Navigating the outcome maze: a scoping review of outcomes and instruments in clinical trials in genetic neurodevelopmental disorders and intellectual disability.

Background: Individuals with genetic neurodevelopmental disorders (GNDs) or intellectual disability (ID) are often affected by complex neuropsychiatric comorbidities. Targeted treatments are increasingly available, but due to the heterogeneity of these patient populations, choosing a key outcome and corresponding outcome measurement instrument remains challenging. Objectives: The aim of this scoping review was to describe the research on outcomes and instruments used in clinical trials in GNDs and ID. Eligibility criteria: Clinical trials in individuals with GNDs and ID for any intervention over the past 10 years were included in the review. Sources of evidence: MEDLINE, PsycINFO, and Cochrane CENTRAL were searched. Titles and abstracts were independently screened for eligibility with a subsample of 10% double-screening for interrater reliability. Data from full texts were independently reviewed. Discrepancies were discussed until consensus was reached. Charting methods: Information was recorded on patient populations, interventions, designs, outcomes, measurement instruments, and type of reporter when applicable. Qualitative and descriptive analyses were performed. Results: We included 312 studies reporting 91 different outcomes, with cognitive function most frequently measured (28%). Various outcome measurement instruments (n = 457) were used, with 288 in only a single clinical trial. There were 18 genetic condition-specific instruments and 16 measures were designed ad-hoc for one particular trial. Types of report included proxy-report (39%), self-report (22%), clinician-report (16%), observer-report (6%), self-assisted report (1%), or unknown (16%). Conclusion: This scoping review of current practice reveals a myriad of outcomes and outcome measurement instruments for clinical trials in GNDs and ID. This complicates generalization, evidence synthesis, and evaluation. It underlines the need for consensus on suitability, validity, and relevancy of instruments, ultimately resulting in a core outcome set. A series of steps is proposed to move from the myriad of measures to a more unified approach.

Navigating the maze of outcome measures in rare disorders Treatments for genetic neurodevelopmental disorders and intellectual disability are increasingly available. However, it is hard to find appropriate instruments to measure whether these treatments are working. This hampers research and means some patients might not get the treatment they need. This scoping review provides an overview of investigated outcomes in this group, and with which instruments these are measured. It reveals that many different and overlapping outcomes are measured, complicating gathering, combining, and comparing of evidence. This scoping review underlines the need for harmonization and consensus on suitability, validity, and relevancy. Steps are proposed to move from the maze of outcome measures to a unified approach. Also, we provided recommendations for researchers to measure what matters to affected individuals and patient-centered care.

Influence of study characteristics, methodological rigour and publication bias on efficacy of pharmacotherapy in obsessive-compulsive disorder: a systematic review and meta-analysis of randomised, placebo-controlled trials.

QUESTION: We examined the effect of study characteristics, risk of bias and publication bias on the efficacy of pharmacotherapy in randomised controlled trials (RCTs) for obsessive-compulsive disorder (OCD). STUDY SELECTION AND ANALYSIS: We conducted a systematic search of double-blinded, placebo-controlled, short-term RCTs with selective serotonergic reuptake inhibitors (SSRIs) or clomipramine. We performed a random-effect meta-analysis using change in the Yale-Brown Obsessive-Compulsive Scale (YBOCS) as the primary outcome. We performed meta-regression for risk of bias, intervention, sponsor status, number of trial arms, use of placebo run-in, dosing, publication year, age, severity, illness duration and gender distribution. Furthermore, we analysed publication bias using a Bayesian selection model. FINDINGS: We screened 3729 articles and included 21 studies, with 4102 participants. Meta-analysis showed an effect size of -0.59 (Hedges' G, 95% CI -0.73 to -0.46), equalling a 4.2-point reduction in the YBOCS compared with placebo. The most recent trial was performed in 2007 and most trials were at risk of bias. We found an indication for publication bias, and subsequent correction for this bias resulted in a depleted effect size. In our meta-regression, we found that high risk of bias was associated with a larger effect size. Clomipramine was more effective than SSRIs, even after correcting for risk of bias. After correction for multiple testing, other selected predictors were non-significant. CONCLUSIONS: Our findings reveal superiority of clomipramine over SSRIs, even after adjusting for risk of bias. Effect sizes may be attenuated when considering publication bias and methodological rigour, emphasising the importance of robust studies to guide clinical utility of OCD pharmacotherapy. PROSPERO REGISTRATION NUMBER: CRD42023394924.

Intermethod agreement of self-reports compared to register data collection for return to work and sickness absence: a systematic review and meta-analysis.

