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Background Neonates with suspected sepsis are commonly treated with gentamicin, an aminoglycoside. These antibiotics are associated with high risk of ototoxicity, including profound bilateral deafness, in people with the m.1555A>G mitochondrial genetic variant. Objective This early value assessment summarised and critically assessed the clinical effectiveness and cost-effectiveness of the Genedrive MT-RNR1 ID Kit for identifying the gene m.1555A>G variant in neonates and mothers of neonates needing antibiotics or anticipated to need antibiotics. Following feedback from the scoping workshop and specialist assessment subgroup meeting, we also considered the Genedrive MT-RNR1 ID Kit for identifying the m.1555A>G variant in mothers prior to giving birth. Data sources For clinical effectiveness, we searched three major databases in October 2022: MEDLINE, EMBASE and CINAHL (Cumulative Index to Nursing and Allied Health Literature). For cost-effectiveness, in addition to the three mentioned databases we searched Cochrane and RePEc-IDEAS. Study selection Study selection and risk-of-bias assessment were conducted by two independent reviewers (Ryan PW Kenny and Akvile Stoniute for clinical effectiveness and Hosein Shabaninejad and Tomos Robinson for cost-effectiveness). Any differences were resolved through discussion, or by a third reviewer (Nick Meader). Study appraisal Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. One study (n = 751 neonates recruited) was included in the clinical effectiveness review and no studies were included in the cost-effectiveness review. All except one outcome (test failure rate: low risk of bias) were rated as being at moderate risk of bias. The study reported accuracy of the test (sensitivity 100%, 95% confidence interval 29.2% to 100%; specificity 99.2%, 95% confidence interval 98% to 99.7%), number of neonates successfully tested (n = 424/526 admissions), test failure rate (17.1%, although this was reduced to 5.7%), impact on antibiotic use (all those with a m.1555A>G genotype avoided aminoglycosides), time taken to obtain a sample (6 minutes), time to genotyping (26 minutes), time to antibiotic treatment (55.18 minutes) and the number of neonates with m.1555A>G (n = 3). Limitations The economic component of this work identified key evidence gaps for which further data are required before a robust economic evaluation can be conducted. These include the sensitivity of the Genedrive MT-RNR1 ID Kit for identifying the gene m.1555A>G variant in neonates, the magnitude of risk for aminoglycoside-induced hearing loss in neonates with m.1555A>G, and the prevalence of the m.1555A>G variant. Other potentially important gaps include how data regarding maternal inheritance may potentially be used in the clinical pathway. Conclusions This early value assessment suggests that the Genedrive MT-RNR1 ID Kit has the potential to identify the m.1555A>G variant and to be cost-effective. The Genedrive MT-RNR1 ID Kit dominates the current standard of care over the lifetime, as it is less costly and more effective. For a 50-year time horizon, the Genedrive MT-RNR1 ID Kit was also the dominant strategy. For a 10-year time horizon, the incremental cost-effectiveness ratio was estimated to be £103 per quality-adjusted life-year gained. Nevertheless, as anticipated, there is insufficient evidence to conduct a full diagnostic assessment of the clinical effectiveness and cost-effectiveness of the Genedrive MT-RNR1 ID Kit in neonates directly or in their mothers. This report includes a list of research priorities to reduce the uncertainty around this early value assessment and to provide the additional data needed to inform a full diagnostic assessment, including cost-effectiveness modelling. Study registration This study is registered as PROSPERO (CRD42022364770). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135636) and is published in full in Health Technology Assessment; Vol. 28, No. 75. See the NIHR Funding and Awards website for further award information. Plain language summary Our immune system usually fights off invading germs, such as bacteria, viruses, fungi or parasites, in order to prevent infection. Sometimes the immune system stops fighting the ‘invaders’ and begins to turn in on itself. This life-threatening reaction is known as sepsis. Bacterial infections and sepsis are significant causes of death and illness in newborns. Newborns with suspected bacterial infection or sepsis are normally treated with an aminoglycoside antibiotic called gentamicin (a type of medicine that is meant to kill bacteria). These antibiotics are associated with a very high risk of ototoxicity (damage to the ear, including deafness) among people with the m.1555A>G MT-RNR1 gene variant [a specific change to the small section of deoxyribonucleic acid storing biological information] within their mitochondrial deoxyribonucleic acid (small circles of deoxyribonucleic acid located in the mitochondria, the cell’s energy producer). The aim of this review was to summarise and critically evaluate existing evidence on how effective (the degree to which a test does more harm than good) and cost-effective (how effective a test is in relation to its cost) the Genedrive MT-RNR1 ID Kit is for identifying the m.1555A>G gene variant in newborns or in their mothers. We collected and analysed all relevant research studies, one moderate quality study was included in the clinical effectiveness review and no studies were included in the cost-effectiveness review. The quality of the included study was assessed as moderate for most of the outcomes (things measured to monitor the degree to which the test does more good than harm) reported due to uncertainty regarding the failure rate of the test. The results suggested that the test was capable of identifying newborns with the m.1555A>G variant. This was accomplished by successfully testing 424 out of 526 patients, with three newborns identified as carrying the gene and avoiding aminoglycoside treatment. Because of these small numbers, there does remain some uncertainty regarding the accuracy of the test. Additionally, time to antibiotic administration was not negatively impacted by the test. Similar time for treatment initiation was taken for those tested as for those not tested. This review shows that the Genedrive MT-RNR1 ID Kit has the potential to identify the m.1555A>G variant and the potential to provide value for money for the National Health Service. However, as expected, there is not enough evidence to conduct a full assessment of the clinical effectiveness and cost-effectiveness of Genedrive MT-RNR1 ID Kit in newborns directly, or their mothers. This could be addressed by generating further evidence. The risk and severity of hearing loss from aminoglycoside use is of particular interest, as is further testing