Effectiveness and implementation of lower-intensity weight management interventions delivered by the non-specialist workforce in postnatal women: a mixed-methods systematic review.

Lower-intensity interventions delivered in primary and community care contacts could provide more equitable and scalable weight management support for postnatal women. This mixed-methods systematic review aimed to explore the effectiveness, implementation, and experiences of lower-intensity weight management support delivered by the non-specialist workforce. We included quantitative and qualitative studies of any design that evaluated a lower-intensity weight management intervention delivered by non-specialist workforce in women up to 5 years post-natal, and where intervention effectiveness (weight-related and/or behavioural outcomes), implementation and/or acceptability were reported. PRISMA guidelines were followed, and the review was prospectively registered on PROSPERO (CRD42022371828). Nine electronic databases were searched to identify literature published between database inception to January 2023. This was supplemented with grey literature searches and citation chaining for all included studies and related reviews (completed June 2023). Screening, data extraction and risk of bias assessments were performed in duplicate. Risk of bias was assessed using the Joanna Briggs Institute appraisal tools. Narrative methods were used to synthesise outcomes. Seven unique studies described in 11 reports were included from the Netherlands (n = 2), and the United Kingdom, Germany, Taiwan, Finland, and the United States (n = 1 each). All studies reported weight-related outcomes; four reported diet; four reported physical activity; four reported intervention implementation and process outcomes; and two reported intervention acceptability and experiences. The longest follow-up was 13-months postnatal. Interventions had mixed effects on weight-related outcomes: three studies reported greater weight reduction and/or lower postnatal weight retention in the intervention group, whereas four found no difference or mixed effects. Most studies reporting physical activity or diet outcomes showed no intervention effect, or mixed effects. Interventions were generally perceived as acceptable by women and care providers, although providers had concerns about translation into routine practice. The main limitations of the review were the limited volume of evidence available, and significant heterogeneity in interventions and outcome reporting which limited meaningful comparisons across studies. There is a need for more intervention studies, including process evaluations, with longer follow-up in the postnatal period to understand the role of primary and community care in supporting women's weight management. Public Health Wales was the primary funder of this review.

A mapping exercise using automated techniques to develop a search strategy to identify systematic review tools.

The Systematic Review Toolbox aims provide a web-based catalogue of tools that support various tasks within the systematic review and wider evidence synthesis process. Identifying publications surrounding specific systematic review tools is currently challenging, leading to a high screening burden for few eligible records. We aimed to develop a search strategy that could be regularly and automatically run to identify eligible records for the SR Toolbox, thus reducing time on task and burden for those involved. We undertook a mapping exercise to identify the PubMed IDs of papers indexed within the SR Toolbox. We then used the Yale MeSH Analyser and Visualisation of Similarities (VOS) Viewer text-mining software to identify the most commonly used MeSH terms and text words within the eligible records. These MeSH terms and text words were combined using Boolean Operators into a search strategy for Ovid MEDLINE. Prior to the mapping exercise and search strategy development, 81 software tools and 55 'Other' tools were included within the SR Toolbox. Since implementation of the search strategy, 146 tools have been added. There has been an increase in tools added to the toolbox since the search was developed and its corresponding auto-alert in MEDLINE was originally set up. Developing a search strategy based on a mapping exercise is an effective way of identifying new tools to support the systematic review process. Further research could be conducted to help prioritise records for screening to reduce reviewer burden further and to adapt the strategy for disciplines beyond healthcare.

Clinical and cost effectiveness of endoscopic bipolar radiofrequency ablation for the treatment of malignant biliary obstruction: a systematic review.