OBJECTIVES: To determine the intermethod agreement of self-reported vs. register data of 'sickness absence' (SA) and 'return to work' (RTW) outcome measurements. STUDY DESIGN AND SETTING: We conducted a systematic review and a meta-analysis of studies reporting mean differences (MDs) and sensitivity and specificity for self-report vs. register data and an inductive analysis of the self-report question formulations. An information specialist searched Medline, Embase, PsycINFO for studies published from inception to November 2022. Screening and data extraction was done by two authors independently. RESULTS: Twenty-three studies were included of which eighteen with an overall high risk of bias. Self-reports had a pooled MD of 1.84 SA days (95% confidence interval [CI] 0.26-3.41, I2 98%, 18 studies, 38,716 participants) compared to registries which varied among studies from 204 more to 17 days less. The median average sick leave in studies in the self-report group was 8 days (interquartile range 4-23 days). Being absent from work measured with self-report had a sensitivity of 0.83 (0.76-0.88 95% CI) and a specificity of 0.92 (0.88-0.94 95% CI) compared to registry data. The high heterogeneity amongst the studies could not be explained by recall time, gender, register type, prospective or retrospective self-reports, health problem, SA at baseline or risk of bias. Studies lacked standard outcome reporting, had unclearly formulated questions in self-reports and there was little information on the registers' quality. CONCLUSION: Current self-reports may differ from register-based absence data but in an inconsistent way. Due to inconsistency and high risk of bias the evidence is judged to be of very low certainty. Further research is needed to develop clear standard questions which can be used for SA and RTW self-reports. Quality of registers needs to be better evaluated. Percentage positive and negative agreement, MDs and 2 × 2 tables should be reported for studies investigating agreement between SA and RTW outcome measures.

The impact of cardiovascular diagnostics and treatments on fall risk in older adults: a scoping review and evidence map.

BACKGROUND: We aimed to summarize the published evidence on the fall risk reducing potential of cardiovascular diagnostics and treatments in older adults. METHODS: Design: scoping review and evidence map. DATA SOURCES: Medline and Embase. ELIGIBILITY CRITERIA: all available published evidence; Key search concepts: "older adults," "cardiovascular evaluation," "cardiovascular intervention," and "falls." Studies reporting on fall risk reducing effect of the diagnostic/treatment were included in the evidence map. Studies that investigated cardiovascular diagnostics or treatments within the context of falls, but without reporting a fall-related outcome, were included in the scoping review for qualitative synthesis. RESULTS: Two articles on cardiovascular diagnostics and eight articles on cardiovascular treatments were included in the evidence map. Six out of ten studies concerned pacemaker intervention of which one meta-analyses that included randomized controlled trials with contradictory results. A combined cardiovascular assessment/evaluation (one study) and pharmacotherapy in orthostatic hypotension (one study) showed fall reducing potential. The scoping review contained 40 articles on cardiovascular diagnostics and one on cardiovascular treatments. It provides an extensive overview of several diagnostics (e.g., orthostatic blood pressure measurements, heart rhythm assessment) useful in fall prevention. Also, diagnostics were identified, that could potentially provide added value in fall prevention (e.g., blood pressure variability and head turning). CONCLUSION: Although the majority of studies showed a reduction in falls after the intervention, the total amount of evidence regarding the effect of cardiovascular diagnostics/treatments on falls is small. Our findings can be used to optimize fall prevention strategies and develop an evidence-based fall prevention care pathway. Adhering to the World guidelines on fall prevention recommendations, it is crucial to undertake a standardized assessment of cardiovascular risk factors, followed by supplementary testing and corresponding interventions, as effective components of fall prevention strategies. In addition, accompanying diagnostics such as blood pressure variability and head turning can be of added value.

Inherited metabolic disorders in adults: systematic review on patient characteristics and diagnostic yield of broad sequencing techniques (exome and genome sequencing).

Background/Objectives: The timely diagnosis of inherited metabolic disorders (IMD) is essential for initiating treatment, prognostication and genetic testing of relatives. Recognition of IMD in adults is difficult, because phenotypes are different from those in children and influenced by symptoms from acquired conditions. This systematic literature review aims to answer the following questions: (1) What is the diagnostic yield of exome/genome sequencing (ES/GS) for IMD in adults with unsolved phenotypes? (2) What characteristics do adult patients diagnosed with IMD through ES/GS have? Methods: A systematic search was conducted using the following search terms (simplified): "Whole exome sequencing (WES)," "Whole genome sequencing (WGS)," "IMD," "diagnostics" and the 1,450 known metabolic genes derived from ICIMD. Data from 695 articles, including 27,702 patients, were analyzed using two different methods. First, the diagnostic yield for IMD in patients presenting with a similar phenotype was calculated. Secondly, the characteristics of patients diagnosed with IMD through ES/GS in adulthood were established. Results: The diagnostic yield of ES and/or GS for adult patients presenting with unexplained neurological symptoms is 11% and for those presenting with dyslipidemia, diabetes, auditory and cardiovascular symptoms 10, 9, 8 and 7%, respectively. IMD patients diagnosed in adulthood (n = 1,426), most frequently portray neurological symptoms (65%), specifically extrapyramidal/cerebellar symptoms (57%), intellectual disability/dementia/psychiatric symptoms (41%), pyramidal tract symptoms/myelopathy (37%), peripheral neuropathy (18%), and epileptic seizures (16%). The second most frequently observed symptoms were ophthalmological (21%). In 47% of the IMD diagnosed patients, symptoms from multiple organ systems were reported. On average, adult patients are diagnosed 15 years after first presenting symptoms. Disease-related abnormalities in metabolites in plasma, urine or cerebral spinal fluid were identified in 40% of all patients whom underwent metabolic screening. In 52% the diagnosis led to identification of affected family members with the same IMD. Conclusion: ES and/or GS is likely to yield an IMD diagnosis in adult patients presenting with an unexplained neurological phenotype, as well as in patients with a phenotype involving multiple organ systems. If a gene panel does not yield a conclusive diagnosis, it is worthwhile to analyze all known disease genes. Further prospective research is needed to establish the best diagnostic approach (type and sequence of metabolic and genetic test) in adult patients presenting with a wide range of symptoms, suspected of having an IMD. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42021295156.

