Periodontitis and Outer Retinal Thickness: a Cross-Sectional Analysis of the United Kingdom Biobank Cohort.

Purpose: Periodontitis, a ubiquitous severe gum disease affecting the teeth and surrounding alveolar bone, can heighten systemic inflammation. We investigated the association between very severe periodontitis and early biomarkers of age-related macular degeneration (AMD), in individuals with no eye disease. Design: Cross-sectional analysis of the prospective community-based cohort United Kingdom (UK) Biobank. Participants: Sixty-seven thousand three hundred eleven UK residents aged 40 to 70 years recruited between 2006 and 2010 underwent retinal imaging. Methods: Macular-centered OCT images acquired at the baseline visit were segmented for retinal sublayer thicknesses. Very severe periodontitis was ascertained through a touchscreen questionnaire. Linear mixed effects regression modeled the association between very severe periodontitis and retinal sublayer thicknesses, adjusting for age, sex, ethnicity, socioeconomic status, alcohol consumption, smoking status, diabetes mellitus, hypertension, refractive error, and previous cataract surgery. Main Outcome Measures: Photoreceptor layer (PRL) and retinal pigment epithelium-Bruch's membrane (RPE-BM) thicknesses. Results: Among 36 897 participants included in the analysis, 1571 (4.3%) reported very severe periodontitis. Affected individuals were older, lived in areas of greater socioeconomic deprivation, and were more likely to be hypertensive, diabetic, and current smokers (all P < 0.001). On average, those with very severe periodontitis were hyperopic (0.05 ± 2.27 diopters) while those unaffected were myopic (-0.29 ± 2.40 diopters, P < 0.001). Following adjusted analysis, very severe periodontitis was associated with thinner PRL (-0.55 µm, 95% confidence interval [CI], -0.97 to -0.12; P = 0.022) but there was no difference in RPE-BM thickness (0.00 µm, 95% CI, -0.12 to 0.13; P = 0.97). The association between PRL thickness and very severe periodontitis was modified by age (P < 0.001). Stratifying individuals by age, thinner PRL was seen among those aged 60 to 69 years with disease (-1.19 µm, 95% CI, -1.85 to -0.53; P < 0.001) but not among those aged < 60 years. Conclusions: Among those with no known eye disease, very severe periodontitis is statistically associated with a thinner PRL, consistent with incipient AMD. Optimizing oral hygiene may hold additional relevance for people at risk of degenerative retinal disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Age-specific nasal epithelial responses to SARS-CoV-2 infection.

Children infected with SARS-CoV-2 rarely progress to respiratory failure. However, the risk of mortality in infected people over 85 years of age remains high. Here we investigate differences in the cellular landscape and function of paediatric (<12 years), adult (30-50 years) and older adult (>70 years) ex vivo cultured nasal epithelial cells in response to infection with SARS-CoV-2. We show that cell tropism of SARS-CoV-2, and expression of ACE2 and TMPRSS2 in nasal epithelial cell subtypes, differ between age groups. While ciliated cells are viral replication centres across all age groups, a distinct goblet inflammatory subtype emerges in infected paediatric cultures and shows high expression of interferon-stimulated genes and incomplete viral replication. In contrast, older adult cultures infected with SARS-CoV-2 show a proportional increase in basaloid-like cells, which facilitate viral spread and are associated with altered epithelial repair pathways. We confirm age-specific induction of these cell types by integrating data from in vivo COVID-19 studies and validate that our in vitro model recapitulates early epithelial responses to SARS-CoV-2 infection.

Distribution-free hyperrectangular tolerance regions for setting multivariate reference regions in laboratory medicine.

Reference regions are important in laboratory medicine to interpret the test results of patients, and usually given by tolerance regions. Tolerance regions of p ( ≥ 2 ) $$ p\;\left(\ge 2\right) $$ dimensions are highly desirable when the test results contains p $$ p $$ outcome measures. Nonparametric hyperrectangular tolerance regions are attractive in real problems due to their robustness with respect to the underlying distribution of the measurements and ease of intepretation, and methods to construct them have been recently provided by Young and Mathew [Stat Methods Med Res. 2020;29:3569-3585]. However, their validity is supported by a simulation study only. In this paper, nonparametric hyperrectangular tolerance regions are constructed by using Tukey's [Ann Math Stat. 1947;18:529-539; Ann Math Stat. 1948;19:30-39] elegant results of equivalence blocks. The validity of these new tolerance regions is proven mathematically in [Ann Math Stat. 1947;18:529-539; Ann Math Stat. 1948;19:30-39] under the only assumption that the underlying distribution of the measurements is continuous. The methodology is applied to analyze the kidney function problem considered in Young and Mathew [Stat Methods Med Res. 2020;29:3569-3585].