Background: Early evidence suggests that using radiofrequency ablation as an adjunct to standard care (i.e. endoscopic retrograde cholangiopancreatography with stenting) may improve outcomes in patients with malignant biliary obstruction. Objectives: To assess the clinical effectiveness, cost-effectiveness and potential risks of endoscopic bipolar radiofrequency ablation for malignant biliary obstruction, and the value of future research. Data sources: Seven bibliographic databases, three websites and seven trials registers were searched from 2008 until 21 January 2021. Review methods: The study inclusion criteria were as follows: patients with biliary obstruction caused by any form of unresectable malignancy; the intervention was reported as an endoscopic biliary radiofrequency ablation to ablate malignant tissue that obstructs the bile or pancreatic ducts, either to fit a stent (primary radiofrequency ablation) or to clear an obstructed stent (secondary radiofrequency ablation); the primary outcomes were survival, quality of life or procedure-related adverse events; and the study design was a controlled study, an observational study or a case report. Risk of bias was assessed using Cochrane tools. The primary analysis was meta-analysis of the hazard ratio of mortality. Subgroup analyses were planned according to the type of probe, the type of stent (i.e. metal or plastic) and cancer type. A de novo Markov model was developed to model cost and quality-of-life outcomes associated with radiofrequency ablation in patients with primary advanced bile duct cancer. Insufficient data were available for pancreatic cancer and secondary bile duct cancer. An NHS and Personal Social Services perspective was adopted for the analysis. A probabilistic analysis was conducted to estimate the incremental cost-effectiveness ratio for radiofrequency ablation and the probability that radiofrequency ablation was cost-effective at different thresholds. The population expected value of perfect information was estimated in total and for the effectiveness parameters. Results: Sixty-eight studies (1742 patients) were included in the systematic review. Four studies (336 participants) were combined in a meta-analysis, which showed that the pooled hazard ratio for mortality following primary radiofrequency ablation compared with a stent-only control was 0.34 (95% confidence interval 0.21 to 0.55). Little evidence relating to the impact on quality of life was found. There was no evidence to suggest an increased risk of cholangitis or pancreatitis, but radiofrequency ablation may be associated with an increase in cholecystitis. The results of the cost-effectiveness analysis were that the costs of radiofrequency ablation was £2659 and radiofrequency ablation produced 0.18 quality-adjusted life-years, which was more than no radiofrequency ablation on average. With an incremental cost-effectiveness ratio of £14,392 per quality-adjusted life-year, radiofrequency ablation was likely to be cost-effective at a threshold of £20,000 per quality-adjusted life-year across most scenario analyses, with moderate uncertainty. The source of the vast majority of decision uncertainty lay in the effect of radiofrequency ablation on stent patency. Limitations: Only 6 of 18 comparative studies contributed to the survival meta-analysis, and few data were found concerning secondary radiofrequency ablation. The economic model and cost-effectiveness meta-analysis required simplification because of data limitations. Inconsistencies in standard reporting and study design were noted. Conclusions: Primary radiofrequency ablation increases survival and is likely to be cost-effective. The evidence for the impact of secondary radiofrequency ablation on survival and of quality of life is limited. There was a lack of robust clinical effectiveness data and, therefore, more information is needed for this indication. Future work: Future work investigating radiofrequency ablation must collect quality-of-life data. High-quality randomised controlled trials in secondary radiofrequency ablation are needed, with appropriate outcomes recorded. Study registration: This study is registered as PROSPERO CRD42020170233. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 7. See the NIHR Journals Library website for further project information.

The bile and pancreatic ducts transport fluids to the intestines to help people digest their food properly. Some types of cancer can cause these ducts to become totally or partially blocked. We wanted to know if endoscopic radiofrequency ablation is safe and works well to treat people who have one of these blockages that cannot be removed by surgery. Radiofrequency ablation burns away a blockage by hitting it with radio waves. Endoscopic means that the radio waves are directed to the blockage using a thin, tube-like wire with a camera at the end. During radiofrequency ablation, a person might have a small tube called a stent put into their bile or pancreatic duct to keep it open or to replace an already blocked stent.

We searched for research studies that looked at (1) whether or not radiofrequency ablation was able to remove blockages from the ducts, (2) if radiofrequency ablation allowed people to live longer, (3) if patients had a better quality of life after radiofrequency ablation, (4) if radiofrequency ablation caused any side effects and (5) how much it costs to treat people with radiofrequency ablation.