of the Genedrive MT-RNR1 ID Kit in both neonates and mothers or neonates who need treatment. Such testing conducted in other settings would be of great importance. Scientific summary Background Sepsis and bacterial infections are a significant cause of mortality and morbidity in neonates (up to and including a corrected gestational age of 28 days). Expert opinion suggests that the incidence of culture-confirmed neonatal infection is around 1 in 2000 deliveries. But a larger proportion of babies will go on to receive precautionary antibiotic treatment for suspected infection [e.g. 30–60 in 1000 for those admitted to neonatal intensive care units (NICUs)]. Treatment for suspected infection or sepsis is commonly conducted using gentamicin, an antibiotic of the aminoglycoside family. This antibiotic is associated with a high risk of ototoxicity in those with a genetic variation of the mitochondrial MT-RNR1 gene, specifically m.1555A>G. The purpose of this assessment was to investigate the use of the Genedrive MT-RNR1 ID Kit for identifying the m.1555A>G variant in neonates with suspected infection or sepsis. This technology has the potential to identify those at most risk of ototoxicity from aminoglycoside antibiotics and inform treatment decisions within the time frame recommended by National Institute for Health and Care Excellence (NICE) guidance. Aim The overall aim of this early value assessment was to summarise and critically appraise existing evidence on the clinical effectiveness and cost-effectiveness of the Genedrive MT-RNR1 ID Kit for identifying the m.1555A>G gene variant in neonates or their mothers. Methods A rapid review methodology was used to identify eligible studies for clinical effectiveness and cost-effectiveness. Databases searches were conducted on MEDLINE, EMBASE and CINAHL (Cumulative Index to Nursing and Allied Health Literature) for both aspects of the review; additionally, the cost-effectiveness review searched Cochrane and RePEc-IDEAS from 2010 to November 2022. Search results were screened by two independent reviewers. Only one study met the inclusion criteria for the clinical effectiveness rapid review, and no studies met the eligibility criteria for the cost-effectiveness rapid review. Data extraction and quality appraisal of the clinical effectiveness study were completed by one reviewer and checked for accuracy by another. Quality appraisal was conducted per outcome, the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool was used to assess diagnostic test accuracy outcomes, and the ROBINS-I (Risk Of Bias In Non-randomized Studies – of Interventions) tool was used for all other outcomes. Meta-analyses were not possible as only one study was included in the clinical effectiveness rapid review. Care pathways with and without the use of the Genedrive MT-RNR1 ID Kit were developed and from these a conceptual economic evaluation model was developed. This was used to identify the information required to parameterise the model. Attempts were then made to identify relevant parameter values and evidence gaps where no or few data were identified. Using available information, an early health economic model was developed to provide initial estimates of the incremental cost per quality-adjusted life-year (QALY) gained for the comparison of the use of Genedrive MT-RNR1 ID Kit with current standard care. Results The evidence to inform this early value assessment was extremely limited. Only one study was included in the clinical effectiveness rapid review, for which risk of bias was rated as being moderate for most of the outcomes measured. The included study suggested high diagnostic test accuracy (sensitivity 100%, specificity 99.2%). Estimates of sensitivity were very uncertain due to a small number of true-positive cases (i.e. people with the m.1555A>G variant), but no false negatives were identified. However, there were some false positives (n = 5 of 8), and the specificity estimate was very high with sufficient precision. This was established from 424 successful tests, with a test failure rate of 17.1% (90 patients). The failure rate was reduced to 5.1% in repeated testing of samples after modifications were made to the assay buffer and the test cartridge was redesigned. Overall, three neonates were identified with the genetic variant. The trial research team were able to genotype the m.1555A>G variant using the Genedrive MT-RNR1 ID Kit in 26 minutes. Time to antibiotics when using the Genedrive MT-RNR1 ID Kit did not differ from normal practice (i.e. not using the test kit). Difference between groups was not statistically significant (mean difference –0.87 minutes, 95% confidence interval –5.96 to 4.23 minutes) and the 95% confidence interval was within the predefined boundary for statistical equivalence. We did not identify any studies that reported on the following intermediate, clinical or patient-related outcomes: impact of test implementation and use on healthcare resources, usability of the test, mortality and morbidity. Additionally, no studies assessed the use of the point-of-care test in mothers. No relevant economic evaluations were identified. From the conceptual economic model, key evidence gaps were identified. These include the sensitivity of the Genedrive MT-RNR1 ID Kit for identifying the m.1555A>G gene variant in neonates, the magnitude of risk for aminoglycoside-induced hearing loss (AIHL) in neonates and mothers with m.1555A>G, and the prevalence of the gene m.1555A>G variant. Other potential important gaps include how data regarding maternal inheritance may potentially be used in the clinical pathway. The early health economic model focused on some of those parameters where, on consideration of the available data, the estimates of cost-effectiveness would be most sensitive to changes. The results of this model showed that the use of the Genedrive MT-RNR1 ID Kit for identification of the m.1555A>G genetic variant could potentially be cost-effective, with lower costs (£58.48) and higher effectiveness in terms of QALYs (0.01) over the patient lifetime. In a deterministic sensitivity analysis, the results were shown to be most sensitive to changes in the time horizon, the sensitivity of the Genedrive MT-RNR1 ID Kit system, the proportion of neonates with m.1555A>G variant suffering from AIHL after being exposed to aminoglycosides and the prevalence of the m.1555A>G variant in the UK population. Conclusions There is limited evidence for the assessment of the Genedrive MT-RNR1 ID Kit for identification of the m.1555A>G genetic variant. The test was conducted in two large NICUs and thus may not be generalisable to smaller NICUs or other hospitals. Therefore, the use of the Genedrive MT-RNR1 Kit should be investigated further in varying settings. Furthermore, although modifications were made to the kit to reduce its failure rate, when it was used in the