Accuracy of antenatal ultrasound in predicting large-for-gestational-age babies: population-based cohort study.

BACKGROUND: Pregnancies with large-for-gestational-age fetuses are at increased risk of adverse maternal and neonatal outcomes. There is uncertainty about how to manage birth in such pregnancies. Current guidelines recommend a discussion with women of the pros and cons of options, including expectant management, induction of labor, and cesarean delivery. For women to make an informed decision about birth, antenatal detection of large for gestational age is essential. OBJECTIVE: To investigate the ability of antenatal ultrasound scans to predict large for gestational age at birth. STUDY DESIGN: In this retrospective cohort study, we analyzed data from a routinely collected database from the West Midlands, United Kingdom. We included pregnancies that had an antenatal ultrasound-estimated fetal weight between 35+0 and 38+0 weeks gestation for any indication and a subgroup where the reason for the scan was that the fetus was suspected to be big. Large for gestational age was defined as >90th customized GROW percentile for estimated fetal weight as well as neonatal weight. In addition, we tested the performance of an uncustomized standard, with Hadlock fetal weight >90th percentile and neonatal weight >4 kg. We calculated diagnostic characteristics for the whole population and groups with different maternal body mass indexes. RESULTS: The study cohort consisted of 26,527 pregnancies, which, on average, had a scan at 36+4 weeks gestation and delivered 20 days later at a median of 39+3 weeks (interquartile range 15). In total, 2241 (8.4%) of neonates were large for gestational age by customized percentiles, of which 1459 (65.1%) had a scan estimated fetal weight >90th percentile, with a false positive rate of 8.6% and a positive predictive value of 41.0%. In the subgroup of 912 (3.4%) pregnancies scanned for a suspected large fetus, 293 (32.1%) babies were large for gestational age at birth, giving a positive predictive value of 50.3%, with a sensitivity of 77.1% and false positive rate of 36.0%. When comparing subgroups from low (<18.5 kg/m2) to high body mass index (>30 kg/m2), sensitivity increased from 55.6% to 67.8%, false positive rate from 5.2% to 11.5%, and positive predictive value from 32.1% to 42.3%. A total of 2585 (9.7%) babies were macrosomic (birthweight >4 kg), and of these, 1058 (40.9%) were large for gestational age (>90th percentile) antenatally by Hadlock's growth standard, with a false positive rate of 4.9% and a positive predictive value 41.0%. Analysis within subgroups showed better performance by customized than uncustomized standards for low body mass index (<18.5; diagnostic odds ratio, 23.0 vs 6.4) and high body mass index (>30; diagnostic odds ratio, 16.2 vs 8.8). CONCLUSION: Late third-trimester ultrasound estimation of fetal weight for any indication has a good ability to identify and predict large for gestational age at birth and improves with the use of a customized standard. The detection rate is better when an ultrasound is performed for a suspected large fetus but at the risk of a higher false positive diagnosis. Our results provide information for women and clinicians to aid antenatal decision-making about the birth of a fetus suspected of being large for gestational age.

Fetal size vs growth: comparative analysis of 3 models of growth velocity based on third trimester estimated fetal weights for identifying stillbirth risk.

BACKGROUND: Fetal growth velocity is being recognized as an important parameter by which to monitor fetal wellbeing, in addition to assessment of fetal size. However, there are different models and standards in use by which velocity is being assessed. OBJECTIVE: We wanted to investigate 3 clinically applied methods of assessing growth velocity and their ability to identify stillbirth risk, in addition to that associated with small for gestational age. STUDY DESIGN: Retrospective analysis of prospectively recorded routine-care data of pregnancies with 2 or more third trimester scans in New Zealand. Results of the last 2 scans were used for the analysis. The models investigated to define slow growth were (1) 50+ centile drop between measurements, (2) 30+ centile drop, and (3) estimated fetal weight below a projected optimal weight range, based on predefined, scan interval specific cut-offs to define normal growth. Each method's ability to identify stillbirth risk was assessed against that associated with small-for-gestational age at last scan. RESULTS: The study cohort consisted of 71,576 pregnancies. The last 2 scans in each pregnancy were performed at an average of 32+1 and 35+6 weeks of gestation. The 3 models defined "slow growth" at the following differing rates: (1) 50-centile drop 0.9%, (2) 30-centile drop 5.1%, and (3) below projected optimal weight range 10.8%. Neither of the centile-based models identified at-risk cases that were not also small for gestational age at last scan. The projected weight range method identified an additional 79% of non-small-for-gestational-age cases as slow growth, and these were associated with a significantly increased stillbirth risk (relative risk, 2.0; 95% CI, 1.2-3.4). CONCLUSION: Centile-based methods fail to reflect adequacy of fetal weight gain at the extremes of the distribution. Guidelines endorsing such models might hinder the potential benefits of antenatal assessment of fetal growth velocity. A new, measurement-interval-specific projection model of expected fetal weight gain can identify fetuses that are not small for gestational age, yet at risk of stillbirth because of slow growth. The velocity between scans can be calculated using a freely available growth rate calculator (www.perinatal.org.uk/growthrate).