We found that treatment with radiofrequency ablation before giving a person a stent helped them to live a little longer with their cancer. We did not find any evidence that radiofrequency ablation increased pain or swelling in the bile duct or pancreatic duct. Radiofrequency ablation might cause more swelling in the gall bladder than having a stent without radiofrequency ablation, but there was not enough research available for us to be certain of this.

Radiofrequency ablation before inserting a stent could be a safe option to add to treatment of bile and pancreatic duct blockages caused by cancer. There is limited research evidence and so we are unable to recommend radiofrequency ablation as a treatment for standard clinical practice.

Are there socioeconomic inequalities in polypharmacy among older people? A systematic review and meta-analysis.

BACKGROUND: Socioeconomic status (SES) may influence prescribing, concordance and adherence to medication regimens. This review set out to investigate the association between polypharmacy and an individual's socioeconomic status. METHODS: A systematic review and meta-analyses of observational studies was conducted across four databases. Older people (≥ 55 years) from any healthcare setting and residing location were included. The search was conducted across four databases: Medline (OVID), Web of Science, Embase (OVID) and CINAHL. Observational studies from 1990 that reported polypharmacy according to SES were included. A random-effects model was undertaken comparing those with polypharmacy (≥ 5 medication usage) with no polypharmacy. Unadjusted odds ratios (ORs), 95% confidence intervals (CIs) and standard errors (SE) were calculated for each study. RESULTS: Fifty-four articles from 13,412 hits screened met the inclusion criteria. The measure of SES used were education (50 studies), income (18 studies), wealth (6 studies), occupation (4 studies), employment (7 studies), social class (5 studies), SES categories (2 studies) and deprivation (1 study). Thirteen studies were excluded from the meta-analysis. Lower SES was associated with higher polypharmacy usage: individuals of lower educational backgrounds displayed 21% higher odds to be in receipt of polypharmacy when compared to those of higher education backgrounds. Similar findings were shown for occupation, income, social class, and socioeconomic categories. CONCLUSIONS: There are socioeconomic inequalities in polypharmacy among older people, with people of lower SES significantly having higher odds of polypharmacy. Future work could examine the reasons for these inequalities and explore the interplay between polypharmacy and multimorbidity.

Are non-invasive or minimally invasive autopsy techniques for detecting cause of death in prenates, neonates and infants accurate? A systematic review of diagnostic test accuracy.

OBJECTIVES: To assess the diagnostic accuracy of non-invasive or minimally invasive autopsy techniques in deaths under 1 year of age. DESIGN: This is a systematic review of diagnostic test accuracy. The protocol is registered on PROSPERO. PARTICIPANTS: Deaths from conception to one adjusted year of age. SEARCH METHODS: MEDLINE (Ovid), EMBASE (Ovid), CINAHL (EBSCO), the Cochrane Library, Scopus and grey literature sources were searched from inception to November 2021. DIAGNOSTIC TESTS: Non-invasive or minimally invasive diagnostic tests as an alternative to traditional autopsy. DATA COLLECTION AND ANALYSIS: Studies were included if participants were under one adjusted year of age, with index tests conducted prior to the reference standard.Data were extracted from eligible studies using piloted forms. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. A narrative synthesis was conducted following the Synthesis without Meta-Analysis guidelines. Vote counting was used to assess the direction of effect. MAIN OUTCOME MEASURES: Direction of effect was expressed as percentage of patients per study. FINDINGS: We included 54 direct evidence studies (68 articles/trials), encompassing 3268 cases and eight index tests. The direction of effect was positive for postmortem ultrasound and antenatal echography, although with varying levels of success. Conversely, the direction of effect was against virtual autopsy. For the remaining tests, the direction of effect was inconclusive.A further 134 indirect evidence studies (135 articles/trials) were included, encompassing 6242 perinatal cases. The addition of these results had minimal impact on the direct findings yet did reveal other techniques, which may be favourable alternatives to autopsy.Seven trial registrations were included but yielded no results. CONCLUSIONS: Current evidence is insufficient to make firm conclusions about the generalised use of non-invasive or minimally invasive autopsy techniques in relation to all perinatal population groups.PROSPERO registration numberCRD42021223254.