clinical setting this was not completely eradicated. However, there is evidence to suggest that the use of the kit did not substantially impact on time to antibiotics and has the potential to identify the m.1555A>G variant. There were no existing economic evaluations that addressed this topic. The total cost per test to the NHS was estimated to be £130; however, there is uncertainty surrounding this estimate given that this cost is likely to vary by size and type of site. The results of the early economic evaluation model suggest that the use of the Genedrive MT-RNR1 ID Kit to identify the m.1555A>G genetic variant could potentially be cost-effective. Once evidence regarding the reported evidence gaps has been identified, a full diagnostic assessment should be undertaken to establish the cost-effectiveness of the Genedrive MT-RNR1 ID Kit. Suggested priorities for further research This report identifies two key priorities for research required to reduce the uncertainty around this early value assessment and to provide the additional data needed to inform a full diagnostic assessment, including cost-effectiveness modelling. The risk and the severity of AIHL in neonates with the m.1555A>G variant was identified as key uncertainties in the economic model. Limitations of the current literature, which is primarily based on case–control studies in hearing-impaired populations with the m.1555A>G variant, are provided in more detail below. Future studies, perhaps including existing cohorts in the UK, are required to identify sufficient numbers of people with the m.1555A>G variant who have been exposed to aminoglycosides in a sample that includes participants with and participants without hearing impairment. A second priority for research is further validation of the Genedrive MT-RNR1 ID Kit in both neonates and mothers of neonates who need or may need aminoglycoside treatment. The sensitivity of the test was an important uncertainty in the economic model. Further studies including more people with the m.1555A>G variant will increase the precision of the estimated sensitivity of the test. In addition, only the pharmacogenetics to avoid loss of hearing (PALOH) study has investigated the validity of the Genedrive MT-RNR1 ID Kit. This study was conducted in two large NICUs, and further research is needed to assess if the findings of the PALOH study generalise to smaller NICUs and other relevant hospital settings. In addition, our focus group with parents and a review of parents’ comments on internet forums identified that further work may be required to obtain informed consent. A final area for further research is to provide updated and more comprehensive estimates of health state utility values. Data that are currently available are restricted in terms of health states considered or use health-related quality-of-life tools whose relevance to UK decision-makers may be limited. Study registration This study is registered as PROSPERO (CRD42022364770). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135636) and is published in full in Health Technology Assessment; Vol. 28, No. 75. See the NIHR Funding and Awards website for further award information.

Background: To inform radiofrequency electromagnetic field (RF-EMF) exposure guidelines the World Health Organization (WHO) is bringing together evidence on RF-EMF in relation to health outcomes prioritised for evaluation by experts in this field. Given this, a network of topic experts and methodologists have conducted a series of systematic reviews collecting, assessing, and synthesising data of relevance to these guidelines. Here we present a systematic review of the effect of RF-EMF exposure on adverse pregnancy outcomes in human observational studies which follows the WHO handbook for guideline development and the COSTER conduct guidelines. Methods: We conducted a broad, sensitive search for potentially relevant records within the following bibliographic databases: MEDLINE; Embase; and the EMF Portal. Grey literature searches were also conducted through relevant databases (including OpenGrey), organisational websites and via consultation of RF-EMF experts. We included quantitative human observational studies on the effect of RF-EMF exposure in adults’ preconception or pregnant women on pre-term birth, small for gestational age (SGA; associated with intrauterine growth restriction), miscarriage, stillbirth, low birth weight (LBW) and congenital anomalies. In blinded duplicate, titles and abstracts then full texts were screened against eligibility criteria. A third reviewer gave input when consensus was not reached. Citation chaining of included studies was completed. Two reviewers’ data extracted and assessed included studies for risk of bias using the Office of Health Assessment and Translation (OHAT) tool. Random effects meta-analyses of the highest versus the lowest exposures and dose–response meta-analysis were conducted as appropriate and plausible. Two reviewers assessed the certainty in each body of evidence using the OHAT GRADE tool. Results: We identified 18 studies in this review; eight were general public studies (with the general public as the population of interest) and 10 were occupational studies (with the population of interest specific workers/workforces).General public studies.From pairwise meta-analyses of general public studies, the evidence is very uncertain about the effects of RF-EMF from mobile phone exposure on preterm birth risk (relative risk (RR) 1.14, 95% confidence interval (CI): 0.97–1.34, 95% prediction interval (PI): 0.83–1.57; 4 studies), LBW (RR 1.14, 95% CI: 0.96–1.36, 95% PI: 0.84–1.57; 4 studies) or SGA (RR 1.13, 95% CI: 1.02–1.24, 95% PI: 0.99–1.28; 2 studies) due to very low-certainty evidence. It was not feasible to meta-analyse studies reporting on the effect of RF-EMF from mobile phone exposure on congenital anomalies or miscarriage risk. The reported effects from the studies assessing these outcomes varied and the studies were at some risk of bias. No studies of the general public assessed the impact of RF-EMF exposure on stillbirth.Occupational studies.In occupational studies, based on dose–response meta-analyses, the evidence is very uncertain about the effects of RF-EMF amongst female physiotherapists using shortwave diathermy on miscarriage due to very low-certainty evidence (OR 1.02 95% CI 0.94–1.1; 2 studies). Amongst offspring of female physiotherapists using shortwave diathermy, the evidence is very uncertain about the effects of RF-EMF on the risk of congenital malformations due to very low-certainty evidence (OR 1.4, 95% CI 0.85 to 2.32; 2 studies). From pairwise meta-analyses, the evidence is very uncertain about the effects of RF-EMF on the risk of miscarriage (RR 1.06, 95% CI 0.96 to 1.18; very low-certainty evidence), pre-term births (RR 1.19, 95% CI 0.32 to 4.37; 3 studies; very low-certainty