Rapid desensitization through immunoadsorption during cardiopulmonary bypass. A novel method to facilitate human leukocyte antigen incompatible heart transplantation.

BACKGROUND: Anti-human leukocyte antigen (HLA)-antibody production represents a major barrier to heart transplantation, limiting recipient compatibility with potential donors and increasing the risk of complications with poor waiting-list outcomes. Currently there is no consensus to when desensitization should take place, and through what mechanism, meaning that sensitized patients must wait for a compatible donor for many months, if not years. We aimed to determine if intraoperative immunoadsorption could provide a potential desensitization methodology. METHODS: Anti-HLA antibody-containing whole blood was added to a Cardiopulmonary bypass (CPB) circuit set up to mimic a 20 kg patient undergoing heart transplantation. Plasma was separated and diverted to a standalone, secondary immunoadsorption system, with antibody-depleted plasma returned to the CPB circuit. Samples for anti-HLA antibody definition were taken at baseline, when combined with the CPB prime (on bypass), and then every 20 min for the duration of treatment (total 180 min). RESULTS: A reduction in individual allele median fluorescence intensity (MFI) to below clinically relevant levels (<1000 MFI), and in the majority of cases below the lower positive detection limit (<500 MFI), even in alleles with a baseline MFI >4000 was demonstrated. Reduction occurred in all cases within 120 min, demonstrating efficacy in a time period usual for heart transplantation. Flowcytometric crossmatching of suitable pseudo-donor lymphocytes demonstrated a change from T cell and B cell positive channel shifts to negative, demonstrating a reduction in binding capacity. CONCLUSIONS: Intraoperative immunoadsorption in an ex vivo setting demonstrates clinically relevant reductions in anti-HLA antibodies within the normal timeframe for heart transplantation. This method represents a potential desensitization technique that could enable sensitized children to accept a donor organ earlier, even in the presence of donor-specific anti-HLA antibodies.

Seasonality of presentation and birth in catatonia.

BACKGROUND: Catatonia is a neuropsychiatric syndrome associated with both psychiatric disorders and medical conditions. Understanding of the pathophysiology of catatonia remains limited, and the role of the environment is unclear. Although seasonal variations have been shown for many of the disorders underlying catatonia, the seasonality of this syndrome has not yet been adequately explored. METHODS: Clinical records were screened to identify a cohort of patients suffering from catatonia and a control group of psychiatric inpatients, from 2007 to 2016 in South London. In a cohort study, the seasonality of presentation was explored fitting regression models with harmonic terms, while the effect of season of birth on subsequent development of catatonia was analyzed using regression models for count data. In a case-control study, the association between month of birth and catatonia was studied fitting logistic regression models. RESULTS: In total, 955 patients suffering from catatonia and 23,409 controls were included. The number of catatonic episodes increased during winter, with a peak in February. Similarly, an increasing number of cases was observed during summer, with a second peak in August. However, no evidence for an association between month of birth and catatonia was found. CONCLUSIONS: The presentation of catatonia showed seasonal variation in accordance with patterns described for many of the disorders underlying catatonia, such as mood disorders and infections. We found no evidence for an association between season of birth and risk of developing catatonia. This may imply that recent triggers may underpin catatonia, rather than distal events.

Determinants of non-attendance at face-to-face and telemedicine ophthalmic consultations.