Investigation of text-mining methodologies to aid the construction of search strategies in systematic reviews of diagnostic test accuracy-a case study.

Current methodologies for designing search strategies rely heavily on the knowledge and expertise of information specialists. Yet, the volume and complexity of scientific literature is overwhelming for even the most experienced information specialists, making it difficult to produce robust search strategies for complex systematic reviews. In this case study, we aimed to assess and describe the benefits and limitations of using semi-automated text-mining tools for designing search strategies in a systematic review of diagnostic test accuracy. An experienced information specialist designed a search strategy using traditional methods. This strategy was then amended to include additional terms identified by text-mining tools. We evaluated the usability and expertise required, risk of introducing bias to the search, precision of the search strategy and rated the usefulness of the tools. Thirteen of the 16 investigated tools produced a total of 40 additional terms, beyond those in the original search strategy. This resulted in 11 previously unidentified relevant articles being retrieved. Precision was reduced or remained the same in all cases. After considering all aspects of the investigation we rated each application, with two being 'extremely useful', three being 'useful', three having 'no impact' and eight being 'not very useful'. Comparative analysis revealed discrepancies between similar tools. Our findings have implications for the way in which these methodologies are used and applied to search strategies. If semi-automated techniques are to become mainstream in information retrieval for complex systematic reviews, we need tailored tools that fit information specialists' requirements across disciplines.

The Systematic Review Toolbox: keeping up to date with tools to support evidence synthesis.

BACKGROUND: The Systematic Review (SR) Toolbox was developed in 2014 to collate tools that can be used to support the systematic review process. Since its inception, the breadth of evidence synthesis methodologies has expanded greatly. This work describes the process of updating the SR Toolbox in 2022 to reflect these changes in evidence synthesis methodology. We also briefly analysed included tools and guidance to identify any potential gaps in what is currently available to researchers. METHODS: We manually extracted all guidance and software tools contained within the SR Toolbox in February 2022. A single reviewer, with a second checking a proportion, extracted and analysed information from records contained within the SR Toolbox using Microsoft Excel. Using this spreadsheet and Microsoft Access, the SR Toolbox was updated to reflect expansion of evidence synthesis methodologies and brief analysis conducted. RESULTS: The updated version of the SR Toolbox was launched on 13 May 2022, with 235 software tools and 112 guidance documents included. Regarding review families, most software tools (N = 223) and guidance documents (N = 78) were applicable to systematic reviews. However, there were fewer tools and guidance documents applicable to reviews of reviews (N = 66 and N = 22, respectively), while qualitative reviews were less served by guidance documents (N = 19). In terms of review production stages, most guidance documents surrounded quality assessment (N = 70), while software tools related to searching and synthesis (N = 84 and N = 82, respectively). There appears to be a paucity of tools and guidance relating to stakeholder engagement (N = 2 and N = 3, respectively). CONCLUSIONS: The SR Toolbox provides a platform for those undertaking evidence syntheses to locate guidance and software tools to support different aspects of the review process across multiple review types. However, this work has also identified potential gaps in guidance and software that could inform future research.

Oral nutritional interventions in frail older people who are malnourished or at risk of malnutrition: a systematic review.