ABO and Rh blood groups and risk of infection: systematic review and meta-analysis.

BACKGROUND: Persons with non-O and Rh-positive blood types are purported to be more susceptible to infection, including SARS-CoV-2, but there remains uncertainty about the degree to which this is so for both non-viral and viral infections. METHODS: We systematically reviewed Embase and PubMed from January 1st 1960 to May 31st 2022. English-language publications were selected that separately investigated the relation between ABO and/or Rh blood group and risk of SARS-CoV-2 and non-SARS-CoV-2 infection. Pooled odds ratios (ORp) and 95% confidence intervals (CI) were then generated for each. RESULTS: Non-O blood groups had a higher ORp for SARS-CoV-2 than O blood groups, both within 22 case-control studies (2.13, 95% CI 1.49- 3.04) and 15 cohort studies (1.89, 95% CI 1.56- 2.29). For non-SARS-CoV-2 viral infections, the respective ORp were 1.98 (95% CI 1.49-2.65; 4 case-control studies) and 1.87 (95% CI 1.53-2.29; 12 cohort studies). For non-viral infections, the ORp were 1.56 (95% CI 0.98-2.46; 13 case-control studies) and 2.11 (95% CI 1.67-6.67; 4 cohort studies). Rh-positive status had a higher ORp for SARS-CoV-2 infection within 6 case-control studies (13.83, 95% CI 6.18-30.96) and 6 cohort studies (19.04, 95% CI 11.63-31.17), compared to Rh-negative persons. For Rh status, non-SARS-CoV-2 infections, the ORp were 23.45 (95% CI 16.28-33.76) among 7 case-control studies, and 9.25 (95% CI 2.72-31.48) within 4 cohort studies. High measures of heterogeneity were notably observed for all analyses. CONCLUSIONS: Non-O and Rh-positive blood status are each associated with a higher risk of SARS-CoV-2 infection, in addition to other viral and non-viral infections.

Functional Specialization of the Medial Temporal Lobes in Human Recognition Memory: Dissociating Effects of Hippocampal versus Parahippocampal Damage.

A central debate in the systems neuroscience of memory concerns whether different medial temporal lobe (MTL) structures support different processes in recognition memory. Using two recognition memory paradigms, we tested a rare patient (MH) with a perirhinal lesion that appeared to spare the hippocampus. Consistent with a similar previous case, MH showed impaired familiarity and preserved recollection. When compared with patients with hippocampal lesions appearing to spare perirhinal cortex, MH showed greater impairment on familiarity and less on recollection. Nevertheless, the hippocampal patients also showed impaired familiarity compared with healthy controls. However, when replacing this traditional categorization of patients with analyses relating memory performance to continuous measures of damage across patients, hippocampal volume uniquely predicted recollection, whereas parahippocampal, rather than perirhinal, volume uniquely predicted familiarity. We consider whether the familiarity impairment in MH and our patients with hippocampal lesions arises from "subthreshold" damage to parahippocampal cortex (PHC). Our data provide the most compelling neuropsychological support yet for dual-process models of recognition memory, whereby recollection and familiarity depend on different MTL structures, and may support a role for PHC in familiarity. Our study highlights the value of supplementing single-case studies with examinations of continuous brain-behavior relationships across larger patient groups.

