Acceptability of Using Real-World Data to Estimate Relative Treatment Effects in Health Technology Assessments: Barriers and Future Steps.

OBJECTIVES: Evidence about the comparative effects of new treatments is typically collected in randomized controlled trials (RCTs). In some instances, RCTs are not possible, or their value is limited by an inability to capture treatment effects over the longer term or in all relevant population subgroups. In these cases, nonrandomized studies (NRS) using real-world data (RWD) are increasingly used to complement trial evidence on treatment effects for health technology assessment (HTA). However, there have been concerns over a lack of acceptability of this evidence by HTA agencies. This article aims to identify the barriers to the acceptance of NRS and steps that may facilitate increases in the acceptability of NRS in the future. METHODS: Opinions of the authorship team based on their experience in real-world evidence research in academic, HTA, and industry settings, supported by a critical assessment of existing studies. RESULTS: Barriers were identified that are applicable to key stakeholder groups, including HTA agencies (eg, the lack of comprehensive methodological guidelines for using RWD), evidence generators (eg, avoidable deviations from best practices), and external stakeholders (eg, data controllers providing timely access to high-quality RWD). Future steps that may facilitate future acceptability of NRS include improvements in the quality, integration, and accessibility of RWD, wider use of demonstration projects to highlight the value and applicability of nonrandomized designs, living, and more detailed HTA guidelines, and improvements in HTA infrastructure relating to RWD. CONCLUSION: NRS can represent a crucial source of evidence on treatment effects for use in HTA when RCT evidence is limited.

Design of thiamine analogues for inhibition of thiamine diphosphate (ThDP)-dependent enzymes: Systematic investigation through Scaffold-Hopping and C2-Functionalisation.

Thiamine diphosphate (ThDP), the bioactive form of vitamin B1, is an essential coenzyme needed for processes of cellular metabolism in all organisms. ThDP-dependent enzymes all require ThDP as a coenzyme for catalytic activity, although individual enzymes vary significantly in substrate preferences and biochemical reactions. A popular way to study the role of these enzymes through chemical inhibition is to use thiamine/ThDP analogues, which typically feature a neutral aromatic ring in place of the positively charged thiazolium ring of ThDP. While ThDP analogues have aided work in understanding the structural and mechanistic aspects of the enzyme family, at least two key questions regarding the ligand design strategy remain unresolved: 1) which is the best aromatic ring? and 2) how can we achieve selectivity towards a given ThDP-dependent enzyme? In this work, we synthesise derivatives of these analogues covering all central aromatic rings used in the past decade and make a head-to-head comparison of all the compounds as inhibitors of several ThDP-dependent enzymes. Thus, we establish the relationship between the nature of the central ring and the inhibitory profile of these ThDP-competitive enzyme inhibitors. We also demonstrate that introducing a C2-substituent onto the central ring to explore the unique substrate-binding pocket can further improve both potency and selectivity.

The relative effects of non-pharmaceutical interventions on wave one Covid-19 mortality: natural experiment in 130 countries.

BACKGROUND: Non-pharmaceutical interventions have been implemented around the world to control Covid-19 transmission. Their general effect on reducing virus transmission is proven, but they can also be negative to mental health and economies, and transmission behaviours can also change voluntarily, without mandated interventions. Their relative impact on Covid-19 attributed mortality, enabling policy selection for maximal benefit with minimal disruption, is not well established due to a lack of definitive methods. METHODS: We examined variations in timing and strictness of nine non-pharmaceutical interventions implemented in 130 countries and recorded by the Oxford COVID-19 Government Response Tracker (OxCGRT): 1) School closing; 2) Workplace closing; 3) Cancelled public events; 4) Restrictions on gatherings; 5) Closing public transport; 6) Stay at home requirements ('Lockdown'); 7) Restrictions on internal movement; 8) International travel controls; 9) Public information campaigns. We used two time periods in the first wave of Covid-19, chosen to limit reverse causality, and fixed country policies to those implemented: i) prior to first Covid-19 death (when policymakers could not possibly be reacting to deaths in their own country); and, ii) 14-days-post first Covid-19 death (when deaths were still low, so reactive policymaking still likely to be minimal). We then examined associations with daily deaths per million in each subsequent 24-day period, which could only be affected by the intervention period, using linear and non-linear multivariable regression models. This method, therefore, exploited the known biological lag between virus transmission (which is what the policies can affect) and mortality for statistical inference. RESULTS: After adjusting, earlier and stricter school (- 1.23 daily deaths per million, 95% CI - 2.20 to - 0.27) and workplace closures (- 0.26, 95% CI - 0.46 to - 0.05) were associated with lower Covid-19 mortality rates. Other interventions were not significantly associated with differences in mortality rates across countries. Findings were robust across multiple statistical approaches. CONCLUSIONS: Focusing on 'compulsory', particularly school closing, not 'voluntary' reduction of social interactions with mandated interventions appears to have been the most effective strategy to mitigate early, wave one, Covid-19 mortality. Within 'compulsory' settings, such as schools and workplaces, less damaging interventions than closing might also be considered in future waves/epidemics.

