increasing cardiometabolic risk. The results will be published in a peer-reviewed journal.

PROSPERO REGISTRATION NUMBER: CRD42022309665.

BACKGROUND: Conotruncal congenital heart defects (CTD) are a subset of congenital heart diseases (CHD) that involve structural anomalies of the right, left, or both cardiac outflow tracts. CHD is caused by multifactorial inheritance and changes in the genes or chromosomes. Recently, CHD was found to be due to epigenetic alterations, which are a combination of genetic and other environmental factors. Epigenetics is the study of how a gene's function changes as a result of environmental and behavioral influences. These causative factors can indirectly cause CHD by altering the DNA through epigenetic modifications. This is a protocol for a systematic review and meta-analysis that aims to explore whether the strength of association between various epigenetic changes and CTD types varies by race. Furthermore, to determine and compare the changes in gene expression of each mutation.

METHODS: Our protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines. A comprehensive pre-search has been developed in PubMed and PubMed's Medical Subject Headings (MeSH). The final search will be performed in June 2023 in PubMed, Embase, Scopus, Web of Science, Cochrane Library, CIANHL, and PsycInfo, without restrictions on publication years. The Covidence systematic review software will be used for blinded screening and selection. Conflicts will be resolved by a third, independent reviewer. The risk of bias in selected studies will be assessed using the National Heart, Lung, and Blood Institute (NHLBI) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The data to be extracted will cover basic information on the included studies, study sample size, number of patients with various types of epigenetic changes, number of patients with various CTD types, measures of association and their 95% confidence interval between each epigenetic change and each CTD. The protocol has been registered with the International Prospero Register of Systematic Review (PROSPERO) [CRD42023377597].

DISCUSSION: To the best of our knowledge, this protocol outlines the first systematic review and meta-analysis of the epigenetics of CTD. There is a growing body of evidence on epigenetics and its indirect involvement in disease by altering the DNA through epigenetic modifications in the genes associated with the causative factors for CHD. We will conduct a comprehensive and systematic search for literature in the above-mentioned seven core biomedical databases. It is very important to identify population-specific risk factors for CHD, which will have significant creative, custom-made, and effective prevention programs for the future generation.

Pain is a common symptom which can result in disability and lower quality of life. The current review covers the use of medicinal plants as an alternative therapy for pain relief, as traditional painkillers like NSAIDs, opioids, and antidepressants can have serious side effects. Medicinal plants are effective, easily available, low-cost, and have fewer side effects. The review examines commonly used medicinal plants, their active components, their pharmacological activity, and their mechanism of action for different types of pain in humans and animal models. The review also discusses the use of herbal therapies for pain in various conditions, such as rheumatoid arthritis, neuropathies, osteoarthritis, dysmenorrhea, headache, migraine, wounds, low back pain, and chest pain, and weighs the advantages and disadvantages of using herbal therapies in light of recent research.

Background: Immune checkpoint inhibitors (ICIs) have emerged as an effective treatment for colorectal cancer (CRC). Studies indicate that the composition of gut microbiota could potentially serve as a biomarker for predicting the clinical effectiveness of immune checkpoint inhibitors.

Methods: Following PRISMA guidelines, the review was conducted after registering the protocol with PROSPERO. A comprehensive literature search was carried out across five databases: PubMed, Scopus, Web of Science, Embase, and Cochrane Library. Assessment tools from the National Institutes of Health (NIH) were used to gauge the quality of the studies.

Results: A total of 5,132 papers were identified, and three studies and one conference abstract published between 2017-2022 met the inclusion criteria and were summarized in a descriptive synthesis table. These four studies were in accord with the following findings, four main phyla, Firmicutes, Bacteroidata, Actinobacteria, and Verrucomicrobiota were associated with CRC patients' clinical response toward ICIs treatment. Ruminococcaceae was predominantly related to CRC patients responding to therapy, while the Micrococcaceae family was more common among the non-responders. Bacterial taxa such as Faecalibacterium and Prevotellaceae were associated with better responses to ICIs and could be predictive biomarkers. The signature of fecal microbiota with Akkermansia muciniphila and Eubacterium rectale enrichment, and Rothia mucilaginosa depletion could independently predict better response to ICIs in patients with CRC.