Renal Autologous Cell Therapy in Type 2 Diabetes with Late Stage 4 Diabetes-Related Chronic Kidney Disease: Trial Design and Early Analysis.

INTRODUCTION: Cell-based therapies potentially delay the trajectory toward end-stage kidney disease (ESKD) in late stage 4 diabetic chronic kidney disease (DKD). We describe the trial design, baseline patient characteristics, and early results of an IRB-approved phase II multicenter clinical trial, utilizing Renal Autologous Cell Therapy (REACT) in adults with pre-ESKD due to type 2 DKD. The trial objectives were safety and tolerability of REACT by assessment of the procedure, product administration, and renal-specific adverse events in addition to evaluate the impact on renal function following injection. METHODS: Ten adults with an eGFR of 14-20 mL/min/1.73 m2 were enrolled in a single-arm open-label trial. Following a percutaneous kidney biopsy, an ex vivo expansion of selected renal cells that form the REACT was injected into the cortex of the biopsied kidney with CT image guidance. Each participant received two doses of the REACT product at 6-month intervals. A 6-month observation pre-trial was required to establish patients' "own" baseline and rate of DKD progression. RESULTS: Five men and 5 women underwent 19 REACT injections (1 participant received only one injection). Their baseline characteristics were as follows: 3 Hispanic/Latino, 7 non-Hispanic, 7 white; mean (SD) age: 58.9 years (5.22), BMI 35.8 (8.2), eGFR (sCR) 15.5 (2.72), eGFR (sCR + Cys-C) 17.7 (3.67) mL/min/1.73 m2, sCr 3.6 mg/mL (0.73), Cys-C 2.6 mg/mL (0.52), and log random UACR 7.9 mg/g (1.01). The pre- and post-injection eGFR slope was -6.5 mL/min/1.73 m2 and -3.9 mL/min/1.73 m2. No cell-related adverse events occurred, and two procedure-related hematomas required observation without transfusion or angiographic interventions. Dialysis was delayed a mean of 16 months (range 6-28 months). At 15 months, 2 patients (20%) have eGFR slope stability and have not commenced renal replacement therapy. CONCLUSION: Trials that include patients with an eGFR of <20 mL/min/1.73 m2 are uncommon, and none to date involve autologous homologous cell-based treatments. REACT has the potential to stabilize or delay dialysis in high-risk late stage 4 DKD.

Five-year illness trajectories across racial groups in the UK following a first episode psychosis.

PURPOSE: Psychosis disproportionally affects ethnic minority groups in high-income countries, yet evidence of disparities in outcomes following intensive early intervention service (EIS) for First Episode Psychosis (FEP) is less conclusive. We investigated 5-year clinical and social outcomes of young people with FEP from different racial groups following EIS care. METHOD: Data were analysed from the UK-wide NIHR SUPEREDEN study. The sample at baseline (n = 978) included White (n = 750), Black (n = 71), and Asian (n = 157) individuals, assessed during the 3 years of EIS, and up to 2 years post-discharge (n = 296; Black [n = 23]; Asian [n = 52] and White [n = 221]). Outcome trajectories were modelled for psychosis symptoms (positive, negative, and general), functioning, and depression, using linear mixed effect models (with random intercept and slopes), whilst controlling for social deprivation. Discharge service was also explored across racial groups, 2 years following EIS. RESULTS: Variation in linear growth over time was accounted for by racial group status for psychosis symptoms-positive (95% CI [0.679, 1.235]), negative (95% CI [0.315, 0.783]), and general (95% CI [1.961, 3.428])-as well as for functioning (95% CI [11.212, 17.677]) and depressive symptoms (95% CI [0.261, 0.648]). Social deprivation contributed to this variance. Black individuals experienced greater levels of deprivation (p < 0.001, 95% CI [0.187, 0.624]). Finally, there was a greater likelihood for Asian (OR = 3.04; 95% CI [2.050, 4.498]) and Black individuals (OR = 2.47; 95% CI [1.354, 4.520]) to remain in secondary care by follow-up. CONCLUSION: Findings suggest variations in long-term clinical and social outcomes following EIS across racial groups; social deprivation contributed to this variance. Black and Asian individuals appear to make less improvement in long-term recovery and are less likely to be discharged from mental health services. Replication is needed in large, complete data, to fully understand disparities and blind spots to care.