BACKGROUND/AIMS: Evaluation of telemedicine care models has highlighted its potential for exacerbating healthcare inequalities. This study seeks to identify and characterise factors associated with non-attendance across face-to-face and telemedicine outpatient appointments. METHODS: A retrospective cohort study at a tertiary-level ophthalmic institution in the UK, between 1 January 2019 and 31 October 2021. Logistic regression modelled non-attendance against sociodemographic, clinical and operational exposure variables for all new patient registrations across five delivery modes: asynchronous, synchronous telephone, synchronous audiovisual and face to face prior to the pandemic and face to face during the pandemic. RESULTS: A total of 85 924 patients (median age 55 years, 54.4% female) were newly registered. Non-attendance differed significantly by delivery mode: (9.0% face to face prepandemic, 10.5% face to face during the pandemic, 11.7% asynchronous and 7.8%, synchronous during pandemic). Male sex, greater levels of deprivation, a previously cancelled appointment and not self-reporting ethnicity were strongly associated with non-attendance across all delivery modes. Individuals identifying as black ethnicity had worse attendance in synchronous audiovisual clinics (adjusted OR 4.24, 95% CI 1.59 to 11.28) but not asynchronous. Those not self-reporting their ethnicity were from more deprived backgrounds, had worse broadband access and had significantly higher non-attendance across all modes (all p<0.001). CONCLUSION: Persistent non-attendance among underserved populations attending telemedicine appointments highlights the challenge digital transformation faces for reducing healthcare inequalities. Implementation of new programmes should be accompanied by investigation into the differential health outcomes of vulnerable populations.

Neutrophil responses to RSV infection show differences between infant and adult neutrophils.

INTRODUCTION: Respiratory syncytial virus (RSV) causes a severe respiratory condition, bronchiolitis, in infants but not in adults. Bronchiolitis is characterised by neutrophilic infiltration in the airways, but whether neutrophils enhance recovery from infection or contribute to its pathology remains unknown. METHODS: We used a novel in-vitro model to compare term umbilical cord blood (infant) (n=17 donors) and adult neutrophils (n=15 donors) during migration across RSV-infected differentiated human nasal airway epithelial cells (AECs) in a basolateral to apical direction. RESULTS: Greater numbers of infant neutrophils (mean (95% CI)) (336 684 (242 352 to 431 015)) migrated across RSV-infected AECs to the apical compartment (equivalent to the airway lumen) compared with adult neutrophils (56 586 (24 954 to 88 218)) (p<0.0001). Having reached the apical compartment of infected AECs, much greater numbers of infant neutrophils (140 787 (103 117 to 178 456)) became apoptotic compared with adult (5853 (444 to 11 261)) (p=0.002). Infant neutrophils displayed much greater expression of CD11b, CD64, neutrophil elastase (NE) and myeloperoxidase (MPO) than adult neutrophils at baseline and at all points of migration. However, as adult neutrophils migrated, expression of CD11b, CD64, NE and MPO became greater than at baseline. DISCUSSION: The high proportion of infant neutrophils migrating across RSV-infected AECs correlates with the neutrophilic infiltrate seen in infants with severe RSV bronchiolitis, with large numbers undergoing apoptosis, which may represent a protective mechanism during infection. Compared with adult neutrophils, infant neutrophils already have high expression of surface markers before contact with AECs or migration, with less capacity to increase further in response to RSV infection or migration.

Salivary IgA and vimentin differentiate in vitro SARS-CoV-2 infection: A study of 290 convalescent COVID-19 patients.

SARS-CoV-2 initially infects cells in the nasopharynx and oral cavity. The immune system at these mucosal sites plays a crucial role in minimizing viral transmission and infection. To develop new strategies for preventing SARS-CoV-2 infection, this study aimed to identify proteins that protect against viral infection in saliva. We collected 551 saliva samples from 290 healthcare workers who had tested positive for COVID-19, before vaccination, between June and December 2020. The samples were categorized based on their ability to block or enhance infection using in vitro assays. Mass spectrometry and enzyme-linked immunosorbent assay experiments were used to identify and measure the abundance of proteins that specifically bind to SARS-CoV-2 antigens. Immunoglobulin (Ig)A specific to SARS-CoV-2 antigens was detectable in over 83% of the convalescent saliva samples. We found that concentrations of anti-receptor-binding domain IgA >500 pg/µg total protein in saliva correlate with reduced viral infectivity in vitro. However, there is a dissociation between the salivary IgA response to SARS-CoV-2, and systemic IgG titers in convalescent COVID-19 patients. Then, using an innovative technique known as spike-baited mass spectrometry, we identified novel spike-binding proteins in saliva, most notably vimentin, which correlated with increased viral infectivity in vitro and could serve as a therapeutic target against COVID-19.