Excess mortality for care home residents during the first 23 weeks of the COVID-19 pandemic in England: a national cohort study.

BACKGROUND: To estimate excess mortality for care home residents during the COVID-19 pandemic in England, exploring associations with care home characteristics. METHODS: Daily number of deaths in all residential and nursing homes in England notified to the Care Quality Commission (CQC) from 1 January 2017 to 7 August 2020. Care home-level data linked with CQC care home register to identify home characteristics: client type (over 65s/children and adults), ownership status (for-profit/not-for-profit; branded/independent) and size (small/medium/large). Excess deaths computed as the difference between observed and predicted deaths using local authority fixed-effect Poisson regressions on pre-pandemic data. Fixed-effect logistic regressions were used to model odds of experiencing COVID-19 suspected/confirmed deaths. RESULTS: Up to 7 August 2020, there were 29,542 (95% CI 25,176 to 33,908) excess deaths in all care homes. Excess deaths represented 6.5% (95% CI 5.5 to 7.4%) of all care home beds, higher in nursing (8.4%) than residential (4.6%) homes. 64.7% (95% CI 56.4 to 76.0%) of the excess deaths were confirmed/suspected COVID-19. Almost all excess deaths were recorded in the quarter (27.4%) of homes with any COVID-19 fatalities. The odds of experiencing COVID-19 attributable deaths were higher in homes providing nursing services (OR 1.8, 95% CI 1.6 to 2.0), to older people and/or with dementia (OR 5.5, 95% CI 4.4 to 6.8), amongst larger (vs. small) homes (OR 13.3, 95% CI 11.5 to 15.4) and belonging to a large provider/brand (OR 1.2, 95% CI 1.1 to 1.3). There was no significant association with for-profit status of providers. CONCLUSIONS: To limit excess mortality, policy should be targeted at care homes to minimise the risk of ingress of disease and limit subsequent transmission. Our findings provide specific characteristic targets for further research on mechanisms and policy priority.

The effects of unexpected changes in demand on the performance of emergency departments.

Crowding in emergency departments (EDs) is increasing in many health systems. Previous studies of the relationship between crowding and care quality are limited by the use of data from single hospitals, a focus on particular patient groups, a focus on a narrow set of quality measures, and use of crowding measures which induce bias from unobserved hospital and patient characteristics. Using data from 139 hospitals covering all major EDss in England, we measure crowding using quasi-exogenous variation in the volume of EDs attendances and examine its impacts on indicators of performance across the entire EDs care pathway. We exploit variations from expected volume estimated using high-dimensional fixed effects capturing hospital-specific variation in attendances by combinations of month and hour-of-the-week. Unexpected increases in attendance volume result in substantially longer waiting times, lower quantity and complexity of care, more patients choosing to leave without treatment, changes in referral and discharge decisions, but only small increases in reattendances and no increase in mortality. Causal bounds under potential omitted variable bias are narrow and exclude zero for the majority of outcomes. Results suggest that physician and patient responses may largely mitigate the impacts of demand increases on patient outcomes in the short-run.

Long-term effect of hospital pay for performance on mortality in England.