"We are Human too.": The Challenges of Being an End-of-Life Doula.

End-of-life (EOL) doulas are emerging professionals who provide an intimate approach to the death process by focusing on the psychological, social, spiritual, and emotional needs of dying individuals. EOL doula work is stressful; it exposes individuals to recurring stressors such as suffering and grief. Trained professionals are needed to help advocate for the dying individual and their families. Despite the growing literature on EOL doulas, information regarding the challenges of being an EOL doula is underrepresented in the literature. This paper is one of the first to address this concept. Twelve in-depth, semi-structured interviews regarding the EOL doula experience were conducted as a part of a larger exploratory study. Three overarching themes emerged from the larger project: motivations to become an EOL doula, roles of an EOL doula, and challenges of an EOL doula. In this article, only challenges of EOL are discussed, along with subsequent subordinate themes.

2-Arachidonoylglycerol-mediated endocannabinoid signaling modulates mechanical hypersensitivity associated with alcohol withdrawal in mice.

BACKGROUND: Alcohol use disorder (AUD) commonly occurs in patients with chronic pain, and a major barrier to achieving abstinence and preventing relapse is the emergence of hyperalgesia during alcohol withdrawal. Elucidating novel therapeutic approaches to target hyperalgesia associated with alcohol withdrawal could have important implications for treating AUD. Here, we examined the role of 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid (eCB) signaling in the regulation of hyperalgesia associated with alcohol withdrawal in mice. We tested the hypothesis that pharmacological augmentation of 2-AG signaling could reduce hyperalgesia during withdrawal. METHODS: Male and female C57BL/6J mice were tested during withdrawal from a continuous access two-bottle choice (2BC) paradigm to investigate how eCB signaling modulates mechanical and thermal sensitivity during withdrawal. Mice were pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184 to elevate levels of 2-AG. Rimonabant or AM630 were given to block CB1 and CB2 receptor activity, respectively. DO34 was given to reduce 2-AG by inhibiting the 2-AG synthetic enzyme diacylglycerol lipase (DAGL). RESULTS: After 72 h of withdrawal, male and female mice exhibited increased mechanical, but not thermal, hypersensitivity, which normalized by 7 days. This effect was reversed by pretreatment with JZL184. The effects of JZL184 were prevented by coadministration of either the CB1 or the CB2 antagonist. DO34, Rimonabant, and AM630 exacerbated mechanical hypersensitivity during alcohol withdrawal, causing an earlier onset and persistent hypersensitivity even 1 week into withdrawal. CONCLUSIONS: Our findings demonstrate the critical role of 2-AG signaling in the bidirectional regulation of mechanical sensitivity during alcohol withdrawal, with enhancement of 2-AG levels reducing sensitivity, and inhibition of 2-AG signaling exacerbating sensitivity. These data suggest that 2-AG augmentation represents a novel approach to the treatment of alcohol withdrawal-associated hyperalgesia and AUD in patients with comorbid pain disorders.

Hispanic Ethnic Density May Be Protective for Older Black/African American and Non-Hispanic White Populations for Some Health Conditions: An Exploration of Support and Neighborhood Mechanisms.

BACKGROUND AND PURPOSE: Hispanic ethnic density (HED) is associated with salubrious health outcomes for Hispanics, yet recent research suggests it may also be protective for other groups. The purpose of this study was to test whether HED was protective for other racial-ethnic groups. We tested whether social support or neighborhood social integration mediated the association between high HED and depressive symptoms (CES-D) and physical morbidity 5 years later. Lastly, we tested whether race-ethnicity moderated both main and indirect effects. METHODS: We used Waves 1 (2005-2006), and 2 (2010-2011) from The National Social Life, Health, and Aging Project, a national study of older U.S. adults. Our sample was restricted to Wave 1 adults who returned at Wave 2, did not move from their residence between waves, and self-identified as Hispanic, non-Hispanic White (NHW), or non-Hispanic Black (NHB; n = 1,635). We geo-coded respondents' addresses to a census-tract and overlaid racial-ethnic population data. Moderated-mediation models using multiple imputation (to handle missingness) and bootstrapping were used to estimate indirect effects for all racial-ethnic categories. RESULTS: Depressive symptoms were lower amongst racial-ethnic minorities in ethnically (Hispanic) dense neighborhoods; this effect was not stronger in Hispanics. HED was not associated with physical morbidity. Sensitivity analyses revealed that HED was protective for cardiovascular events in all racial-ethnic groups, but not arthritis, or respiratory disease. Social support and neighborhood social integration were not mediators for the association between HED and outcomes, nor were indirect effects moderated by race-ethnicity. CONCLUSIONS: This study offers some evidence that HED may be protective for some conditions in older adults; however, the phenomena underlying these effects remains a question for future work.