Evaluating the Quantity and Quality of Health Economic Literature in Blinding Childhood Disorders: A Systematic Literature Review.

BACKGROUND: Evidence on the socioeconomic burden associated with childhood visual impairment, severe visual impairment and blindness (VI/SVI/BL) is needed to inform economic evaluations of existing and emerging interventions aimed at protecting or improving vision. This study aimed to evaluate the quantity and quality of literature on resource use and/or costs associated with childhood VI/SVI/BL disorders. METHODS: PubMed, Web of Science (Ovid), the National Health Service (NHS) Economic Evaluation Database and grey literature were searched in November 2020. The PubMed search was rerun in February 2022. Original articles reporting unique estimates of resource use or cost data on conditions resulting in bilateral VI/SVI/BL were eligible for data extraction. Quality assessment (QA) was undertaken using the Drummond checklist adapted for cost-of-illness (COI) studies. RESULTS: We identified 31 eligible articles, 27 from the peer-reviewed literature and four from the grey literature. Two reported on resource use, and 29 reported on costs. Cerebral visual impairment and optic nerve disorders were not examined in any included studies, whereas retinopathy of prematurity was the most frequently examined condition. The quality of studies varied, with economic evaluations having higher mean QA scores (82%) compared to COI studies (77%). Deficiencies in reporting were seen, particularly in the clinical definitions of conditions in economic evaluations and a lack of discounting and sensitivity analyses in COI studies. CONCLUSIONS: There is sparse literature on resource use or costs associated with childhood visual impairment disorders. The first step in addressing this important evidence gap is to ensure core visual impairment outcomes are measured in future randomised control trials of interventions as well as cohort studies and are reported as a discrete health outcome.

Global birth prevalence of Robin sequence in live-born infants: a systematic review and meta-analysis.

Robin sequence (RS), a congenital disorder of jaw maldevelopment and glossoptosis, poses a substantial healthcare burden and has long-term health implications if airway obstruction is suboptimally treated. This study describes the global birth prevalence of RS and investigates whether prevalence estimates differ by geographical location, ethnicity or study data source (registry versus non-registry data). The protocol was prospectively registered with PROSPERO.Databases were searched using keywords and subject terms for "Robin sequence", "epidemiology", "incidence" and "birth prevalence". Meta-analysis was performed fitting random effects models with arcsine transformation.From 34 eligible studies (n=2722 RS cases), pooled birth prevalence was 9.5 per 100 000 live births (95% CI 7.1-12.1) with statistical heterogeneity. One third of studies provided a case definition for RS and numerous definitions were used. A total of 22 countries were represented, predominantly from European populations (53% of studies). There was a trend towards higher birth prevalence in European populations and lower prevalence from registry-based studies. Only two studies reported ethnicity.This study indicates that RS occurs globally. To investigate geographical differences in prevalence, additional studies from non-European populations and reporting of ethnicity are needed. Heterogeneity of estimates may be due to variable diagnostic criteria and ascertainment methods. Recently published consensus diagnostic criteria may reduce heterogeneity among future studies.

Development and Pilot Implementation of Neotree, a Digital Quality Improvement Tool Designed to Improve Newborn Care and Survival in 3 Hospitals in Malawi and Zimbabwe: Cost Analysis Study.