BACKGROUND: Malnutrition worsens the health of frail older adults. Current treatments for malnutrition may include prescribed oral nutritional supplements, which are multinutrient products containing macronutrients and micronutrients. OBJECTIVE: To assess the effectiveness and cost-effectiveness of oral nutritional supplements (with or without other dietary interventions) in frail older people who are malnourished or at risk of malnutrition. DATA SOURCES: MEDLINE, EMBASE, Cochrane Library, Scopus, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and grey literature were searched from inception to 13 September 2021. REVIEW METHODS: A systematic review and meta-analysis was conducted to evaluate the effectiveness and cost-effectiveness of oral nutritional supplements in frail older people (aged ≥ 65 years) who are malnourished or at risk of malnutrition (defined as undernutrition as per National Institute for Health and Care Excellence guidelines). Meta-analysis and network meta-analysis were undertaken, where feasible, along with a narrative synthesis. A cost-effectiveness review was reported narratively. A de novo model was developed using effectiveness evidence identified in the systematic review to estimate the cost-effectiveness of oral nutritional supplements. RESULTS: Eleven studies (n = 822 participants) were included in the effectiveness review, six of which were fully or partly funded by industry. Meta-analyses suggested positive effects of oral nutritional supplements compared with standard care for energy intake (kcal) (standardised mean difference 1.02, 95% confidence interval 0.15 to 1.88; very low quality evidence) and poor mobility (mean difference 0.03, p < 0.00001, 95% confidence interval 0.02 to 0.04; very low quality evidence) but no evidence of an effect for body weight (mean difference 1.31, 95% confidence interval -0.05 to 2.66; very low quality evidence) and body mass index (mean difference 0.54, 95% confidence interval -0.03 to 1.11; very low quality evidence). Pooled results for other outcomes were statistically non-significant. There was mixed narrative evidence regarding the effect of oral nutritional supplements on quality of life. Network meta-analysis could be conducted only for body weight and grip strength; there was evidence of an effect for oral nutritional supplements compared with standard care for body weight only. Study quality was mixed; the randomisation method was typically poorly reported. One economic evaluation, in a care home setting, was included. This was a well-conducted study showing that oral nutritional supplements could be cost-effective. Cost-effectiveness analysis suggested that oral nutritional supplements may only be cost-effective for people with lower body mass index (< 21 kg/m2) using cheaper oral nutritional supplements products that require minimal staff time to administer. LIMITATIONS: The review scope was narrow in focus as few primary studies used frailty measures (or our proxy criteria). This resulted in only 11 included studies. The small evidence base and varied quality of evidence meant that it was not possible to determine accurate estimates of the effectiveness or cost-effectiveness of oral nutritional supplements. Furthermore, only English-language publications were considered. CONCLUSIONS: Overall, the review found little evidence of oral nutritional supplements having significant effects on reducing malnutrition or its adverse outcomes in frail older adults. FUTURE WORK: Future research should focus on independent, high-quality, adequately powered studies to investigate oral nutritional supplements alongside other nutritional interventions, with longer-term follow-up and detailed analysis of determinants, intervention components and cost-effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42020170906. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 51. See the NIHR Journals Library website for further project information.

WHAT WAS THE QUESTION?: Malnutrition, in the form of undernutrition, is very common in frail older people. Dietary advice is recommended (e.g. adding nutrients to meals) for older adults who are malnourished, while powdered or liquid supplements (oral nutritional supplements) can be prescribed to those who are malnourished or at risk of becoming malnourished. In this study, we reviewed previous studies to see if oral nutritional supplements (as a form of dietary support) work at reducing malnutrition in frail older adults and whether or not they are value for money. WHAT DID WE DO?: We searched for studies up to September 2021 on frail older people who were at risk of malnutrition or were malnourished in care homes, hospitals or the community in any country. We included studies that measured malnutrition and the consequences of malnutrition, quality of life, survival, costs and hospitalisations. We assessed the difference in malnutrition between those receiving oral nutritional supplements and those receiving usual care or other dietary (or nutritional) interventions. We also looked at the value for money of oral nutritional supplements. WHAT DID WE FIND?: We found 12 studies (11 studies looking at whether the supplements worked and one study looking at value for money). Most of which were of low quality, and many were funded by industry. Studies often did not report on longer-term effects, or how older people felt about the supplements. There was no clear or strong evidence that oral nutritional supplements worked or were value for money in reducing malnutrition or its consequences (such as the ability to perform everyday tasks). WHAT DOES THIS MEAN?: There is weak evidence for oral nutritional supplements in frail older adults. Future high-quality studies should be independent, assess longer-term effects, and have better reporting on factors that influence the impacts of oral nutritional supplements.