Sexual Minority Stressors and Intimate Partner Violence Among Same-Sex Couples: Commitment as a Resource.

Accumulating evidence has been found for the associations from sexual minority stressors to intimate partner violence (IPV) among same-sex couples. Yet key gaps still exist, including the rare utilization of couple dyadic data, the understudied moderating and mediating mechanisms, and the few studies conducted during the transitional period of same-sex marriage legalization. To address these gaps, we used cross-sectional, dyadic data collected from 144 US same-sex couples during the 2014-2015 national campaign for the legalization of same-sex marriage. Guided by the systemic transactional model (STM), we examined associations from sexual minority stressors (including both internalized homophobia and discrimination) to same-sex IPV and tested whether commitment moderated or mediated these associations. Overall, we found evidence supporting the STM: (1) High internalized homophobia and discrimination were related to high prevalence and/or frequency of IPV perpetration; (2) high commitment attenuated positive associations between high discrimination and high prevalence and/or frequency of IPV perpetration; and (3) high internalized homophobia was related to low commitment, which in turn was related to high prevalence and/or frequency of IPV perpetration. Collectively, our study identified commitment as both a moderator and mediator in associations from sexual minority stressors to same-sex IPV. Further, the roles of commitment (i.e., moderator or mediator) depend on whether the focal sexual minority stressors are distal and more intermittent (i.e., heterosexist discrimination) or proximal and more constant (i.e., internalized homophobia).

Evaluating the Growth Assessment Protocol for stillbirth prevention: progress and challenges.

Many stillbirths are associated with fetal growth restriction, and are hence potentially avoidable. The Growth Assessment Protocol (GAP) is a multidisciplinary program with an evidence based care pathway, training in risk assessment, fetal growth surveillance with customised charts and rolling audit. Antenatal detection of small for gestational age (SGA) has become an indicator of quality of care. Evaluation is essential to understand the impact of such a prevention program. Randomised trials will not be effective if they cannot ensure proper implementation before assessment. Observational studies have allowed realistic evaluation in practice, with other factors excluded that may have influenced the outcome. An award winning 10 year study of stillbirth data in England has been able to assess the effect of GAP in isolation, and found a strong, causal association with improved antenatal detection of SGA babies, and the sustained decline in national stillbirth rates. The challenge now is to apply this program more widely in low and middle income settings where the main global burden of stillbirth is, and to adapt it to local needs and resources.

Coordination in interpersonal systems.

Coordinated group behaviour can result in conflict or social cohesion. Thus having a better understanding of coordination in social groups could help us tackle some of our most challenging social problems. Historically, the most common way to study group behaviour is to break it down into sub-processes, such as cognition and emotion, then ideally manipulate them in a social context in order to predict some behaviour such as liking versus distrusting a target person. This approach has gotten us partway to understanding many important collective behaviours, but I argue that making major changes in the world will require a more integrated approach. In this review, I introduce dynamic systems theory, with a focus on interpersonal systems, where all the processes we typically study in individuals, such as cognition and emotion, become intertwined between social partners over time. I focus on the concept of coordination, defined as a temporal correlation between interacting components of a system (or systems) arising due to coupling between them. Finally, I show how this perspective could be used to guide investigations of social problems such as polarisation.

Does the Hispanic Mortality Advantage Vary by Marital Status Among Postmenopausal Women in the Women's Health Initiative?