Background: Two-thirds of the 2.4 million newborn deaths that occurred in 2020 within the first 28 days of life might have been avoided by implementing existing low-cost evidence-based interventions for all sick and small newborns. An open-source digital quality improvement tool (Neotree) combining data capture with education and clinical decision support is a promising solution for this implementation gap. Objective: We present results from a cost analysis of a pilot implementation of Neotree in 3 hospitals in Malawi and Zimbabwe. Methods: We combined activity-based costing and expenditure approaches to estimate the development and implementation cost of a Neotree pilot in 1 hospital in Malawi, Kamuzu Central Hospital (KCH), and 2 hospitals in Zimbabwe, Sally Mugabe Central Hospital (SMCH) and Chinhoyi Provincial Hospital (CPH). We estimated the costs from a provider perspective over 12 months. Data were collected through expenditure reports, monthly staff time-use surveys, and project staff interviews. Sensitivity and scenario analyses were conducted to assess the impact of uncertainties on the results or estimate potential costs at scale. A pilot time-motion survey was conducted at KCH and a comparable hospital where Neotree was not implemented. Results: Total cost of pilot implementation of Neotree at KCH, SMCH, and CPH was US $37,748, US $52,331, and US $41,764, respectively. Average monthly cost per admitted child was US $15, US $15, and US $58, respectively. Staff costs were the main cost component (average 73% of total costs, ranging from 63% to 79%). The results from the sensitivity analysis showed that uncertainty around the number of admissions had a significant impact on the costs in all hospitals. In Malawi, replacing monthly web hosting with a server also had a significant impact on the costs. Under routine (nonresearch) conditions and at scale, total costs are estimated to fall substantially, up to 76%, reducing cost per admitted child to as low as US $5 in KCH, US $4 in SMCH, and US $14 in CPH. Median time to admit a baby was 27 (IQR 20-40) minutes using Neotree (n=250) compared to 26 (IQR 21-30) minutes using paper-based systems (n=34), and the median time to discharge a baby was 9 (IQR 7-13) minutes for Neotree (n=246) compared to 3 (IQR 2-4) minutes for paper-based systems (n=50). Conclusions: Neotree is a time- and cost-efficient tool, comparable with the results from limited similar mHealth decision-support tools in low- and middle-income countries. Implementation costs of Neotree varied substantially between the hospitals, mainly due to hospital size. The implementation costs could be substantially reduced at scale due to economies of scale because of integration to the health systems and reductions in cost items such as staff and overhead. More studies assessing the impact and cost-effectiveness of large-scale mHealth decision-support tools are needed.

Individual, family, and environmental determinants of vision-related quality of life of children and young people with visual impairment.

Childhood visual impairment can have a significant impact on an individual's development. To improve clinical care and develop appropriate psychosocial interventions of these patients, it is necessary to understand the contributing and modifiable factors that both identify individuals in greater need and could be targeted in interventions. Here we investigate the broader individual, family, and environmental factors associated with vision-related quality of life (VQoL) of children and young people with visual impairment (CYP-VI). Data for this cross-sectional study were collected from September 2014 to May 2017 to develop and validate two vision-specific patient-reported outcome measures (PROMs) for CYP-VI. Patients were recruited from 22 hospitals in the United Kingdom and were aged 7-18 years with visual impairment as per WHO criteria. Participants self-completed the two PROMs, VQoL and Functional Vision Questionnaires. Clinical characteristics were extracted from medical records. Their carers provided information on family sociodemographic backgrounds. Associations between the VQoL scores and other factors were examined using Spearman's correlation, Kruskal-Wallis, Wilcoxon rank-sum tests, and quantile regression models. The sample consisted of 152 CYP-VI (67 females). Better VQoL was significantly associated with better functional vision overall (rSpearman = -0.52), parent-reported absence of additional chronic conditions (dCohen = 0.46), attending mainstream (versus other) school (dCohen = 0.44), higher socio-economic status (rSpearman = 0.17) and higher parental education level (rSpearman = 0.20). No other investigated factors were significantly associated with VQoL. The final quantile regression model included functional vision scores and the presence of additional health condition. Variation in self-reported VQoL in CYP-VI can be partly accounted for by factors relating to the clinical status of the affected child and, more importantly, by non-health-related factors. This needs to be considered in clinical practice when assessing vision-specific outcomes and providing support to CYP-VI, as well as in the development of future interventions.

Trends in the long-term impact of childhood visual impairment on health and social outcomes in the UK: a cross-cohort study across three decades of disability-related legislation and policy implementation.