Effectiveness and cost-effectiveness of oral nutritional supplements in frail older people who are malnourished or at risk of malnutrition: a systematic review and meta-analysis.

BACKGROUND: Current management of malnutrition can include prescribed oral nutritional supplements (ONS); however, there is uncertainty whether these supplements are effective in people who are older (≥65 years) and frail. We assessed the effectiveness, cost-effectiveness, and adherence and acceptability of ONS in frail older people who are malnourished or at risk of malnutrition. METHODS: In this systematic review and meta-analysis, five bibliographic databases (MEDLINE, EMBASE, Cochrane Library, Scopus, and CINAHL) and grey literature sources were searched from inception to Sept 13, 2021, to identify studies assessing the effectiveness and cost-effectiveness of ONS (with or without other dietary interventions) in frail older people who are malnourished or at risk of malnutrition. Multiple reviewers independently did study screening, data extraction, and risk of bias assessment. Quality was assessed using version 1.0 of the Cochrane risk of bias tool for randomised controlled trials (RCTs), and the BMJ Drummond checklist was used to assess the quality of the included cost-effectiveness study. A meta-analysis was done for the effectiveness review; for the other reviews, a narrative synthesis approach was used. This systematic review and meta-analysis was registered on PROSPERO, CRD42020170906. FINDINGS: Of 8492 records retrieved and screened, we included 11 RCTs involving 822 participants, six of which were fully or partly funded by industry. For the majority of the outcomes for which meta-analyses were possible (11/12), Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) assessments suggested that the evidence was of very low certainty. Results suggested that ONS might have a slightly positive effect on energy (kcal) intake (standardised mean difference 1·02 [95% CI 0·15 to 1·88]; I2=87%; four studies), protein intake (standardised mean difference 1·67 [-0·03 to 3·37; I2=97%; four studies), and mobility (mean difference 0·03 [0·02 to 0·04]; I2=0%; four studies), compared with standard care. Narrative syntheses suggested that the effect of ONS on quality of life, compared with standard care, was mixed. In the identified studies, there was very little information related to active components, determinants, or acceptability of interventions. One economic evaluation, done in a care home setting, showed that ONS could be cost-effective. INTERPRETATION: We found little evidence of ONS reducing malnutrition or its associated adverse outcomes in older people who are frail. High-quality, non-industry-funded, adequately powered studies reporting on short-term and long-term health outcomes, determinants, and participant characteristics are needed. FUNDING: UK National Institute of Health and Care Research (NIHR) Health Technology Assessment (NIHR128729).

The damage-independent evolution of ageing by selective destruction.

Ageing is widely believed to reflect the accumulation of molecular damage due to energetic costs of maintenance, as proposed in disposable soma theory (DST). Here we use agent-based modelling to describe an alternative theory by which ageing could undergo positive selection independent of energetic costs. We suggest that the selective advantage of aberrant cells with fast growth might necessitate a mechanism of counterselection we name selective destruction that specifically removes the faster cells from tissues, preventing the morbidity and mortality risks they pose. The resulting survival advantage of slower mutants could switch the direction of selection, allowing them to outcompete both fast mutants and wildtype cells, causing them to spread and induce ageing in the form of a metabolic slowdown. Selective destruction could therefore provide a proximal cause of ageing that is both consistent with the gene expression hallmarks of ageing, and independent of accumulating damage. Furthermore, negligible senescence would acquire a new meaning of increased basal mortality.

Does moderate alcohol consumption accelerate the progression of liver disease in NAFLD? A systematic review and narrative synthesis.