evidence), and low birth weight (RR 2.90, 95% CI: 0.69 to 12.23; 3 studies; very low-certainty evidence). Results for stillbirth and SGA could not be pooled in meta-analyses. The results from the studies reporting these outcomes were inconsistent and the studies were at some risk of bias. Discussion: Most of the evidence identified in this review was from general public studies assessing localised RF-EMF exposure from mobile phone use on female reproductive outcomes. In occupational settings, each study was of heterogenous whole-body RF-EMF exposure from radar, short or microwave diathermy, surveillance and welding equipment and its effect on female reproductive outcomes. Overall, the body of evidence is very uncertain about the effect of RF-EMF exposure on female reproductive outcomes.Further prospective studies conducted with greater rigour (particularly improved accuracy of exposure measurement and using appropriate statistical methods) are required to identify any potential effects of RF-EMF exposure on female reproductive outcomes of interest.

Background: The World Health Organization (WHO) is bringing together evidence on radiofrequency electromagnetic field (RF-EMF) exposure in relation to health outcomes, previously identified as priorities for research and evaluation by experts in the field, to inform exposure guidelines. A suite of systematic reviews have been undertaken by a network of topic experts and methodologists to collect, assess and synthesise data relevant to these guidelines. Following the WHO handbook for guideline development and the COSTER conduct guidelines, we systematically reviewed the evidence on the potential effects of RF-EMF exposure on male fertility in human observational studies. Methods: We conducted a broad and sensitive search for potentially relevant records within the following bibliographic databases: MEDLINE; Embase; Web of Science and EMF Portal. We also conducted searches of grey literature through relevant databases including OpenGrey, and organisational websites and consulted RF-EMF experts. We hand searched reference lists of included study records and for citations of these studies. We included quantitative human observational studies on the effect of RF-EMF exposure in adult male participants on infertility: sperm concentration; sperm morphology; sperm total motility; sperm progressive motility; total sperm count; and time to pregnancy. Titles and abstracts followed by full texts were screened in blinded duplicate against pre-set eligibility criteria with consensus input from a third reviewer as required. Data extraction from included studies was completed by two reviewers, as was risk of bias assessment using the Office of Health Assessment and Translation (OHAT) tool. We conducted a dose–response meta-analysis as possible and appropriate. Certainty of the evidence was assessed by two reviewers using the OHAT GRADE tool with input from a third reviewer as required. Results: We identified nine studies in this review; seven were general public studies (with the general public as the population of interest) and two were occupational studies (with specific workers/workforces as the population of interest).General public studies.Duration of phone use: The evidence is very uncertain surrounding the effects of RF-EMF on sperm concentration (10/6 mL) (MD (mean difference) per hour of daily phone use 1.6 106/mL, 95 % CI −1.7 to 4.9; 3 studies), sperm morphology (MD 0.15 percentage points of deviation of normal forms per hour, 95 % CI −0.21 to 0.51; 3 studies), sperm progressive motility (MD −0.46 percentage points per hour, 95 % CI −1.04 to 0.13; 2 studies) and total sperm count (MD per hour −0.44 106/ejaculate, 95 % CI −2.59 to 1.7; 2 studies) due to very low-certainty evidence. Four additional studies reported on the effect of mobile phone use on sperm motility but were unsuitable for pooling; only one of these studies identified a statistically significant effect. All four studies were at risk of exposure characterisation and selection bias; two of confounding, selective reporting and attrition bias; three of outcome assessment bias and one used an inappropriate statistical method.Position of phone: There may be no or little effect of carrying a mobile phone in the front pocket on sperm concentration, total count, morphology, progressive motility or on time to pregnancy.Of three studies reporting on the effect of mobile phone location on sperm total motility and, or, total motile count, one showed a statistically significant effect. All three studies were at risk of exposure characterisation and selection bias; two of confounding, selective reporting and attrition bias; three of outcome assessment bias and one used inappropriate statistical method.RF-EMF Source: One study indicates there may be little or no effect of computer or other electric device use on sperm concentration, total motility or total count. This study is at probably high risk of exposure characterisation bias and outcome assessment bias.Occupational studies.With only two studies of occupational exposure to RF-EMF and heterogeneity in the population and exposure source (technicians exposed to microwaves or seamen exposed to radar equipment), it was not plausible to statistically pool findings. One study was at probably or definitely high risk of bias across all domains, the other across domains for exposure characterisation bias, outcome assessment bias and confounding. Discussion: The majority of evidence identified was assessing localised RF-EMF exposure from mobile phone use on male fertility with few studies assessing the impact of phone position. Overall, the evidence identified is very uncertain about the effect of RF-EMF exposure from mobile phones on sperm outcomes. One study assessed the impact of other RF-EMF sources on male fertility amongst the general public and two studies assessed the impact of RF-EMF exposure in occupational cohorts from different sources (radar or microwave) on male fertility.Further prospective studies conducted with greater rigour (in particular, improved accuracy of exposure measurement and appropriate statistical method use) would build the existing evidence base and are required to have greater certainty in any potential effects of RF-EMF on male reproductive outcomes. Prospero Registration: CRD42021265401 (SR3A)

Abstract Evidence and gap maps (EGMs) are an increasinly popular approach used in evidence synthesis. As an approach they address broad research questions, describing the existing evidence base, highlighting evidence gaps and providing an interactive visual tool for knowledge users. The purpose of this methodological study is to explore the the processes used in the development of EGM's and how they are reported. The aim is to better understand current practice and identify where clearer guidance is needed to support their production.