BACKGROUND: Childhood vision impairment (VI) can adversely impact health and social outcomes and limit life chances. We investigated whether its adverse impacts into adult life changed during a period in which legislation, policy and services to address inequalities relating to disability were implemented. METHODS: Cross-cohort study comprising 14 247 participants from the 1946, 1958 and 1970 British birth cohorts (BC). Participants dichotomized as VI at age 15/16 (distance visual acuity was 6/12 or worse in the better-seeing eye) or normally sighted. Associations of childhood VI with health, well-being, socioeconomic and social participation outcomes in mid-adult life were investigated using regression models adjusted for participants' early life socioeconomic markers and sex. Change in adjusted odds ratios of >10% in the same direction in successive cohorts, or a > 20% difference between 1970BC and one older cohort were considered meaningful. RESULTS: Trends over time in impacts of childhood onset VI into mid-adult life were complex. This included worsening of odds of poorer physical health (odds ratio 1.47; 95% confidence interval 1.02-2.14), living in unsatisfactory (1.54; 1.03-2.29) or overcrowded (2.34; 1.26-4.06) households, being unemployed (2.19; 1.19-3.97) and not gaining additional educational qualifications during mid-adult life (1.61; 1.08-2.47). By contrast the odds of not participating in some social activities (e.g. seeing friends) improved over time. Associations with other outcomes were unchanged. CONCLUSIONS: Many adverse impacts of childhood VI do not appear ameliorated over time by legislation, policies and provision that would have been expected to reduce inequalities. Moreover, some were increased. Childhood VI continues to cast a life-long shadow.

Retinal Optical Coherence Tomography Features Associated With Incident and Prevalent Parkinson Disease.

BACKGROUND AND OBJECTIVES: Cadaveric studies have shown disease-related neurodegeneration and other morphological abnormalities in the retina of individuals with Parkinson disease (PD); however, it remains unclear whether this can be reliably detected with in vivo imaging. We investigated inner retinal anatomy, measured using optical coherence tomography (OCT), in prevalent PD and subsequently assessed the association of these markers with the development of PD using a prospective research cohort. METHODS: This cross-sectional analysis used data from 2 studies. For the detection of retinal markers in prevalent PD, we used data from AlzEye, a retrospective cohort of 154,830 patients aged 40 years and older attending secondary care ophthalmic hospitals in London, United Kingdom, between 2008 and 2018. For the evaluation of retinal markers in incident PD, we used data from UK Biobank, a prospective population-based cohort where 67,311 volunteers aged 40-69 years were recruited between 2006 and 2010 and underwent retinal imaging. Macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GCIPL), and inner nuclear layer (INL) thicknesses were extracted from fovea-centered OCT. Linear mixed-effects models were fitted to examine the association between prevalent PD and retinal thicknesses. Hazard ratios for the association between time to PD diagnosis and retinal thicknesses were estimated using frailty models. RESULTS: Within the AlzEye cohort, there were 700 individuals with prevalent PD and 105,770 controls (mean age 65.5 ± 13.5 years, 51.7% female). Individuals with prevalent PD had thinner GCIPL (-2.12 µm, 95% CI -3.17 to -1.07, p = 8.2 × 10-5) and INL (-0.99 µm, 95% CI -1.52 to -0.47, p = 2.1 × 10-4). The UK Biobank included 50,405 participants (mean age 56.1 ± 8.2 years, 54.7% female), of whom 53 developed PD at a mean of 2,653 ± 851 days. Thinner GCIPL (hazard ratio [HR] 0.62 per SD increase, 95% CI 0.46-0.84, p = 0.002) and thinner INL (HR 0.70, 95% CI 0.51-0.96, p = 0.026) were also associated with incident PD. DISCUSSION: Individuals with PD have reduced thickness of the INL and GCIPL of the retina. Involvement of these layers several years before clinical presentation highlight a potential role for retinal imaging for at-risk stratification of PD.

The bioelectrical impedance analysis (BIA) international database: aims, scope, and call for data.