Clinical Prediction Models and Predictors for Death or Adverse Neurodevelopmental Outcome in Term Newborns with Hypoxic-Ischemic Encephalopathy: A Systematic Review of the Literature.

BACKGROUND: Although many predictive parameters have been studied, an internationally accepted, validated predictive model to predict the clinical outcome of asphyxiated infants suffering from hypoxic-ischemic encephalopathy is currently lacking. The aim of this study was to identify, appraise and summarize available clinical prediction models, and provide an overview of all investigated predictors for the outcome death or neurodevelopmental impairment in this population. METHODS: A systematic literature search was performed in Medline and Embase. Two reviewers independently included eligible studies and extracted data. The quality was assessed using PROBAST for prediction model studies and QUIPS assessment tools for predictor studies. RESULTS: A total of nine prediction models were included. These models were very heterogeneous in number of predictors assessed, methods of model derivation, and primary outcomes. All studies had a high risk of bias following the PROBAST assessment and low applicability due to complex model presentation. A total of 104 predictor studies were included investigating various predictors, showing tremendous heterogeneity in investigated predictors, timing of predictors, primary outcomes, results, and methodological quality according to QUIPS. Selected high-quality studies with accurate discriminating performance provide clinicians and researchers an evidence map of predictors for prognostication after HIE in newborns. CONCLUSION: Given the low methodological quality of the currently published clinical prediction models, implementation into clinical practice is not yet possible. Therefore, there is an urgent need to develop a prediction model which complies with the PROBAST guideline. An overview of potential predictors to include in a prediction model is presented.

Linking leadership development programs for physicians with organization-level outcomes: a realist review.

BACKGROUND: Hospitals invest in Leadership Development Programs (LDPs) for physicians, assuming they benefit the organization's performance. Researchers have listed the advantages of LDPs, but knowledge of how and why organization-level outcomes are achieved is missing. OBJECTIVE: To investigate how, why and under which circumstances LDPs for physicians can impact organization-level outcomes. METHODS: We conducted a realist review, following the RAMESES guidelines. Scientific articles and grey literature published between January 2010 and March 2021 evaluating a leadership intervention for physicians in the hospital setting were considered for inclusion. The following databases were searched: Medline, PsycInfo, ERIC, Web of Science, and Academic Search Premier. Based on the included documents, we developed a LDP middle-range program theory (MRPT) consisting of Context-Mechanism-Outcome configurations (CMOs) describing how specific contexts (C) trigger certain mechanisms (M) to generate organization-level outcomes (O). RESULTS: In total, 3904 titles and abstracts and, subsequently, 100 full-text documents were inspected; 38 documents with LDPs from multiple countries informed our MRPT. The MRPT includes five CMOs that describe how LDPs can impact the organization-level outcomes categories 'culture', 'quality improvement', and 'the leadership pipeline': 'Acquiring self-insight and people skills (CMO1)', 'Intentionally building professional networks (CMO2)', 'Supporting quality improvement projects (CMO3)', 'Tailored LDP content prepares physicians (CMO4)', and 'Valuing physician leaders and organizational commitment (CMO5)'. Culture was the outcome of CMO1 and CMO2, quality improvement of CMO2 and CMO3, and the leadership pipeline of CMO2, CMO4, and CMO5. These CMOs operated within an overarching context, the leadership ecosystem, that determined realizing and sustaining organization-level outcomes. CONCLUSIONS: LDPs benefit organization-level outcomes through multiple mechanisms. Creating the contexts to trigger these mechanisms depends on the resources invested in LDPs and adequately supporting physicians. LDP providers can use the presented MRPT to guide the development of LDPs when aiming for specific organization-level outcomes.

Victims of Child Abuse Dropping Out of Trauma-Focused Treatment: A Meta-Analysis of Risk Factors.