Abstract Introduction Patient and public involvement (PPI) is an expectation when conducting research, including Health Technology Assessment (HTA), but practical guidance for those wishing to embed PPI into the grant application process is not always easily accessible. We wanted to ensure that PPI was central when preparing a proposal for an investigator‐led evidence synthesis HTA investigating nonsurgical interventions for pelvic organ prolapse (POP) in women. Here, we describe our methods. Methods We recruited two patient co‐applicants separately through an open process to help ensure that patient voice was present within our proposal's management and direction. We invited co‐applicants to attend research team meetings and comment on the full proposal. We designed, recruited to and facilitated a scoping workshop, as well as undertook its subsequent evaluation. The insight shared within the workshop for patients with a lived experience of POP, including our patient co‐applicants, helped us develop the scope and rationale behind our HTA proposal. We particularly considered the interventions to include within the evidence synthesis. We also considered the outcome measures for both the evidence synthesis and economic evaluation. We elicited ideas about where and how results could be disseminated. Feedback suggested the workshop was as valuable for the attendees as it was for the researchers, making them feel valued and listened to. The time spent by researchers working on the activity was substantial and not directly funded but a necessary and valuable activity in developing our potential HTA. Our work was informed using the UK Standards for Public Involvement and the Authors and Consumers Together Impacting on eVidencE (ACTIVE) framework. Conclusions PPI can be enormously valuable in both developing and strengthening research proposals. However, further guidance is needed to help researchers recognise the level and type of involvement to use at this early stage, particularly given the large time investment needed to embed meaningful PPI. Patient and Public Contribution Women with a lived experience of POP were involved at every stage of the grant application process; their involvement is documented in full throughout this work.

BackgroundHealth technology innovation is increasingly supported by a bottom-up approach to priority setting, aiming to better reflect the concerns of its intended beneficiaries. Web-based forums provide parents with an outlet to share concerns, advice, and information related to parenting and the health and well-being of their children. They provide a rich source of data on parenting concerns and priorities that could inform future child health research and innovation. ObjectiveThe aim of the study is to identify common concerns expressed on 2 major web-based forums and cluster these to identify potential family health concern topics as indicative priority areas for future research and innovation. MethodsWe text-mined the r/Parenting subreddit (69,846 posts) and the parenting section of Mumsnet (99,848 posts) to create a large corpus of posts. A generative statistical model (latent Dirichlet allocation) was used to identify the most discussed topics in the corpus, and content analysis was applied to identify the parenting concerns found in a subset of posts. ResultsA model with 25 topics produced the highest coherence and a wide range of meaningful parenting concern topics. The most frequently expressed parenting concerns are related to their child’s sleep, self-care, eating (and food), behavior, childcare context, and the parental context including parental conflict. Topics directly associated with infants, such as potty training and bottle feeding, were more common on Mumsnet, while parental context and screen time were more common on r/Parenting. ConclusionsLatent Dirichlet allocation topic modeling can be applied to gain a rapid, yet meaningful overview of parent concerns expressed on a large and diverse set of social media posts and used to complement traditional insight gathering methods. Parents framed their concerns in terms of children’s everyday health concerns, generating topics that overlap significantly with established family health concern topics. We provide evidence of the range of family health concerns found at these sources and hope this can be used to generate material for use alongside traditional insight gathering methods.