BACKGROUND: Bioelectrical impedance analysis (BIA) is a technique widely used for estimating body composition and health-related parameters. The technology is relatively simple, quick, and non-invasive, and is currently used globally in diverse settings, including private clinicians' offices, sports and health clubs, and hospitals, and across a spectrum of age, body weight, and disease states. BIA parameters can be used to estimate body composition (fat, fat-free mass, total-body water and its compartments). Moreover, raw measurements including resistance, reactance, phase angle, and impedance vector length can also be used to track health-related markers, including hydration and malnutrition, and disease-prognostic, athletic and general health status. Body composition shows profound variability in association with age, sex, race and ethnicity, geographic ancestry, lifestyle, and health status. To advance understanding of this variability, we propose to develop a large and diverse multi-country dataset of BIA raw measures and derived body components. The aim of this paper is to describe the 'BIA International Database' project and encourage researchers to join the consortium. METHODS: The Exercise and Health Laboratory of the Faculty of Human Kinetics, University of Lisbon has agreed to host the database using an online portal. At present, the database contains 277,922 measures from individuals ranging from 11 months to 102 years, along with additional data on these participants. CONCLUSION: The BIA International Database represents a key resource for research on body composition.

Performance on the iSTEP and 10 m-ISWT in boys with haemophilia.

INTRODUCTION: Boys with haemophilia (BwH) have improved health outcomes. Measures of physical function in haemophilia are not challenging or sensitive enough to reflect physical limitations or guide rehabilitation. To identify meaningful tests, we aimed to: evaluate the performance of BwH on two physical performance measures: iSTEP and 10 m-ISWT; identify factors which predict performance and compare BwH to their unaffected peers. METHODS: BwH completed both iSTEP and 10 m-ISWT. Disease severity, age, BMI, HJHS, lower limb muscle torque, time spent in moderate to vigorous physical activity, sedentary time, were included as factors to predict performance. Results were compared to unaffected peers. RESULTS: 43 boys median age 10 (10 mild/moderate, 26 severe, 7 inhibitors) were recruited. BwH were less likely to complete the iSTEP and performed less well on the 10 m-ISWT than age matched peers. Ceiling effects were apparent for iSTEP, but not the 10 m-ISWT test. Age was the only significant predictor for performance in the iSTEP, with older boys being more likely to achieve a higher level or complete the test. Greater age, lower BMI, milder disease severity and more time spent in MVPA all predicted better performance on the 10 m-ISWT, with BMI and habitual physical activity a potential rehabilitation focus for underperforming individuals. HJHS and muscle strength did not predict performance on either test. CONCLUSION: Despite the space need to conduct the 10 m-ISWT, it appears to be a superior performance measure than the iSTEP in BwH and provides clinically meaningful information, which can be interpreted using age-specific normative reference equations.

Maternal mental health and economic autonomy in lowland rural Nepal: Do parents-in-law provide constraint or support?

Background and objectives: In patrilocal societies, married women typically co-reside with their parents-in-law, who may act in their son's reproductive interests. These relationships may shape maternal mental health and autonomy. Few studies have examined these dynamics from an evolutionary perspective. Theoretically, marital kin may increase their fitness by increasing maternal investment or by reducing paternity uncertainty. We explored how co-residence with parents-in-law and husband is associated with maternal outcomes to evaluate whether marital kin provide support or constraint. Methodology: We analysed data from 444 households in rural lowland Nepal. Maternal mental health was assessed by General Health Questionnaire. Logistic regression models investigated whether, relative to mothers living with both husband and parents-in-law, those co-resident with other combinations of relatives had poorer mental health and lower household economic autonomy (decision-making, bargaining power), adjusting for socio-economic confounders. Results: Co-residence with husband only, or neither husband nor parents-in-law, was associated with higher odds of mothers reporting feeling worthless and losing sleep but also earning income and making household expenditure decisions. Husband co-residence was associated with overall maternal distress but also with less unpaid care work and greater decision-making responsibility. There were no differences in maternal outcomes for mothers living with parents-in-law only, relative to those living with both husbands and parents-in-law. Conclusions and implications: Co-residence of parents-in-law and husbands was associated with contrasting patterns of maternal mental health and economic autonomy. We suggest that different marital kin place different economic demands on mothers, while restricting their autonomy in different ways as forms of 'mate-guarding'.

Model Based Estimation of Posaconazole Tablet and Suspension Bioavailability in Hospitalized Children Using Real-World Therapeutic Drug Monitoring Data in Patients Receiving Intravenous and Oral Dosing.