A substantial number of children who experienced child maltreatment drop out of evidence-based trauma-focused treatments (TF-CBT). Identifying child, family, and treatment-related factors associated with treatment dropout is important to be able to prevent this from happening and to effectively treat children's trauma-related symptoms. Methods: A quantitative review was performed based on a systematic synthesis of the literature on potential risk factors for dropout of trauma-focused treatment in maltreated children. Results: Eight studies were included, that examined TF-CBT, reporting on 139 effects of potential risk factors for dropout. Each factor was classified into one of ten domains. Small but significant effects were found for the "Demographic and Family" risk domain (r = .121), with factors including being male, child protective services involvement or placement, and minority status, and for the "Youth Alliance" risk domain (r = .207), with factors including low therapist-child support and low youth perception of parental approval. Moderator analyses suggested that family income and parental education may better predict the risk for TF-CBT dropout than other variables in the "Demographic and Family" domain. Conclusions: Our results provide a first overview of risk factors for dropout of trauma-focused treatments (TF-CBT) after child maltreatment, and highlight the role of the therapeutic relationship in this. Supplementary Information: The online version contains supplementary material available at 10.1007/s40653-022-00500-2.

Predicting Clinical Deterioration and Mortality at Differing Stages During Hospitalization: A Systematic Review of Risk Prediction Models in Children in Low- and Middle-Income Countries.

OBJECTIVE: To determine which risk prediction model best predicts clinical deterioration in children at different stages of hospital admission in low- and middle-income countries. METHODS: For this systematic review, Embase and MEDLINE databases were searched, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The key search terms were "development or validation study with risk-prediction model" AND "deterioration or mortality" AND "age 0-18 years" AND "hospital-setting: emergency department (ED), pediatric ward (PW), or pediatric intensive care unit (PICU)" AND "low- and middle-income countries." The Prediction Model Risk of Bias Assessment Tool was used by two independent authors. Forest plots were used to plot area under the curve according to hospital setting. Risk prediction models used in two or more studies were included in a meta-analysis. RESULTS: We screened 9486 articles and selected 78 publications, including 67 unique predictive models comprising 1.5 million children. The best performing models individually were signs of inflammation in children that can kill (SICK) (ED), pediatric early warning signs resource limited settings (PEWS-RL) (PW), and Pediatric Index of Mortality (PIM) 3 as well as pediatric sequential organ failure assessment (pSOFA) (PICU). Best performing models after meta-analysis were SICK (ED), pSOFA and Pediatric Early Death Index for Africa (PEDIA)-immediate score (PW), and pediatric logistic organ dysfunction (PELOD) (PICU). There was a high risk of bias in all studies. CONCLUSIONS: We identified risk prediction models that best estimate deterioration, although these risk prediction models are not routinely used in low- and middle-income countries. Future studies should focus on large scale external validation with strict methodological criteria of multiple risk prediction models as well as study the barriers in the way of implementation. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews: Prospero ID: CRD42021210489.

The use of specific antihypertensive medication and skin cancer risk: A systematic review of the literature and meta-analysis.

BACKGROUND: The use of hydrochlorothiazide has recently been linked to skin cancer in observational studies. This may be explained by its photosensitizing properties, but photosensitivity has also been reported for other antihypertensive drugs. We conducted a systematic review and meta-analysis to compare skin cancer risk among antihypertensive drug classes and individual blood pressure lowering drugs. METHODS: We searched Medline, Embase, Cochrane and the Web of Science and included studies that investigated the association between antihypertensive medication exposure and non-melanoma skin cancer (NMSC) or cutaneous malignant melanoma (CMM). We combined the extracted odds ratios (OR) using a random effects model. RESULTS: We included 42 studies with a total of 16,670,045 subjects. Diuretics, in particular hydrochlorothiazide, were examined most frequently. Only 2 studies provided information about antihypertensive co-medication. Exposure to diuretics (OR 1.27 [1.09-1.47]) and calcium channel blockers (OR 1.06 [1.04-1.09]) was associated with an increased risk for NMSC. The increased risk for NMSC was only observed in case control studies and studies that did not correct for sun exposure, skin phototype or smoking. Studies that did correct for covariates as well as cohort studies did not show a significantly increased risk for NMSC. Egger's test revealed a significant publication bias for the subgroup of diuretics, hydrochlorothiazide and case-control studies concerning NMSC (p < 0.001). CONCLUSION: The available studies investigating the potential skin cancer risk that is associated with antihypertensive medication have significant shortcomings. Also, a significant publication bias is present. We found no increased skin cancer risk when analyzing cohort studies or studies that corrected for important covariates. (PROSPERO (CRD42020138908)).

Pediatric patient engagement in clinical care, research and intervention development: a scoping review.