Objectives To identify prognostic models for melanoma survival, recurrence and metastasis among American Joint Committee on Cancer stage I and II patients postsurgery; and evaluate model performance, including overall survival (OS) prediction.Design Systematic review and narrative synthesis.Data sources Searched MEDLINE, Embase, CINAHL, Cochrane Library, Science Citation Index and grey literature sources including cancer and guideline websites from 2000 to September 2021.Eligibility criteria Included studies on risk prediction models for stage I and II melanoma in adults ≥18 years. Outcomes included OS, recurrence, metastases and model performance. No language or country of publication restrictions were applied.Data extraction and synthesis Two pairs of reviewers independently screened studies, extracted data and assessed the risk of bias using the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies checklist and the Prediction study Risk of Bias Assessment Tool. Heterogeneous predictors prevented statistical synthesis.Results From 28 967 records, 15 studies reporting 20 models were included; 8 (stage I), 2 (stage II), 7 (stages I–II) and 7 (stages not reported), but were clearly applicable to early stages. Clinicopathological predictors per model ranged from 3–10. The most common were: ulceration, Breslow thickness/depth, sociodemographic status and site. Where reported, discriminatory values were ≥0.7. Calibration measures showed good matches between predicted and observed rates. None of the studies assessed clinical usefulness of the models. Risk of bias was high in eight models, unclear in nine and low in three. Seven models were internally and externally cross-validated, six models were externally validated and eight models were internally validated.Conclusions All models are effective in their predictive performance, however the low quality of the evidence raises concern as to whether current follow-up recommendations following surgical treatment is adequate. Future models should incorporate biomarkers for improved accuracy.PROSPERO registration number CRD42018086784.

Objective UK long-term care facility residents account for 185 000 emergency hospital admissions each year. Avoidance of unnecessary hospital transfers benefits residents, reduces demand on the healthcare systems but is difficult to implement. We synthesised evidence on interventions that influence unplanned hospital admissions or attendances by long-term care facility residents.Methods This is a systematic review of randomised controlled trials. PubMed, MEDLINE, EMBASE, ISI Web of Science, CINAHL and the Cochrane Library were searched from 2012 to 2022, building on a review published in 2013. We included randomised controlled trials that evaluated interventions that influence (decrease or increase) acute hospital admissions or attendances of long-term care facility residents. Risk of bias and evidence quality were assessed using Cochrane Risk Of Bias-2 and Grading of Recommendations Assessment, Development and Evaluation.Results Forty-three randomised studies were included in this review. A narrative synthesis was conducted and the weight of evidence described with vote counting. Advance care planning and goals of care setting appear to be effective at reducing hospitalisations from long-term care facilities. Other effective interventions, in order of increasing risk of bias, were: nurse practitioner/specialist input, palliative care intervention, influenza vaccination and enhancing access to intravenous therapies in long-term care facilities.Conclusions Factors that affect hospitalisation and emergency department attendances of long-term care facility residents are complex. This review supports the already established use of advance care planning and influenza vaccination to reduce unscheduled hospital attendances. It is likely that more than one intervention will be needed to impact on healthcare usage across the long-term care facility population. The findings of this review are useful to identify effective interventions that can be combined, as well as highlighting interventions that either need evaluation or are not effective at decreasing healthcare usage.PROSPERO registration number CRD42020169604.

Obstetric fistula is prevalent in low- and middle-income countries, with between 50,000 and 100,000 new cases each year. The World Health Organization aims to eradicate it by 2030 but a clear idea of the extant evidence is unavailable. This evidence map compiled evidence on treatments for obstetric fistula to identify potential knowledge gaps. The protocol for this work was published on the Open Science Framework (DOI: 10.17605/OSF.IO/H7J35). A survey was developed, piloted and distributed online through organisations with an interest in obstetric fistula and snowballing. Results informed the evidence map framework. Searches were run on MEDLINE, Embase, CENTRAL, Global Index Medicus and ScanMedicine on 16 February 2022 to identify potentially eligible systematic reviews, randomised controlled trials, cohort studies and case-control studies. Forward and backward citation chaining was undertaken on relevant systematic reviews and included studies. Studies were screened, coded and assessed for risk of bias by a single reviewer, with a second checking a proportion. The evidence map results were compared to survey results. Thirty-nine people responded to the survey, half of which were clinicians. Of 9796 records identified, 37 reports of 28 studies were included in the evidence map. Many included studies were at some risk of bias; for observational studies, this was predominantly due to lack of controlling for confounders. Most studies (71%) assessed surgical interventions alone. Reporting on other intervention types was limited. Regarding outcome measures most important to survey respondents, 24 studies reported on cure/improvement in obstetric fistula and 20 on cure/improvement in urinary incontinence. Reporting on quality of life, faecal incontinence and sexual function was limited. There is currently little robust evidence to guide patients and practitioners on the most effective treatment option for obstetric fistula. Further research is required to address evidence gaps identified.

BackgroundThere is need to consider the value of soft intelligence, leveraged using accessible natural language processing (NLP) tools, as a source of analyzed evidence to support public health research outputs and decision-making. ObjectiveThe aim of this study was to explore the value of soft intelligence analyzed using NLP. As a case study, we selected and used a commercially available NLP platform to identify, collect, and interrogate a large collection of UK tweets relating to mental health during the COVID-19 pandemic. MethodsA search strategy comprised of a list of terms related to mental health, COVID-19, and lockdown restrictions was developed to prospectively collate relevant tweets via Twitter’s advanced search application programming interface over a 24-week period. We deployed a readily and commercially available NLP platform to explore tweet frequency and sentiment across the United Kingdom and identify key topics of discussion. A series of keyword filters were used to clean the initial data retrieved and also set up to track specific mental health problems. All collated tweets were anonymized. ResultsWe identified and analyzed 286,902 tweets posted from UK user accounts from July 23, 2020 to January 6, 2021. The average sentiment score was 50%, suggesting overall neutral sentiment across all tweets over the study period. Major fluctuations in volume (between 12,622 and 51,340) and sentiment (between 25% and 49%) appeared to coincide with key changes to any local and/or national social distancing measures. Tweets around mental health were polarizing, discussed with both positive and negative sentiment. Key topics of consistent discussion over the study period included the impact of the pandemic on people’s mental health (both positively and negatively), fear and anxiety over lockdowns, and anger and mistrust toward the government. ConclusionsUsing an NLP platform, we were able to rapidly mine and analyze emerging health-related insights from UK tweets into how the pandemic may be impacting people’s mental health and well-being. This type of real-time analyzed evidence could act as a useful intelligence source that agencies, local leaders, and health care decision makers can potentially draw from, particularly during a health crisis.