Conclusion: The findings have brought attention to the notable differences in terms of richness and composition of microbiota between patients who responded positively to the treatment and those who did not. Bacterial species and families, such as Faecalibacterium, Bifidobacterium, Lachnospiraceae, Akkermansia sp., Ruminococcaceae, and Prevotellaceae, have consistently surfaced as potential indicators of immunotherapeutic responses. Furthermore, this review also emphasizes the need for additional comprehensive, multi-center studies with larger sample sizes to validate reported microbiota and expand our understanding of the role of gut microbiota in CRC ICIs therapy.

PROSPERO ID: CRD42021277691

Background: Polycystic ovary syndrome (PCOS) is a significant contributor to female infertility and other various metabolic disorders. This systematic review estimates the prevalence of PCOS among infertile women in the Gulf Cooperation Council (GCC) countries.

Methods: The study searched five databases (PubMed, Embase, CINAHL, Web of Science, and SCOPUS), from their inception to 2022 for observational studies conducted in GCC countries. Eligible studies included data on PCOS prevalence among infertile women. A random-effects model assessed the pooled prevalence, stratified by age, BMI, and infertility type.

Results: Out of 855 records screened, seven studies were deemed eligible. Four (57.1%) studies were conducted in Saudi Arabia, while the remaining three studies were carried out in Qatar, Kuwait, and Oman, respectively. The pooled prevalence of PCOS was 30.0% (95% CI: 29.0-38.0%, I-squared: 91.98%). PCOS prevalence was higher in obese (BMI: ≥30kg/m2) women (27.0%, 95% CI: 22.0-32.0%) than those with normal (18.5-24.9kg/m2) BMI (18.0%, 95% CI: 11.0-26.0%). Women aged 35 or older had a PCOS prevalence of 59.0% (95% CI: 45.0-72.0%), compared to 30.0% (95% CI: 29.0-36.0%) in age group 15-24 years old. Primary infertility was associated with higher PCOS prevalence (37.0%, 95% CI: 29.5-46.0%) than secondary infertility (17.0%, 95% CI: 13.0-21.0%).

Conclusion: In four out of six GCC countries, PCOS was diagnosed in three out of every ten infertile women. Older age, obesity, and primary infertility were linked to higher PCOS prevalence. Screening for PCOS in these high-risk groups could improve fertility outcomes. 

Suicide is a health priority and one of the most common causes of death in mood disorders. One of the limitations of this type of research is that studies often establish rates of suicide behaviors in mood disorders by using diverse comparison groups or simply monitoring cohort of patients over a time period. In this study registry-based systematic review, national registers were identified through searches in six academic databases, and information about the occurrence of suicide behaviors in mood disorders was systematically extracted. Odds ratios were subsequently calculated comparing rates of death by suicide in mood disorders in comparison with age and period matched rates of death by suicide in the general population obtained from country-wide national registers. The aim was to provide the most recent summary of epidemiological and clinical factors associated to suicide in mood disorders whilst calculating the likelihood of death by suicide in mood disorders in comparison with non-affected individuals according to national databases. The study follows the Preferred Reporting Guidelines for Systematic Reviews and Meta-analyses and was prespecify registered on Prospero (CRD42020186857). RESULTS: suggest that patients with mood disorders are at substantially increased risk of attempting and dying by suicide. Several epidemiological, clinical and social factors are reported to be associated with clinical populations at risk of suicide. Meta-analyses of completed deaths by suicide suggest that the likelihood for dying by suicide in mood disorders is 8.62 times higher in major depression and 8.66 times higher in bipolar disorder with higher number of untoward events in women compared to men in both conditions. The likelihood of dying by suicide in major depressive disorders is higher in the first year following discharge. Clinical guidelines might consider longer periods of monitoring following discharge from hospital. Overall, due to the higher risk of suicide in mood disorders, efforts should be made to increase detection and prevention whilst focusing on reducing risk in the most severe forms of illness with appropriate treatment to promote response and remission at the earliest convenience.