BACKGROUND: A pay-for-performance program based on the Hospital Quality Incentive Demonstration was introduced in all hospitals in the northwest region of England in 2008 and was associated with a short-term (18-month) reduction in mortality. We analyzed the long-term effects of this program, called Advancing Quality. METHODS: We analyzed 30-day in-hospital mortality among 1,825,518 hospital admissions for eight conditions, three of which were covered by the financial-incentive program. The hospitals studied included the 24 hospitals in the northwest region that were participating in the program and 137 elsewhere in England that were not participating. We used difference-in-differences regression analysis to compare risk-adjusted mortality for an 18-month period before the program was introduced with subsequent mortality in the short term (the first 18 months of the program) and the longer term (the next 24 months). RESULTS: Throughout the short-term and the long-term periods, the performance of hospitals in the incentive program continued to improve and mortality for the three conditions covered by the program continued to fall. However, the reduction in mortality among patients with these conditions was greater in the control hospitals (those not participating in the program) than in the hospitals that were participating in the program (by 0.7 percentage points; 95% confidence interval [CI], 0.3 to 1.2). By the end of the 42-month follow-up period, the reduced mortality in the participating hospitals was no longer significant (-0.1 percentage points; 95% CI, -0.6 to 0.3). From the short term to the longer term, the mortality for conditions not covered by the program fell more in the participating hospitals than in the control hospitals (by 1.2 percentage points; 95% CI, 0.4 to 2.0), raising the possibility of a positive spillover effect on care for conditions not covered by the program. CONCLUSIONS: Short-term relative reductions in mortality for conditions linked to financial incentives in hospitals participating in a pay-for-performance program in England were not maintained.

The use of the truth and deception in dementia care amongst general hospital staff.

OBJECTIVES: Deceptive practice has been shown to be endemic in long-term care settings. However, little is known about the use of deception in dementia care within general hospitals and staff attitudes towards this practice. This study aimed to develop understanding of the experiences of general hospital staff and explore their decision-making processes when choosing whether to tell the truth or deceive a patient with dementia. METHOD: This qualitative study drew upon a constructivist grounded theory approach to analyse data gathered from semi-structured interviews with a range of hospital staff. A model, grounded in participant experiences, was developed to describe their decision-making processes. FINDINGS: Participants identified particular triggers that set in motion the need for a response. Various mediating factors influenced how staff chose to respond to these triggers. Overall, hospital staff were reluctant to either tell the truth or to lie to patients. Instead, 'distracting' or 'passing the buck' to another member of staff were preferred strategies. The issue of how truth and deception are defined was identified. CONCLUSION: The study adds to the growing research regarding the use of lies in dementia care by considering the decision-making processes for staff in general hospitals. Various factors influence how staff choose to respond to patients with dementia and whether deception is used. Similarities and differences with long-term dementia care settings are discussed. Clinical and research implications include: opening up the topic for further debate, implementing staff training about communication and evaluating the impact of these processes.

The experience of caring for patients with dementia within a general hospital setting: a meta-synthesis of the qualitative literature.

OBJECTIVES: The optimal care of people with dementia in general hospitals has become a policy and practice imperative over recent years. However, despite this emphasis, the everyday experience of staff caring for this patient group is poorly understood. This review aimed to synthesise the findings from recent qualitative studies in this topic published prior to January 2014 to develop knowledge and provide a framework to help inform future training needs. METHOD: A systematic search of the literature was conducted across five academic databases and inclusion/exclusion criteria applied to the retrieved papers. A meta-ethnographic approach was utilised to synthesise the resulting 14 qualitative papers. RESULTS: Five key themes were constructed from the findings: overcoming uncertainty in care; constraints of the environmental and wider organisational context; inequality of care; recognising the benefits of person-centred care; and identifying the need for training. These themes explore the opportunities and challenges associated with caring for this group of patients, as well as suggestions to improve staff experiences and patient care. CONCLUSION: The synthesis highlighted a lack of knowledge and understanding of dementia within general hospital staff, particularly with regard to communication with patients and managing behaviours that are considered challenging. This limited understanding, coupled with organisational constraints on a busy hospital ward, contributed to low staff confidence, negative attitudes towards patients with dementia and an inability to provide person-centred care. The benefits of dementia training for both ward staff and hospital management and peer discussion/support for ward staff are discussed.

Examination of the Synthetic Control Method for Evaluating Health Policies with Multiple Treated Units.