Background: The World Health Organization (WHO) is bringing together evidence on radiofrequency electromagnetic field (RF-EMF) exposure in relation to health outcomes, previously identified as priorities for evaluation by experts in the field, to inform exposure guidelines. A suite of systematic reviews are being undertaken by a network of topic experts and methodologists in order to collect, assess and synthesise data relevant to these guidelines. Here, we present the protocol for the systematic review on the effect of exposure to RF on adverse reproductive outcomes (human observational studies), also referred to as Systematic Review (SR) 3 within the series of systematic reviews currently being commissioned. Objectives: Following the WHO handbook for guideline development and the COSTER conduct guidelines, we will systematically review the effect of RF-EMF exposure on both male fertility (SR3A) and adverse pregnancy outcomes (SR3B) in human observational studies. Herein we adhere to the PRISMA-P reporting guidelines. Data sources: We will conduct a broad search for potentially relevant records relevant for both reviews within the following bibliographic databases: MEDLINE; Embase; and EMF Portal. We will also conduct searches of grey literature through relevant databases and organisational websites. RF-EMF experts will also be consulted. We will hand search citation and reference lists of included study records. Study eligibility criteria: We will include quantitative human observational studies on the effect of RF-EMF exposure: (in SR3A) in adult male participants on infertility, sperm morphology, concentration or total sperm count or motility; and (in SR3B) in preconception adults or pregnant women on preterm birth, small for gestational age (associated with intrauterine growth restriction), miscarriage, stillbirth and congenital anomalies. Study appraisal and synthesis methods: Titles, abstracts and then full texts will be screened in blinded duplicate against eligibility criteria with input from a third reviewer as required. Data extraction from included studies will be completed by two reviewers as will risk of bias assessment using the Office of Health Assessment and Translation (OHAT) tool. If appropriate we will undertake meta-analysis to pool effect measures and explore heterogeneity using sub-group analyses or meta-regression as feasible. We will conduct sensitivity analysis to assess the impact of any assumptions made throughout the review process. The OHAT methodology, based on the GRADE guidelines for evidence assessment, will be used to evaluate the certainty of evidence per outcome and to conclude the level of evidence of a health effect. Conclusion: This manuscript details the protocols for two systematic reviews. The aims of publishing details of both protocols are to: pre-specify their scope and methods; reduce the impact of reviewer bias; promote transparency and replicability; and improve the review process. Prospero registration: CRD42021265401 (SR3A), CRD42021266268 (SR3B).

Physical activity (PA) levels are low in Gulf Cooperation Council countries (GCC; Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, United Arab Emirates). We carried out a systematic review (PROSPERO registration number 131817) to assess the effect of interventions to increase PA levels in this region. We also assessed their effects on anthropometry and cardiovascular risk. A systematic search of six databases (Medline, EMBASE, SPORTDiscus, CINAHL, Cochrane, Web of Science) was performed to identify randomized and non-randomized intervention studies performed in adults and children published between January 1985 and November 2020. We included studies published in English or Arabic, and included PA interventions regardless of setting, delivery, and duration. The primary outcomes were changes in PA duration and intensity. Secondary outcomes included anthropometric measures (e.g., weight, body mass index) and cardiovascular risk profiles (e.g., lipid measures, blood glucose). Two independent reviewers screened studies in accordance with pre-determined criteria, extracted data, assessed risk of bias (Cochrane Risk of Bias 2 and Newcastle Ottawa Scale) and undertook a narrative synthesis. From 13,026 records identified, 14 studies were included. Nine studies focussed exclusively on changing PA behaviour, resulting in statistically significant increases in step count ranging from an additional 757 steps/day (95% confidence interval [CI] 0–1,513) to 3,853 steps/day (95% CI 3,703–4,002). Five identified studies were multi-component lifestyle interventions, targeting people at higher risk (due to obesity or type 2 diabetes). Evidence for increases in PA from multi-component studies was limited, although improvements were seen in outcomes e.g. body weight and blood lipid levels. In conclusion, relatively few studies have focussed on changing PA behaviour, despite the urgent need in the GCC. Limited evidence suggested that pedometer-based programmes encouraging step counting and walking were effective in promoting PA, at least in the short term. Policies to roll out such interventions should be implemented and evaluated.