BACKGROUND: In the last decades, pediatric patient engagement has received growing attention and its importance is increasingly acknowledged. Pediatric patient engagement in health care can be defined as the involvement of children and adolescents in the decision-making of daily clinical care, research and intervention development. Although more attention is paid to pediatric patient engagement, a comprehensive overview of the activities that have been done regarding pediatric patient engagement and the changes over time is lacking. Therefore, the aim of this study is to provide an overview of the literature about pediatric patient engagement. METHODS: The methodological framework of Arksey & O'Malley was used to conduct this scoping review. The bibliographic databases Medline, Embase, and PsycINFO were searched for eligible articles. All retrieved articles were screened by at least two researchers in two steps. Articles were included if they focused on pediatric patient engagement, were carried out in the context of clinical care in pediatrics, and were published as full text original article in English or Dutch. Data (year of publication, country in which the study was conducted, disease group of the participants, setting of pediatric patient engagement, used methods, and age of participants) were extracted, synthesized, and tabulated. RESULTS: A total of 288 articles out of the 10,714 initial hits met the inclusion criteria. Over the years, there has been an increase in the number of studies that engage pediatric patients. Pediatric patients, especially patients with multiple conditions or oncology patients, were most involved in studies in the United States, United Kingdom, and Canada. Pediatric patients were most often asked to express their views on questions from daily clinical care and the individual interview was the most used method. In general, the extent to which pediatric patients are engaged in health care increases with age. DISCUSSION: This scoping review shows that there is an increasing interest in pediatric patient engagement. However, lack of uniformity about the definition of pediatric patient engagement and clear information for clinicians hinders engagement. This overview can inform clinicians and researchers about the different ways in which pediatric patient engagement can be shaped and can guide them to engage pediatric patients meaningfully in their projects.

A first step towards a framework for interventions for individual working practice to prevent work-related musculoskeletal disorders: a scoping review.

BACKGROUND: Work-related musculoskeletal disorders (WMSDs) are a key topic in occupational health. In the primary prevention of these disorders, interventions to minimize exposure to work-related physical risk factors are widely advocated. Besides interventions aimed at the work organisation and the workplace, interventions are also aimed at the behaviour of workers, the so-called individual working practice (IWP). At the moment, no conceptual framework for interventions for IWP exists. This study is a first step towards such a framework. METHODS: A scoping review was carried out starting with a systematic search in Ovid Medline, Ovid Embase, Ovid APA PsycInfo, and Web of Science. Intervention studies aimed at reducing exposure to physical ergonomic risk factors involving the worker were included. The content of these interventions for IWP was extracted and coded in order to arrive at distinguishing and overarching categories of these interventions for IWP. RESULTS: More than 12.000 papers were found and 110 intervention studies were included, describing 810 topics for IWP. Eventually eight overarching categories of interventions for IWP were distinguished: (1) Workplace adjustment, (2) Variation, (3) Exercising, (4) Use of aids, (5) Professional skills, (6) Professional manners, (7) Task content & task organisation and (8) Motoric skills. CONCLUSION: Eight categories of interventions for IWP are described in the literature. These categories are a starting point for developing and evaluating effective interventions performed by workers to prevent WMSDs. In order to reach consensus on these categories, an international expert consultation is a necessary next step.

Effect of TNF inhibitors on arterial stiffness and intima media thickness in rheumatoid arthritis: a systematic review and meta-analysis.

Controlling inflammation with tumor necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA) patients is hypothesized to reduce their cardiovascular risk. We performed a systematic review and meta-analysis on the effects of TNF inhibitors on arterial stiffness and carotid intima media thickness (IMT) in RA. MEDLINE, EMBASE, clinicaltrials.gov , and WHO Clinical Trials Registry were searched up to September 2021 for randomized controlled trials, prospective cohort studies, and nonrandomized clinical trials evaluating the effects of TNF inhibitors on pulse wave velocity (PWV), augmentation index (AIx), and IMT in RA. A meta-analysis was performed to assess changes of these measures after therapy during different follow-up periods. Risk of bias assessment was performed using an adjusted Downs and Black checklist (INPLASY: 2022-1-0131). Thirty studies were identified from 1436 records, of which 23 were included in the meta-analysis. PWV and AIx showed a decrease after treatment (PWV: mean difference (MD) -0.51 m/s (95% CI: -0.96, -0.06), p=0.027; AIx: MD -0.57% (95% CI: -2.11, 0.96), p=0.463, sensitivity analysis AIx: MD -1.21% (95% CI: -2.60, 0.19), p=0.089). For IMT, there was a slight increase in the first months of follow-up, but this disappeared on the long-term (overall timepoints MD -0.01 mm (95% CI: -0.04, 0.02), p=0.615). Heterogeneity was high in the overall analyses and subgroups with long follow-up periods (≥12 months). The included studies showed mixed results of the effects of TNF inhibitors on the surrogate markers. The pooled results suggest that PWV and AIx decrease over time, while IMT remains stable. This indicates a favorable effect of TNF inhibitors on the cardiovascular disease risk, all the more since these markers also increase with age.

Efficacy of aerobic exercise on aerobic capacity in slowly progressive neuromuscular diseases: A systematic review and meta-analysis.