This paper examines the synthetic control method in contrast to commonly used difference-in-differences (DiD) estimation, in the context of a re-evaluation of a pay-for-performance (P4P) initiative, the Advancing Quality scheme. The synthetic control method aims to estimate treatment effects by constructing a weighted combination of control units, which represents what the treated group would have experienced in the absence of receiving the treatment. While DiD estimation assumes that the effects of unobserved confounders are constant over time, the synthetic control method allows for these effects to change over time, by re-weighting the control group so that it has similar pre-intervention characteristics to the treated group. We extend the synthetic control approach to a setting of evaluation of a health policy where there are multiple treated units. We re-analyse a recent study evaluating the effects of a hospital P4P scheme on risk-adjusted hospital mortality. In contrast to the original DiD analysis, the synthetic control method reports that, for the incentivised conditions, the P4P scheme did not significantly reduce mortality and that there is a statistically significant increase in mortality for non-incentivised conditions. This result was robust to alternative specifications of the synthetic control method. © 2015 The Authors. Health Economics published by John Wiley & Sons Ltd.

Outbreak of campylobacteriosis associated with a long-distance obstacle adventure race--Nevada, October 2012.

On October 12, 2012, the Nellis Air Force Base Public Health Flight (Nellis Public Health), near Las Vegas, Nevada, was notified by the Mike O'Callaghan Federal Medical Center (MOFMC) emergency department (ED) of three active-duty military patients who went to the ED during October 10-12 with fever, vomiting, and hemorrhagic diarrhea. Initial interviews by clinical staff members indicated that all three patients had participated October 6-7 in a long-distance obstacle adventure race on a cattle ranch in Beatty, Nevada, in which competitors frequently fell face first into mud or had their heads submerged in surface water. An investigation by Nellis Public Health, coordinated with local and state health officials, identified 22 cases (18 probable and four confirmed) of Campylobacter coli infection among active-duty service members and civilians. A case-control study using data provided by patients and healthy persons who also had participated in the race showed a statistically significant association between inadvertent swallowing of muddy surface water during the race and Campylobacter infection (odds ratio = 19.4; p<0.001). Public health agencies and adventure race organizers should consider informing race attendees of the hazards of inadvertent ingestion of surface water.

Racial and Ethnic Disparities in Sports Medicine and the Importance of Diversity.

Within orthopedics surgery as a specialty, sports medicine is one of the least diverse surgical subspecialties. Differences in minority representation between patient and provider populations are thought to contribute to disparities in care, access, and outcomes.

Transporting Comparative Effectiveness Evidence Between Countries: Considerations for Health Technology Assessments.

Internal validity is often the primary concern for health technology assessment agencies when assessing comparative effectiveness evidence. However, the increasing use of real-world data from countries other than a health technology assessment agency's target population in effectiveness research has increased concerns over the external validity, or "transportability", of this evidence, and has led to a preference for local data. Methods have been developed to enable a lack of transportability to be addressed, for example by accounting for cross-country differences in disease characteristics, but their consideration in health technology assessments is limited. This may be because of limited knowledge of the methods and/or uncertainties in how best to utilise them within existing health technology assessment frameworks. This article aims to provide an introduction to transportability, including a summary of its assumptions and the methods available for identifying and adjusting for a lack of transportability, before discussing important considerations relating to their use in health technology assessment settings, including guidance on the identification of effect modifiers, guidance on the choice of target population, estimand, study sample and methods, and how evaluations of transportability can be integrated into health technology assessment submission and decision processes.

The impact of devolution on local health systems: Evidence from Greater Manchester, England.

Devolution and decentralisation policies involving health and other government sectors have been promoted with a view to improve efficiency and equity in local service provision. Evaluations of these reforms have focused on specific health or care measures, but little is known about their full impact on local health systems. We evaluated the impact of devolution in Greater Manchester (England) on multiple outcomes using a whole system approach. We estimated the impact of devolution until February 2020 on 98 measures of health system performance, using the generalised synthetic control method and adjusting for multiple hypothesis testing. We selected measures from existing monitoring frameworks to populate the WHO Health System Performance Assessment framework. The included measures captured information on health system functions, intermediatory objectives, final goals, and social determinants of health. We identified which indicators were targeted in response to devolution from an analysis of 170 health policy intervention documents. Life expectancy (0.233 years, S.E. 0.012) and healthy life expectancy (0.603 years, S.E. 0.391) increased more in GM than in the estimated synthetic control group following devolution. These increases were driven by improvements in public health, primary care, hospital, and adult social care services as well as factors associated with social determinants of health, including a reduction in alcohol-related admissions (-110.1 admission per 100,000, S.E. 9.07). In contrast, the impact on outpatient, mental health, maternity, and dental services was mixed. Devolution was associated with improved population health, driven by improvements in health services and wider social determinants of health. These changes occurred despite limited devolved powers over health service resources suggesting that other mechanisms played an important role, including the allocation of sustainability and transformation funding and the alignment of decision-making across health, social care, and wider public services in the region.