Introduction Prevalence of overweight, obesity and diabetes are high and rising across the Gulf Cooperation Council (GCC) countries (Oman, Bahrain, Kuwait, Qatar, Saudi Arabia and the United Arab Emirates). In parallel, physical activity (PA) levels are low relative to international standards. PA aids weight control and reduces risk of non-communicable diseases including diabetes and cardiovascular disease. It is likely interventions developed elsewhere will not translate to GCC countries due to unique environmental, social and cultural factors. This protocol is for a systematic review assessing the efficacy of interventions promoting PA within GCC countries among generally healthy adults and children. The primary outcome of interest is change in objectively measured or self-reported PA levels, the secondary outcomes of interest are changes in anthropometry or chronic disease risk factors (eg, blood pressure). Interventions will be compared with no intervention or those of differing PA intensity or duration. The relationships between PA change and the following will be assessed: intervention intensity or duration, season in which intervention occurs, sex, age, nationality and sustainability over time.Methods and analysis A systematic search strategy will identify indexed publications on the efficacy of interventions promoting PA. Randomised controlled trials and quasi-experimental studies recruiting predominantly healthy children and adults will be included. Studies of exercise rehabilitation will be excluded. Medline, Embase, Cinahl, Cochrane Library, SportDiscus, Web of Science, Index Medicus for the Eastern Mediterranean Region and Qscience will be searched. Clinical trial registries including the International Clinical Trials Registry Platform, the Iranian Registry of Clinical Trials and ClinicalTrials.gov will be searched for ongoing and unpublished studies. Searches will be ran from database inception until 1 May 2020 and be supplemented by checking references of key articles. Two reviewers will independently screen identified citations then full texts using prespecified inclusion and exclusion criteria. Piloted data extraction forms will be used in duplicate. Inconsistencies in screening or data extraction will be resolved by a third investigator or study author contact. Risk of bias will be independently assessed by two reviewers using validated tools. A narrative summary of findings will be produced supplemented with meta-analyses and exploration of heterogeneity as appropriate.Ethics and Dissemination The review aims to strengthen the findings of the primary studies it incorporates and explore the impact of setting. It will synthesise existing published aggregate patient data. If publications or data with ethical concerns are identified, they will be excluded from the review. Results of the systematic review will be published in full and authors will engage directly with research audiences and key stakeholders to share findings.PROSPERO registration number 131817.

Introduction The prevalence of diet-related non-communicable diseases (NCDs) are rapidly increasing in most parts of the world. In order to ameliorate the related public health burden, evidence-informed policies to improve diet need to be implemented. Financial subsidies that promote healthful consumption patterns have the potential to reduce NCD risk and may also reduce inequality if targeted at those of low socio-economic position. This protocol is for an updated systematic review of such evidence.Methods and analysis A systematic search strategy will be used to identify publications on fiscal intervention studies indexed in Embase, CINAHL, Web of Science, EconLit and PubMed in between January 2013 to February 2019. Two reviewers will independently sift identified citations using prespecified inclusion and exclusion criteria to inform full-text review. The outcomes of interest are: consumption patterns (% change in targeted items and in overall dietary patterns), purchasing patterns (% change) or body mass index. Pretested data capture forms will be used for double data extraction. Any inconsistencies in citation sifting or data extraction will be resolved by a third investigator and study authors will be contacted if needed. Systematic searches will be supplemented by reference checking of key articles. Study quality will be assessed and a narrative summary of findings will be produced. Meta-analyses and exploration of heterogeneity will be completed if appropriate.Ethics and dissemination The review aims to strengthen findings of the primary studies it incorporates. It will synthesise existing published aggregated patient data and only present further aggregate data. Given this, no concerns are held relating to confidentiality and informed consent due to re-use of patient data.If publications or data with ethical concerns are identified, they will be excluded from the review.Results of the systematic review will be published in full and authors will engage directly with research audiences and key stakeholders to share findings.PROSPERO registration number CRD42019125013

The burgeoning epidemic of diabetes mellitus (DM) is one of the major global health challenges. We systematically reviewed the published literature to provide a summary estimate of the association between DM and active tuberculosis (TB). We searched Medline and EMBASE databases for studies reporting adjusted estimates on the TB-DM association published before December 22, 2015, with no restrictions on region and language. In the meta-analysis, adjusted estimates were pooled using a DerSimonian-Laird random-effects model, according to study design. Risk of bias assessment and sensitivity analyses were conducted. 44 eligible studies were included, which consisted of 58,468,404 subjects from 16 countries. Compared with non-DM patients, DM patients had 3.59-fold (95% confidence interval (CI) 2.25-5.73), 1.55-fold (95% CI 1.39-1.72), and 2.09-fold (95% CI 1.71-2.55) increased risk of active TB in four prospective, 16 retrospective, and 17 case-control studies, respectively. Country income level (3.16-fold in low/middle-vs. 1.73-fold in high-income countries), background TB incidence (2.05-fold in countries with >50 vs. 1.89-fold in countries with ≤50 TB cases per 100,000 person-year), and geographical region (2.44-fold in Asia vs. 1.71-fold in Europe and 1.73-fold in USA/Canada) affected appreciably the estimated association, but potential risk of bias, type of population (general versus clinical), and potential for duplicate data, did not. Microbiological ascertainment for TB (3.03-fold) and/or blood testing for DM (3.10-fold), as well as uncontrolled DM (3.30-fold), resulted in stronger estimated association. DM is associated with a two- to four-fold increased risk of active TB. The association was stronger when ascertainment was based on biological testing rather than medical records or self-report. The burgeoning DM epidemic could impact upon the achievements of the WHO "End TB Strategy" for reducing TB incidence.