BACKGROUND: Aerobic exercise aims to improve aerobic capacity. OBJECTIVE: To summarize the evidence on the efficacy of aerobic exercise on aerobic capacity in slowly progressive neuromuscular diseases (NMDs). METHODS: We searched the electronic databases MEDLINE, EMBASE, SPORTDiscus and Web of Science Conference Proceedings Index for articles published up to June 17, 2021, selecting randomized controlled trials that included adults with slowly progressive NMDs and compared aerobic exercise to no aerobic exercise. The primary outcome was peak oxygen uptake (VO2peak) directly post-intervention. Secondary outcomes included other peak test parameters, submaximal test parameters, long-term outcomes ≥8 weeks post-intervention, adherence and adverse events. Meta-analyses were performed for the primary outcome and for secondary outcomes when reported in more than 2 studies. Risk of bias was assessed with the Cochrane Risk of Bias tool and quality of evidence according to GRADE. RESULTS: Nine studies were included (195 participants with 8 different NMDs). Eight studies were rated at high risk of bias and 1 study was rated at some concerns. Duration of exercise programs ranged from 6 to 26 weeks, with 3 weekly training sessions of 20 to 40 min, based on maximal capacity. Meta-analyses revealed short-term moderate beneficial effects of aerobic exercise on VO2peak (standardized mean difference [SMD] 0.55, 95% CI 0.23; 0.86) and peak workload (SMD 0.61, 95% CI 0.24; 0.99). Long-term effects were not assessed. Most training sessions (83-97%) were completed, but time spent in target intensity zones was not reported. Included studies lacked detailed adverse event reporting. CONCLUSIONS: There is low-quality evidence that aerobic exercise is safe and leads to moderate improvement of aerobic capacity directly post-intervention in slowly progressive NMDs, but the long-term efficacy remains unclear. Detailed information about the time spent in target intensity zones and adverse events is lacking. PROSPERO: CRD42020200083.

Microbial effects of prebiotics, probiotics and synbiotics after Caesarean section or exposure to antibiotics in the first week of life: A systematic review.

BACKGROUND AND AIMS: Disruption of the developing microbiota by Caesarean birth or early exposure to antibiotics may impact long-term health outcomes, which can potentially be prevented by nutritional supplements. This systematic review aimed to summarise the evidence regarding the effects of prebiotics, probiotics and synbiotics on the intestinal microbiota composition of term infants born by Caesarean section or exposed to antibiotics in the first week of life. METHODS: A systematic search was performed from inception to August 2022 in Medline and Embase. Two researchers independently performed title and abstract screening (n = 12,230), full-text screening (n = 46) and critical appraisal. We included randomised controlled trials which included term-born infants who were born following Caesarean section or who were exposed to postpartum antibiotics in the first week of life, pre-, pro- or synbiotics were administered <6 weeks after birth and outcome(s) consisted of microbiota analyses. RESULTS: Twelve randomised controlled trials investigating Caesarean born infants and one randomised controlled trial including infants exposed to antibiotics were included. Group sizes varied from 11 to 230 with 1193 infants in total. Probiotic (n = 7) or synbiotic (n = 3) supplementation significantly increased the abundance of the supplemented bacterial species (of the Bifidobacterium and Lactobacillus genus), and there was a decrease in Enterobacteriaceae, especially <4 weeks of age. At phylum level, Actinobacteria (two studies), Proteobacteria (one study) and Firmicutes (one study) increased after probiotic supplementation. In three studies on prebiotics, two studies reported a significant increase in Bifidobacteria and one study found a significant increase in Enterobacteriaceae. DISCUSSION: Prebiotic, probiotic and synbiotic supplements seem to restore dysbiosis after Caesarean section towards a microbial signature of vaginally born infants by increasing the abundance of beneficial bacteria. However, given the variety in study products and study procedures, it is yet too early to advocate specific products in clinical settings.

A systematic review on the use of explainability in deep learning systems for computer aided diagnosis in radiology: Limited use of explainable AI?

OBJECTIVES: This study aims to contribute to an understanding of the explainability of computer aided diagnosis studies in radiology that use end-to-end deep learning by providing a quantitative overview of methodological choices and by discussing the implications of these choices for their explainability. METHODS: A systematic review was executed using the preferred reporting items for systemic reviews and meta-analysis guidelines. Primary diagnostic test accuracy studies using end-to-end deep learning for radiology were identified from the period January 1st, 2016, to January 20th, 2021. Results were synthesized by identifying the explanation goals, measures, and explainable AI techniques. RESULTS: This study identified 490 primary diagnostic test accuracy studies using end-to-end deep learning for radiology, of which 179 (37%) used explainable AI. In 147 out of 179 (82%) of studies, explainable AI was used for the goal of model visualization and inspection. Class activation mapping is the most common technique, being used in 117 out of 179 studies (65%). Only 1 study used measures to evaluate the outcome of their explainable AI. CONCLUSIONS: A considerable portion of computer aided diagnosis studies provide a form of explainability of their deep learning models for the purpose of model visualization and inspection. The techniques commonly chosen by these studies (class activation mapping, feature activation mapping and t-distributed stochastic neighbor embedding) have potential limitations. Because researchers generally do not measure the quality of their explanations, we are agnostic about how effective these explanations are at addressing the black box issues of deep learning in radiology.

Does aerobic exercise reduce NASH and liver fibrosis in patients with non-alcoholic fatty liver disease? A systematic literature review and meta-analysis.