Evaluation of neuropsychological rehabilitation following severe traumatic brain injury: a case report.

This case study presents the evaluation of traumatic brain injury rehabilitation for Jane, a 35-year-old woman who sustained a severe traumatic brain injury (TBI). On-going rehabilitation addressed difficulties within a structured neuro-rehabilitative therapeutic milieu and was holistically evaluated. Results showed improvement in mood and quality of life and at the compensatory level for cognition. At the impairment level, many of the affected areas of cognition remained at least below predicted pre-morbid levels. This supports the view that although TBI impairments may be permanent, structured neuro-rehabilitation can be effective through external and compensatory aids. Recording this holistically contributes to evidencing this.

Evaluating whole system reforms: A structured approach for selecting multiple outcomes.

Whole-system reforms, including devolution and integration of health and social care services, have the potential to impact multiple dimensions of health system performance. Most evaluations focus on a single or narrow subsets of outcomes amenable to change. This approach may not: (i) capture the overall effect of the reform, (ii) identify the mechanisms through which system-wide changes may have occurred, (iii) prevent post-hoc selection of outcomes based on significant results; and (iv) facilitate comparisons across settings. We propose a structured approach for selecting multiple quantitative outcome measures, which we apply for evaluating health and social care devolution in Greater Manchester, England. The approach consists of five-steps: (i) defining outcome domains based on a framework, in our case the World Health Organisation's Health System Performance Assessment Framework; (ii) reviewing performance metrics from national monitoring frameworks; (iii) excluding similar and condition specific outcomes; (iv) excluding outcomes with insufficient data; and (v) mapping implemented policies to identify a subset of targeted outcomes. We identified 99 outcomes, of which 57 were targeted. The proposed approach is detail and time-intensive, but useful for both researchers and policymakers to promote transparency in evaluations and facilitate the interpretation of findings and cross-settings comparisons.

Pharmacokinetics and Proposed Dosing of Levetiracetam in Children With Obesity.

OBJECTIVE: Characterize levetiracetam pharmacokinetics (PK) in children with obesity to inform dosing. METHODS: Children 2 to <21 years old receiving standard of care oral levetiracetam across two opportunistic studies provided blood samples. Levetiracetam plasma PK data were analyzed with a nonlinear mixed-effects modeling approach. Indirect measures for body size and covariates were tested for model inclusion. Individual empirical Bayesian estimates using the final model parameters were compared by obesity status. Monte Carlo simulation using total body weight was performed in children with normal estimated glomerular filtration rate to identify dosing for children with obesity that resulted in comparable exposures to normal weight adults and children after receiving label dosing. RESULTS: The population PK model was developed from 341 plasma concentrations from 169 children. A 1-compartment model best fit the data with fat-free mass as a significant covariate. Compared with children with normal weight, children with obesity had significantly lower body weight-normalized clearance (median [range], 4.77 [1.49-10.44] and 3.71 [0.86-13.55] L/h/70 kg, respectively). After label dosing with the oral formulation in children with obesity 4 to <16 years old, maximum and minimum steady-state concentrations were higher (25% and 41%, respectively [oral solution] and 27% and 19%, respectively [tablet]) compared with children with normal weight. Comparable exposures between children with and without obesity were achieved with weight-tiered dosing regimens of <75 kg or ≥75 kg. CONCLUSIONS: Weight-tiered dosing for levetiracetam oral solution and tablets for children with obesity 4 to <16 years old results in more comparable exposures to children of normal weight.

Estimating the late-life effects of social and emotional skills in childhood using midlife mediators.