BACKGROUND: Literature assessing the effect of marital status on mortality has underrepresented, or altogether omitted Hispanics and the potential moderating effect of Hispanic ethnicity on these relationships. Given cultural and network dynamics, marital advantages in older Hispanic women may be greater than other groups given their family-focused, collectivist orientation. PURPOSE: The purpose of this study was to understand whether older Hispanic women exhibited a more pronounced marital advantage as compared with non-Hispanic Whites. METHODS: We used longitudinal data from the Women's Health Initiative (WHI) Observational Study and Clinical Trials (N = 161,808) collected initially from 1993 to 1998 and followed until 2018. Our sample excluded those respondents indicating "other" as their race-ethnicity and those missing marital status and race-ethnicity variables (N = 158,814). We used Cox-proportional hazards models to assess the association between race-ethnicity, marital status, and the interactive effect of race-ethnicity and marital status on survival. RESULTS: After controlling for socioeconomic status (SES) and health controls, we found a Hispanic survival advantage when compared with non-Hispanic Whites and all other racial-ethnic groups with the exception of Asian/Pacific Islander women (all significant HRs < 0.78, all ps ≤ 0.001). Hispanics had a higher rate of divorce when compared with non-Hispanic Whites. The interactive effect of race-ethnicity and marital status was not significant. CONCLUSIONS: U.S. Hispanic, postmenopausal women exhibit a mortality advantage over and above marital status despite their high rates of divorce. Implications and potential explanations are discussed. CLINICAL TRIAL REGISTRATION: NCT00000611.

A comparative evaluation of telehealth and direct assessment when screening for spasticity in residents of two long-term care facilities.

OBJECTIVE: To evaluate the performance of telehealth as a screening tool for spasticity compared to direct patient assessment in the long-term care setting. DESIGN: Cross-sectional, observational study. SETTING: Two long-term care facilities: a 140-bed veterans' home and a 44-bed state home for individuals with intellectual and developmental disabilities. SUBJECTS: Sixty-one adult residents of two long-term care facilities (aged 70.1 ± 16.2 years) were included in this analysis. Spasticity was identified in 43% of subjects (Modified Ashworth Scale rating mode = 2). Contributing diagnoses included traumatic brain injury, spinal cord injury, birth trauma, stroke, cerebral palsy, and multiple sclerosis. MAIN MEASURES: Movement disorders neurologists conducted in-person examinations to determine whether spasticity was present (reference standard) and also evaluated subjects with spasticity using the Modified Ashworth Scale. Telehealth screening examinations, facilitated by a bedside nurse, were conducted remotely by two teleneurologists using a three-question screening tool. Telehealth screening determinations of spasticity were compared to the reference standard determination to calculate sensitivity, specificity, and the area under the curve (AUC) in receiver operating characteristics. Teleneurologist agreement was evaluated using Cohen's kappa. RESULTS: Teleneurologist 1 had a specificity of 89% and sensitivity of 65% to identify the likely presence of spasticity (n = 61; AUC = 0.770). Teleneurologist 2 showed 100% specificity and 82% sensitivity (n = 16; AUC = 0.909). There was almost perfect agreement between the two examiners at 94% (kappa = 0.875, 95% CI: 0.640-1.000). CONCLUSION: Telehealth may provide a useful, efficient method of identifying residents of long-term care facilities that likely need referral for spasticity evaluation.

Estimands in hematologic oncology trials.

The estimand framework included in the addendum to the ICH E9 guideline facilitates discussions to ensure alignment between the key question of interest, the analysis, and interpretation. Therapeutic knowledge and drug mechanism play a crucial role in determining the strategy and defining the estimand for clinical trial designs. Clinical trials in patients with hematological malignancies often present unique challenges for trial design due to complexity of treatment options and existence of potential curative but highly risky procedures, for example, stem cell transplant or treatment sequence across different phases (induction, consolidation, maintenance). Here, we illustrate how to apply the estimand framework in hematological clinical trials and how the estimand framework can address potential difficulties in trial result interpretation. This paper is a result of a cross-industry collaboration to connect the International Conference on Harmonisation (ICH) E9 addendum concepts to applications. Three randomized phase 3 trials will be used to consider common challenges including intercurrent events in hematologic oncology trials to illustrate different scientific questions and the consequences of the estimand choice for trial design, data collection, analysis, and interpretation. Template language for describing estimand in both study protocols and statistical analysis plans is suggested for statisticians' reference.