Background: Exercise is an effective strategy for the prevention and regression of hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD), but it is unclear whether it can reduce advanced stages of NAFLD, i.e., steatohepatitis and liver fibrosis. Furthermore, it is not evident which modality of exercise is optimal to improve/attenuate NAFLD. Objectives: The aim is to systematically review evidence for the effect of aerobic exercise (AE) on NAFLD, in particular non-alcoholic steatohepatitis (NASH) and liver fibrosis. Methods: A systematic literature search was conducted in Medline and Embase. Studies were screened and included according to predefined criteria, data were extracted, and the quality was assessed by Cochrane risk of bias tools by two researchers independently according to the protocol registered in the PROSPERO database (CRD42021270059). Meta-analyses were performed using a bivariate random-effects model when there were at least three randomized intervention studies (RCTs) with similar intervention modalities and outcome. Results: The systematic review process resulted in an inclusion a total of 24 studies, 18 RCTs and six non-RCTs, encompassing 1014 patients with NAFLD diagnosed by histological or radiological findings. Studies were grouped based on the type of AE: moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT). A total of twelve meta-analyses were conducted. Compared to controls, MICT resulted in a mean difference (MD) in the NAFLD biomarkers alanine transaminase (ALT) and aspartate aminotransferase (AST) of -3.59 (CI: -5.60, -1.59, p<0.001) and -4.05 (CI: -6.39, -1.71, p<0.001), respectively. HIIT resulted in a MD of -4.31 (95% CI: -9.03, 0.41, p=0.07) and 1.02 (95% CI: -6.91, 8.94, p=0.8) for ALT and AST, respectively. Moreover, both AE types compared to controls showed a significantly lower magnetic resonance spectroscopy (MRS) determined liver fat with a MD of -5.19 (95% CI: -7.33, -3.04, p<0.001) and -3.41 (95% CI: -4.74, -2.08, p<0.001), for MICT and HIIT respectively. MICT compared to controls resulted in a significantly higher cardiorespiratory fitness (MD: 4.43, 95% CI: 0.31, 8.55, p=0.03). Conclusion: Liver fat is decreased by AE with a concomitant decrease of liver enzymes. AE improved cardiorespiratory fitness. Further studies are needed to elucidate the impact of different types of AE on hepatic inflammation and fibrosis. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier (CRD42021270059).

Mental health screening and assessment tools for forcibly displaced children: a systematic review.

Background: An unprecedentedly large number of people worldwide are forcibly displaced, of which more than 40 percent are under 18 years of age. Forcibly displaced children and youth have often been exposed to stressful life events and are therefore at increased risk of developing mental health issues. Hence, early screening and assessment for mental health problems is of great importance, as is research addressing this topic. However, there is a lack of evidence regarding the reliability and validity of mental health assessment tools for this population. Objective: The aim of the present study was to synthesise the existing evidence on psychometric properties of patient reported outcome measures [PROMs] for assessing the mental health of asylum-seeking, refugee and internally displaced children and youth. Method: Systematic searches of the literature were conducted in four electronic databases: MEDLINE, PsycINFO, Embase and Web of Science. The methodological quality of the studies was examined using the COSMIN Risk of Bias checklist. Furthermore, the COSMIN criteria for good measurement properties were used to evaluate the quality of the outcome measures. Results: The search yielded 4842 articles, of which 27 met eligibility criteria. The reliability, internal consistency, structural validity, hypotheses testing and criterion validity of 28 PROMs were evaluated. Conclusion: Based on the results with regard to validity and reliability, as well as feasibility, we recommend the use of several instruments to measure emotional and behavioural problems, PTSD symptoms, anxiety and depression in forcibly displaced children and youth. However, despite a call for more research on the psychometric properties of mental health assessment tools for forcibly displaced children and youth, there is still a lack of studies conducted on this topic. More research is needed in order to establish cross-cultural validity of mental health assessment tools and to provide optimal cut-off scores for this population. HIGHLIGHTS Research on the psychometric properties of mental health screening and assessment tools for forcibly displaced children and youth is slowly increasing.However, based on the current evidence on the validity and reliability of screening and assessment tools for forcibly displaced children, we are not able to recommend a core set of instruments. Instead, we provide suggestions for best practice.More research of sufficient quality is important in order to establish crsoss-cultural validity and to provide optimal cut-off scores in mental health screening and assessment tools for different populations of forcibly displaced children and youth.