Social and emotional skills are known to affect health and non-health outcomes, but there is limited evidence on whether these skills in childhood affect late life outcomes because of a shortage of long-running datasets containing this information. We develop a three-stage procedure and use it to estimate the effect of childhood social and emotional skills on health and labour market outcomes in late-life. This procedure makes use of mediators in midlife which are shown to be predicted by childhood skills in one dataset and to predict late-life outcomes in another dataset. We use this method to combine estimates from the National Child Development Survey and the British Household Panel Survey. We find that childhood skills predict marital status, education, home ownership, income and health at age 46 years and these midlife variables predict levels of quality-adjusted life years and labour income accumulated by age 63 years. The combined estimates suggest a standard deviation increase in average Bristol Social Adjustment Guide total score at ages 7 and 11 is associated with 4.2% (standard error = 0.6%) additional quality-adjusted life years and more than 9.9% (£14,539, standard error = £2072) additional accumulated pre-tax earnings by age 63 years. Therefore, childhood interventions to increase social and emotional skills would be expected to reduce future healthcare costs and increase wealth. Our three-stage methodology can be used to predict the life-course effects of investments in childhood skills by combining results from datasets across population cohorts.

Socioeconomic inequality in access to timely and appropriate care in emergency departments.

In publicly-funded healthcare systems, waiting times for care should be based on need rather than ability to pay. Studies have shown that individuals with lower socioeconomic status face longer waits for planned inpatient care, but there is little evidence on inequalities in waiting times for emergency care. We study waiting times in emergency departments (EDs) following arrival by ambulance, where health consequences of extended waits may be severe. Using data from all major EDs in England during the 2016/17 financial year, we find patients from more deprived areas face longer waits during some parts of the ED care pathway. Inequalities in waits are small, but more deprived individuals also receive less complex ED care, are less likely to be admitted for inpatient care, and are more likely to re-attend ED or die shortly after attendance. Patient-physician interactions and unconscious bias towards more deprived patients may be important sources of inequalities.

The effect of devolution on health: a generalised synthetic control analysis of Greater Manchester, England.

BACKGROUND: The devolution of public services from central to local government can increase sensitivity to local population needs but might also reduce the expertise and resources available. Little evidence is available on the impact of devolution on population health. We evaluated the effect of devolution affecting health services and wider determinants of health on life expectancy in Greater Manchester, England. METHODS: We estimated changes in life expectancy in Greater Manchester relative to a control group from the rest of England (excluding London), using a generalised synthetic control method. Using local district-level data collected between Jan 1, 2006 and Dec 31, 2019, we estimated the effect of devolution on the whole population and stratified by sex, district, income deprivation, and baseline life expectancy. FINDINGS: After devolution, from November, 2014, life expectancy in Greater Manchester was 0·196 years (95% CI 0·182-0·210) higher than expected when compared with the synthetic control group with similar pre-devolution trends. Life expectancy was protected from the decline observed in comparable areas in the 2 years after devolution and increased in the longer term. Increases in life expectancy were observed in eight of ten local authorities, were larger among men than women (0·338 years [0·315-0·362] for men; 0·057 years [0·040-0·074] for women), and were larger in areas with high income deprivation (0·390 years [0·369-0·412]) and lower life expectancy before devolution (0·291 years [0·271-0·311]). INTERPRETATION: Greater Manchester had better life expectancy than expected after devolution. The benefits of devolution were apparent in the areas with the highest income deprivation and lowest life expectancy, suggesting a narrowing of inequalities. Improvements were likely to be due to a coordinated devolution across sectors, affecting wider determinants of health and the organisation of care services. FUNDING: The Health Foundation and the National Institute for Health and Care Research.

The effects of in-utero exposure to influenza on mental health and mortality risk throughout the life-course.

Studies examining the later-life health consequences of in-utero exposure to influenza have typically estimated effects on physical health conditions, with little evidence of effects on mental health outcomes or mortality. Previous studies have also relied primarily on reduced-form estimates of the effects of exposure to influenza pandemics, meaning they are unlikely to recover effects of influenza exposure at an individual-level. This paper uses inverse probability of treatment weighting and "doubly-robust" methods alongside rare mother-reported data on in-utero influenza exposure to estimate the individual-level effect of in-utero influenza exposure on mental health and mortality risk throughout childhood and adulthood. We find that in-utero exposure to influenza is associated with small reductions in mental health in mid-childhood, driven by increases in internalising symptoms, and increases in depressive symptoms in mid-life for males. There is also evidence that in-utero influenza exposure is associated with substantial increases in mortality, although these effects are primarily driven by a 75% increase in the probability of being stillborn, with limited evidence of additional survival disadvantages at later ages. The potential for mortality selection implies that estimated effects on mental health outcomes are likely to represent a lower bound.