OBJECTIVES: Liver disease is a leading cause of premature death, partly driven by the increasing incidence of non-alcohol-related fatty liver disease (NAFLD). Many people with a diagnosis of NAFLD drink moderate amounts of alcohol. There is limited guidance for clinicians looking to advise these patients on the effect this will have on their liver disease progression. This review synthesises the evidence on moderate alcohol consumption and its potential to predict liver disease progression in people with diagnosed NAFLD. METHODS: A systematic review of longitudinal observational cohort studies was conducted. Databases (Medline, Embase, The Cochrane Library and ClinicalTrials.gov) were searched up to September 2020. Studies were included that reported progression of liver disease in adults with NAFLD, looking at moderate levels of alcohol consumption as the exposure of interest. Risk of bias was assessed using the Quality in Prognostic factor Studies tool. RESULTS: Of 4578 unique citations, 6 met the inclusion criteria. Pooling of data was not possible due to heterogeneity and studies were analysed using narrative synthesis. Evidence suggested that any level of alcohol consumption is associated with worsening of liver outcomes in NAFLD, even for drinking within recommended limits. Well conducted population based studies estimated up to a doubling of incident liver disease outcomes in patients with NAFLD drinking at moderate levels. CONCLUSIONS: This review found that any level of alcohol intake in NAFLD may be harmful to liver health.Study heterogeneity in definitions of alcohol exposure as well as in outcomes limited quantitative pooling of results. Use of standardised definitions for exposure and outcomes would support future meta-analysis.Based on this synthesis of the most up to date longitudinal evidence, clinicians seeing patients with NAFLD should currently advise abstinence from alcohol. PROSPERO REGISTRATION NUMBER: The protocol was registered with PROSPERO (#CRD42020168022).

A broad comparative genomics approach to understanding the pathogenicity of Complex I mutations.

Disease caused by mutations of mitochondrial DNA (mtDNA) are highly variable in both presentation and penetrance. Over the last 30 years, clinical recognition of this group of diseases has increased. It has been suggested that haplogroup background could influence the penetrance and presentation of disease-causing mutations; however, to date there is only one well-established example of such an effect: the increased penetrance of two Complex I Leber's hereditary optic neuropathy mutations on a haplogroup J background. This paper conducts the most extensive investigation to date into the importance of haplogroup context in the pathogenicity of mtDNA mutations in Complex I. We searched for proven human point mutations across more than 900 metazoans finding human disease-causing mutations and potential masking variants. We found more than a half of human pathogenic variants as compensated pathogenic deviations (CPD) in at least in one animal species from our multiple sequence alignments. Some variants were found in many species, and some were even the most prevalent amino acids across our dataset. Variants were also found in other primates, and in such cases, we looked for non-human amino acids in sites with high probability to interact with the CPD in folded protein. Using this "local interactions" approach allowed us to find potential masking substitutions in other amino acid sites. We suggest that the masking variants might arise in humans, resulting in variability of mutation effect in our species.

COVID-19 Impact on Diagnostic Innovations: Emerging Trends and Implications.

Diagnostic testing remains the backbone of the coronavirus disease 2019 (COVID-19) response, supporting containment efforts to mitigate the outbreak. The severity of this crisis and increasing capacity issues associated with polymerase chain reaction (PCR)-based testing, accelerated the development of diagnostic solutions to meet demands for mass testing. The National Institute for Health Research (NIHR) Innovation Observatory is the national horizon scanning organization in England. Since March, the Innovation Observatory has applied advanced horizon scanning methodologies and tools to compile a diagnostic landscape, based upon data captured for molecular (MDx) and immunological (IDx) based diagnostics (commercialized/in development), for the diagnosis of SARS-CoV-2. In total we identified and tracked 1608 diagnostics, produced by 1045 developers across 54 countries. Our dataset shows the speed and scale in which diagnostics were produced and provides insights into key periods of development and shifts in trends between MDx and IDx solutions as the pandemic progressed. Stakeholders worldwide required timely and detailed intelligence to respond to major challenges, including testing capacity and regulatory issues. Our intelligence assisted UK stakeholders with assessing priorities and mitigation options throughout the pandemic. Here we present the global evolution of diagnostic innovations devised to meet changing needs, their regulation and trends across geographical regions, providing invaluable insights into the complexity of the COVID-19 phenomena.