Antecedentes: Un número sin precedentes de personas en todo el mundo son desplazadas por la fuerza, de las cuales más del 40 por ciento son menores de 18 años. Los niños y jóvenes desplazados por la fuerza a menudo han estado expuestos a eventos vitales estresantes y, por lo tanto, corren un mayor riesgo de desarrollar problemas de salud mental. Por lo tanto, la detección temprana y la evaluación de los problemas de salud mental son de gran importancia, al igual que la investigación que aborda este tema. Sin embargo, hay una falta de evidencia con respecto a la confiabilidad y validez de las herramientas de evaluación de la salud mental para esta población.Objetivo: El objetivo del presente estudio fue sintetizar la evidencia existente sobre las propiedades psicométricas de los instrumentos de medición de resultado reportadas por el paciente [PROM, por sus siglas en inglés] para evaluar la salud mental de los niños y jóvenes solicitantes de asilo, refugiados y desplazados internos.Método: Se realizaron búsquedas sistemáticas de la literatura en cuatro bases de datos electrónicas: MEDLINE, PsycINFO, Embase y Web of Science. La calidad metodológica de los estudios se examinó mediante la lista de verificación de riesgo de sesgo de COSMIN. Además, se utilizaron los criterios COSMIN de buenas propiedades de medición para evaluar la calidad de los instrumentos de medición de resultados.Resultados: La búsqueda arrojó 4842 artículos, de los cuales 27 cumplieron con los criterios de elegibilidad. Se evaluaron la confiabilidad, consistencia interna, validez estructural, prueba de hipótesis y validez de criterio de 28 PROM.Conclusión: En base a los resultados con respecto a la validez y confiabilidad, así como la factibilidad, recomendamos el uso de varios instrumentos para medir problemas emocionales y de conducta, síntomas de TEPT, ansiedad y depresión en niños y jóvenes desplazados por la fuerza. Sin embargo, a pesar de la petición de más investigación sobre las propiedades psicométricas de las herramientas de evaluación de la salud mental para niños y jóvenes desplazados por la fuerza, todavía faltan estudios sobre este tema. Se necesita más investigación para establecer la validez transcultural de las herramientas de evaluación de la salud mental y proporcionar puntajes de corte óptimos para esta población.

Clinical outcomes following pre-, pro- and synbiotic supplementation after caesarean birth or antibiotic exposure in the first week of life in term born infants: A systematic review of the literature.

Background: Caesarean section and early exposure to antibiotics disrupt the developing gastrointestinal microbiome, which is associated with long-term health effects. Objective: The aim of this systematic review was to summarise the impact of prebiotics, probiotics, or synbiotics supplementation on clinical health outcomes of term infants born by caesarean section or exposed to antibiotics in the first week of life. Design: A systematic search was performed in Medline and Embase from inception to August 2021. Title and abstract screening (n = 11,248), full text screening (n = 48), and quality assessment were performed independently by two researchers. Results: Six RCTs studying caesarean born infants were included, group sizes varied between 32-193 with in total 752 children. No studies regarding supplementation after neonatal antibiotic exposure were found. Three studies administered a probiotic, one a prebiotic, one a synbiotic, and one study investigated a prebiotic and synbiotic. Several significant effects were reported at follow-up varying between 10 days and 13 years: a decrease in atopic diseases (n = 2 studies), higher immune response to tetanus and polio vaccinations (n = 2), lower response to influenza vaccination (n = 1), fewer infectious diseases (n = 2), and less infantile colic (n = 1), although results were inconsistent. Conclusions: Supplementation of caesarean-born infants with prebiotics, probiotics, or synbiotics resulted in significant improvements in some health outcomes as well as vaccination responses. Due to the variety of studied products and the paucity of studies, no recommendations can be given yet on the routine application of prebiotics, probiotics, or synbiotics to improve health outcomes after caesarean section or neonatal antibiotic exposure.

Medication reviews and deprescribing as a single intervention in falls prevention: a systematic review and meta-analysis.

BACKGROUND: our aim was to assess the effectiveness of medication review and deprescribing interventions as a single intervention in falls prevention. DESIGN: systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane CENTRAL, PsycINFO until 28 March 2022. ELIGIBILITY CRITERIA: randomised controlled trials of older participants comparing any medication review or deprescribing intervention with usual care and reporting falls as an outcome. STUDY RECORDS: title/abstract and full-text screening by two reviewers. RISK OF BIAS: Cochrane Collaboration revised tool. DATA SYNTHESIS: results reported separately for different settings and sufficiently comparable studies meta-analysed. RESULTS: forty-nine heterogeneous studies were included. COMMUNITY: meta-analyses of medication reviews resulted in a risk ratio (RR) of 1.05 (95% confidence interval, 0.85-1.29, I2 = 0%, 3 studies(s)) for number of fallers, in an RR = 0.95 (0.70-1.27, I2 = 37%, 3 s) for number of injurious fallers and in a rate ratio (RaR) of 0.89 (0.69-1.14, I2 = 0%, 2 s) for injurious falls. HOSPITAL: meta-analyses assessing medication reviews resulted in an RR = 0.97 (0.74-1.28, I2 = 15%, 2 s) and in an RR = 0.50 (0.07-3.50, I2 = 72% %, 2 s) for number of fallers after and during admission, respectively. LONG-TERM CARE: meta-analyses investigating medication reviews or deprescribing plans resulted in an RR = 0.86 (0.72-1.02, I2 = 0%, 5 s) for number of fallers and in an RaR = 0.93 (0.64-1.35, I2 = 92%, 7 s) for number of falls. CONCLUSIONS: the heterogeneity of the interventions precluded us to estimate the exact effect of medication review and deprescribing as a single intervention. For future studies, more comparability is warranted. These interventions should not be implemented as a stand-alone strategy in falls prevention but included in multimodal strategies due to the multifactorial nature of falls.PROSPERO registration number: CRD42020218231.