Estimand framework: Are we asking the right questions? A case study in the solid tumor setting.

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for "intercurrent" events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions ("does the drug delay recurrence if no patient had received subsequent therapy?" vs "does the drug delay recurrence with or without subsequent therapy?" vs "does the drug delay recurrence or start of subsequent therapy?"). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross-industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.

Detection of Transport Intermediates in the Peptidoglycan Flippase MurJ Identifies Residues Essential for Conformational Cycling.

Bacterial cell wall synthesis is an essential process in bacteria and one of the best targets for antibiotics. A critical step on this pathway is the export of the lipid-linked cell wall monomer, Lipid II, by its transporter MurJ. The mechanism by which MurJ mediates the transbilayer movement of Lipid II is not understood because intermediate states of this process have not been observed. Here we demonstrate a method to capture and detect interactions between MurJ and its substrate Lipid II by photo-cross-linking and subsequent biotin-tagging. We show that this method can be used to covalently capture intermediate transport states of Lipid II on MurJ in living cells. Using this strategy we probed several lethal arginine mutants and found that they retain appreciable substrate-binding ability despite being defective in Lipid II transport. We propose that Lipid II binding to these residues during transport induces a conformational change in MurJ required to proceed through the Lipid II transport cycle. The methods described to detect intermediate transport states of MurJ will be useful for characterizing mechanisms of inhibitors.

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. METHODS: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. RESULTS: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. CONCLUSION: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.

Racial-ethnic differences in social networks and perceived support: Measurement considerations and implications for disparities research.

OBJECTIVES: Racial-ethnic differences in physical/mental health are well documented as being associated with disparities; however, emerging conceptual models increasingly suggest that group differences in social functioning and organization contribute to these relationships. There is little work examining whether racial-ethnic groups respond similarly to classic measures of social networks and perceived support and whether there are significant between-groups differences on these measures. METHOD: A multisite, cross-sectional study of 2,793 non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic participants was conducted using common measures of social networks and perceived support. A confirmatory factor analytic model was used to test for the invariance of factor covariance and mean structures in a three latent constructs model including social network, social provisions, and interpersonal support. Between-group differences in structural and functional support were assessed. RESULTS: We established measurement invariance of the latent representations of these measures suggesting that racial-ethnic groups responded comparably. In direct comparisons, Hispanics and NHWs demonstrated similar levels of network structure and support. In contrast, NHWs reported support advantages on a majority of measures compared with NHBs. CONCLUSIONS: Findings support the use of these measures across groups and provide initial support for potential differences in this hypothesized mediator of racial-ethnic health disparities. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Protease-activated receptor 4 protects mice from Coxsackievirus B3 and H1N1 influenza A virus infection.

PAR4 is expressed by a variety of cells, including platelets, cardiac, lung and immune cells. We investigated the contribution of PAR4 to viral infections of the heart and lung. Toll-like receptor (TLR) 3-dependent immune responses were analyzed after co-stimulation of PAR4 in murine bone-marrow derived macrophages, embryonic fibroblasts and embryonic cardiomyocytes. In addition, we analyzed Coxsackievirus B3 (CVB3) or H1N1 influenza A virus (H1N1 IAV) infection of PAR4-/- (ΔPAR4) and wild-type (WT) mice. Lastly, we investigated the effect of platelet inhibition on H1N1 IAV infection. In vitro experiments revealed that PAR4 stimulation enhances the expression of TLR3-dependent CXCL10 expression and decreases TLR3-dependent NFκB-mediated proinflammatory gene expression. Furthermore, CVB3-infected ΔPAR4 mice exhibited a decreased anti-viral response and increased viral genomes in the heart leading to more pronounced CVB3 myocarditis compared to WT mice. Similarly, H1N1 IAV-infected ΔPAR4 mice had increased immune cell numbers and inflammatory mediators in the lung, and increased mortality compared with infected WT controls. The study showed that PAR4 protects mice from viral infections of the heart and lung.