Invasive fungal infections are a major cause of morbidity and mortality for immunocompromised patients. Posaconazole is approved for treatment and prophylaxis of invasive fungal infection in adult patients, with intravenous, oral suspension, and gastroresistant/delayed-released tablet formulations available. In Europe, until very recently, posaconazole was used off-label in children, although a new delayed-release suspension approved for pediatric use is expected to become available soon. A population pharmacokinetic model was developed which uses posaconazole therapeutic drug monitoring data following intravenous and oral dosing in hospitalized children, thus enabling estimation of pediatric suspension and tablet oral bioavailability. In total, 297 therapeutic drug monitoring plasma levels from 104 children were included in this analysis. The final model was a one-compartment model with first-order absorption and nonlinear elimination. Allometric scaling on clearance and volume of distribution was included a priori. Tablet bioavailability was estimated to be 66%. Suspension bioavailability was estimated to decrease with increasing doses, ranging from 3.8% to 32.2% in this study population. Additionally, concomitant use of proton pump-inhibitors was detected as a significant covariate, reducing suspension bioavailability by 41.0%. This is the first population pharmacokinetic study to model posaconazole data from hospitalized children following intravenous, tablet, and suspension dosing simultaneously. The incorporation of saturable posaconazole clearance into the model has been key to the credible joint estimation of tablet and suspension bioavailability. To aid rational posaconazole dosing in children, this model was used alongside published pharmacodynamic targets to predict the probability of target attainment using typical pediatric dosing regimen.

Epidemiology of Robin sequence in the UK and Ireland: an active surveillance study.

BACKGROUND: Birth prevalence of Robin sequence (RS) is commonly reported as 1 case per 8000-14 000 live births. These estimates are based on single-source case ascertainment and may miss infants who did not require hospital admission or those without overt upper airway obstruction at birth. OBJECTIVES: To identify the true birth prevalence of RS with cleft palate in the UK and Ireland from a population-based birth cohort with high case ascertainment. METHODS: Active surveillance of RS with cleft palate was carried out in the UK/Ireland using dual sources of case ascertainment: British Paediatric Surveillance Unit (BPSU) reporting card and nationally commissioned cleft services. Clinical data were collected from notifying clinicians at two time points. RESULTS: 173 live-born infants met the surveillance case definition, giving a birth prevalence of 1 case per 5250 live births (19.1 per 100 000 (95% CI 16.2 to 21.9)), and 1:2690 in Scotland. 47% had non-isolated RS, with Stickler syndrome the most common genetic diagnosis (12% RS cases). Birth prevalence derived from the combined data sources was significantly higher than from BPSU surveillance alone. CONCLUSIONS: Birth prevalence of RS in the UK/Ireland derived from active surveillance is higher than reported by epidemiological studies from several other countries, and from UK-based anomaly registries, but consistent with published retrospective data from Scotland. Dual case ascertainment sources enabled identification of cases with mild or late-onset airway obstruction that were managed without hospital admission. Studies of aetiology and equivalent well-designed epidemiological studies from other populations are needed to investigate the identified geographical variability in birth prevalence.

Neonatal mortality in NHS maternity units by timing and mode of birth: a retrospective linked cohort study.

OBJECTIVES: To compare neonatal mortality in English hospitals by time of day and day of the week according to care pathway. DESIGN: Retrospective cohort linking birth registration, birth notification and hospital episode data. SETTING: National Health Service (NHS) hospitals in England. PARTICIPANTS: 6 054 536 liveborn singleton births from 2005 to 2014 in NHS maternity units in England. MAIN OUTCOME MEASURES: Neonatal mortality. RESULTS: After adjustment for confounders, there was no significant difference in the odds of neonatal mortality attributed to asphyxia, anoxia or trauma outside of working hours compared with working hours for spontaneous births or instrumental births. Stratification of emergency caesareans by onset of labour showed no difference in mortality by birth timing for emergency caesareans with spontaneous or induced onset of labour. Higher odds of neonatal mortality attributed to asphyxia, anoxia or trauma out of hours for emergency caesareans without labour translated to a small absolute difference in mortality risk. CONCLUSIONS: The apparent 'weekend effect' may result from deaths among the relatively small numbers of babies who were coded as born by emergency caesarean section without labour outside normal working hours. Further research should investigate the potential contribution of care-seeking and community-based factors as well as the adequacy of staffing for managing these relatively unusual emergencies.