What can a comparative genomics approach tell us about the pathogenicity of mtDNA mutations in human populations?

Mitochondrial disorders are heterogeneous, showing variable presentation and penetrance. Over the last three decades, our ability to recognize mitochondrial patients and diagnose these mutations, linking genotype to phenotype, has greatly improved. However, it has become increasingly clear that these strides in diagnostics have not benefited all population groups. Recent studies have demonstrated that patients from genetically understudied populations, in particular those of black African heritage, are less likely to receive a diagnosis of mtDNA disease. It has been suggested that haplogroup context might influence the presentation and penetrance of mtDNA disease; thus, the spectrum of mutations that are associated with disease in different populations. However, to date there is only one well-established example of such an effect: the increased penetrance of two Leber's hereditary optic neuropathy mutations on a haplogroup J background. This paper conducted the most extensive investigation to date into the importance of haplogroup context on the pathogenicity of mtDNA mutations. We searched for proven human point mutations across 726 multiple sequence alignments derived from 33 non-human species absent of disease. A total of 58 pathogenic point mutations arise in the sequences of these species. We assessed the sequence context and found evidence of population variants that could modulate the phenotypic expression of these point mutations masking the pathogenic effects seen in humans. This supports the theory that sequence context is influential in the presentation of mtDNA disease and has implications for diagnostic practices. We have shown that our current understanding of the pathogenicity of mtDNA point mutations, primarily built on studies of individuals with haplogroups HVUKTJ, will not present a complete picture. This will have the effect of creating a diagnostic inequality, whereby individuals who do not belong to these lineages are less likely to receive a genetic diagnosis.

Haplogroup Context is Less Important in the Penetrance of Mitochondrial DNA Complex I Mutations Compared to mt-tRNA Mutations.

Mitochondrial diseases are a highly complex, heterogeneous group of disorders. Mitochondrial DNA variants that are linked to disease can exhibit variable expression and penetrance. This has an implication for mitochondrial diagnostics as variants that cause disease in one individual may not in another. It has been suggested that the sequence context in which a variant arises could influence the genotype-phenotype relationship. However, the consequence of sequence variation between different haplogroups on the expression of disease is not well understood. European haplogroups are the most widely studied. To ensure accurate diagnostics for patients globally, we first need to understand how, if at all, the sequence context in which a variant arises contributes to the manifestion of disease. To help us understand this, we used 2752 sequences from 33 non-human species that do not have disease. We searched for variants in the seven complex I genes that are associated with disease in humans. Our findings indicate that only three reported pathogenic complex I variants have arisen in these species. More importantly, only one of these, m.3308T>C, has arisen with its associated amino acid change in the studied non-human species. With the status of m.3308T>C as a disease causing variant being a matter of debate. This is a stark contrast to previous findings in the mitochondrial tRNA genes and suggests that sequence context may be less important in the complex I genes. This information will help us improve the identification and diagnosis of mitochondrial DNA variants in non-European populations.

Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease.

Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases. Reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable affected women to have a genetically related child with a greatly reduced risk of mtDNA disease. Here we report the first preclinical studies on pronuclear transplantation (PNT). Surprisingly, techniques used in proof-of-concept studies involving abnormally fertilized human zygotes were not well tolerated by normally fertilized zygotes. We have therefore developed an alternative approach based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division. This promotes efficient development to the blastocyst stage with no detectable effect on aneuploidy or gene expression. After optimization, mtDNA carryover was reduced to <2% in the majority (79%) of PNT blastocysts. The importance of reducing carryover to the lowest possible levels is highlighted by a progressive increase in heteroplasmy in a stem cell line derived from a PNT blastocyst with 4% mtDNA carryover. We conclude that PNT has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention.