Demographic diversity of US-based participants in GSK-sponsored interventional clinical trials.

BACKGROUND: Demographic diversity among clinical trials is required for representing the real-world populations intended for treatment and disease prevention. Moreover, genetic and environmental differences between ethnic and racial groups necessitate appropriately powered trials for relevant subgroups. We investigate the racial and ethnic demographic diversity of US-based participants in GSK-sponsored interventional trials. We also assess the evaluation of demographic diversity against US Census and epidemiologic data. METHODS: GSK-sponsored interventional phase I-IV clinical trials conducted from 2002 to 2019 across three areas were analyzed: pharmaceutical (includes therapeutic medicines except for vaccines and human immunodeficiency virus (HIV)), vaccine (includes prophylactic and therapeutic vaccines), and ViiV (includes HIV therapies). A total of 1005 global trials encompassing 460,707 global participants were identified, of which 495 had US-based sites with a total of 108,261 (23.5% of global) US participants (pharmaceutical, n = 357 trials; vaccine, n = 45 trials; and ViiV, n = 93 trials). We evaluated how GSK US-based trial recruitment compares with US Census (in line with previously published studies from other groups) and with epidemiologic data. RESULTS: GSK participant data for race and ethnicity combined across areas were generally similar to US Census levels (e.g. GSK versus census: White, 76.5% versus 76.3%; Black or African American, 15.1% versus 13.4%; Asian, 1.8% versus 5.9%; Hispanic or Latino, 14.0% versus 18.5%; Non-Hispanic White, 63.5% versus 60.1%). However, this was not the case for the individual pharmaceutical, vaccine, and ViiV data sets; least represented groups were Asian individuals for pharmaceutical and ViiV trials and American Indian or Alaskan Native individuals for vaccine trials (6.2%, 11.8%, and 11.1% of trials met/exceeded census level representation, respectively). The percentage of trials reaching/exceeding census levels also varied per trial phase for race and ethnicity. Furthermore, disparities in the percentage of trials reaching/exceeding census levels versus epidemiology-based prevalence levels have revealed opportunities to improve industry success metrics; in HIV trials, the proportion of Black or African American individuals (35.1%) exceeded census (13.4%) but not epidemiologic levels (55.3%). CONCLUSION: Further work is required to achieve demographic diversity across clinical trials. We conclude that US Census data are an inappropriate universal benchmark. A shift to epidemiology benchmarking will enable the consideration of global participants into US analyses for highly intrinsic (i.e. influenced by ancestry) diseases and more firm requirements for US-based participants into US analyses for extrinsic (i.e. influenced by location or culture) diseases. Benchmarking in line with epidemiologic data will allow us to set better trial enrollment goals, with the aim of conducting more demographically balanced, diverse, and representative clinical trials and enabling a better understanding of drug safety and efficacy per demographic group.

Congenital hypotonia: systematic approach for prenatal detection.

OBJECTIVES: Congenital hypotonic conditions are rare and heterogeneous, and some are severely debilitating or lethal. Contrary to its prominent postnatal manifestation, the prenatal presentation of hypotonia is frequently subtle, inhibiting prenatal detection. We aimed to characterize the prenatal sonographic manifestation of congenital hypotonia throughout pregnancy, evaluate the yield of diagnostic tests and propose diagnostic models to increase its prenatal detection. METHODS: This was a retrospective observational study of singleton pregnancies with congenital hypotonia, diagnosed either prenatally or immediately after birth, at a single tertiary center between the years 2012 and 2020. Prenatally, hypotonia was diagnosed if a fetus showed sonographic or clinical signs suggestive of hypotonia and had a confirmed underlying genetic condition, or in the absence of a known genetic abnormality if the fetus exhibited multiple prominent signs suggestive of hypotonia. Postnatally, it was diagnosed in neonates displaying reduced muscle tone leading to reduced spontaneous movement, reduced swallowing or feeding difficulty. We reviewed the medical records of pregnant patients carrying fetuses subsequently diagnosed with congenital hypotonia and assessed the yield of ultrasound scans, fetal magnetic resonance imaging, computed tomography and genetic tests. The detection rate of sonographic signs suggesting fetal hypotonia was calculated. The prevalence of non-specific signs, including polyhydramnios, persistent breech presentation, intrauterine growth restriction and maternal perception of reduced fetal movement, were compared between the study group and the local liveborn singleton population. Potential detection rates of different theoretical semiotic diagnostic models, differing in the threshold for referral for a targeted scan, were assessed based on the cohort's data. RESULTS: The study group comprised 26 cases of congenital hypotonia, of which 10 (38.5%) were diagnosed prenatally, and the controls included 95 105 singleton live births, giving a prevalence of congenital hypotonia of 1:3658. Nuchal translucency thickness and the early anomaly scan at 13-17 weeks were normal in all 22 and 23 cases, respectively, in which this was performed. The mid-trimester scan performed at 19-25 weeks was abnormal in four of 24 (16.7%) cases. The overall prenatal detection rate of congenital hypotonic conditions in our cohort was 38.5%. Only cases which underwent a targeted scan were detected and, among the 16 cases which underwent this scan, the prenatal detection rate was 62.5% compared with 0% in pregnancies that did not undergo this scan (P = 0.003). An abnormal genetic diagnosis was obtained in 21 (80.8%) cases using the following modalities: chromosomal microarray analysis (CMA) in two (9.5%), whole-exome sequencing (WES) in 14 (66.7%) and methylation analysis in five (23.8%). CMA was abnormal in 8% (2/25) of the cases and WES detected a causative genetic mutation in 87.5% (14/16) of the cases in which these were performed. Comparison of non-specific signs in the study group with those in the local singleton population showed that hypotonic fetuses had significantly more polyhydramnios (64.0% vs 3.0%, P < 0.0001), persistent breech presentation (58.3% vs 4.2%, P < 0.0001), intrauterine growth restriction (30.8% vs 3.0%, P < 0.0001) and maternal perception of reduced fetal movement (32.0% vs 4.7%, P < 0.0001). Prenatally, the most commonly detected signs supporting a diagnosis of hypotonia were structural anomaly (62.5%, 10/16), reduced fetal movement (46.7%, 7/15), joint contractures (46.7%, 7/15) and undescended testes ≥ 30 weeks (42.9%, 3/7 males). Proposed diagnostic strategies that involved performing a targeted scan for a single non-specific ultrasound sign or two such signs, and then carrying out a comprehensive genetic evaluation for any additional sign, offered theoretical detection rates in our cohort of 88.5% and 57.7%, respectively. CONCLUSIONS: Congenital hypotonic conditions are rare and infrequently detected prenatally. Sonographic signs are visible from the late second trimester. A targeted scan increases prenatal detection significantly. Comprehensive genetic testing, especially WES, is the cornerstone of diagnosis in congenital hypotonia. Theoretical diagnostic models which may increase prenatal detection are provided. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Circulating corticosterone levels mediate the relationship between acute ethanol intoxication and markers of NF-κB activation in male rats.

Binge drinking is a harmful pattern of alcohol use that is associated with a number of serious health problems. Of particular interest are the rapid alterations in neuroimmune gene expression and the concurrent activation of the hypothalamic-pituitary-adrenal (HPA) axis activation associated with high intensity drinking. Using a rat model of acute binge-like ethanol exposure, the present studies were designed to assess the role of corticosterone (CORT) in ethanol-induced neuroimmune gene expression changes, particularly those associated with the NFκB signaling pathway, including rapid induction of IL-6 and IκBα, and suppression of IL-1ß and TNFα gene expression evident after administration of moderate to high doses of ethanol (1.5-3.5 g/kg ip) during intoxication (3 h post-injection). Experiment 1 tested whether inhibition of CORT synthesis with metyrapone and aminoglutethimide (100 mg/kg each, sc) would block ethanol-induced changes in neuroimmune gene expression. Results indicated that rapid alterations in IκBα, IL-1ß, and TNFα expression were completely blocked by pretreatment with the glucocorticoid synthesis inhibitors, an effect that was reinstated by co-administration of exogenous CORT (3.75 mg/kg) in Experiment 2. Experiment 3 assessed whether these rapid alterations in neuroimmune gene expression would be evident when rats were challenged with a subthreshold dose of ethanol (1.5 g/kg) in combination with 2.5 mg/kg CORT, which showed limited evidence for additive effects of low-dose CORT combined with a moderate dose of ethanol. Acute inhibition of mineralocorticoid (spironolactone) or glucocorticoid (mifepristone) receptors, alone (Experiment 4) or combined (Experiment 5) had no effect on ethanol-induced changes in neuroimmune gene expression, presumably due to poor CNS penetrance of these drugs. Finally, Experiments 6 and 7 showed that dexamethasone (subcutaneous; a GR agonist) recapitulated effects of ethanol. Overall, we conclude that ethanol-induced CORT synthesis and release is responsible for suppression of IL-1ß, TNFα, and induction of IκBα in the hippocampus through GR signaling. Interventions designed to curb these changes may reduce drinking, and subdue detrimental neuroimmune activation induced by ethanol.

Parent and Provider Preferences for Parenting Intervention Delivery in Rural Appalachia: A Qualitative Analysis Guiding Adaptation.

The public health impact of behavioral parent training (BPT) is limited, especially in underserved communities such as rural central Appalachia. To improve access to BPT in this region, we completed the first two steps of the ADAPT-ITT framework for systematic adaptation of evidence-based interventions: (1) assessing community perspectives about BPT delivery, and (2) deciding upon a specific intervention and adaptations needed to increase its acceptability and accessibility in rural central Appalachian counties. Guided by a community advisory board, we conducted key informant interviews with parents (N = 21) and three focus groups with child service providers to elicit stakeholders' perspectives about child behavior problems in their communities; existing resources; and preferences regarding four characteristics of BPT delivery: interventionist, modality, dose, and location. Results of directed content analysis led to the selection of local, trusted community health workers to deliver a brief, tailored BPT with flexibility in modality and location.

Fall prevalence in people with multiple sclerosis who use wheelchairs and scooters.

Falls are a serious health concern for persons with multiple sclerosis (PwMS) who use wheelchairs or scooters as their primary mode of mobility. Unfortunately, little is known about the fall prevalence and characteristics of this large segment of the multiple sclerosis (MS) community. The purpose of this study is to determine the prevalence and circumstances of falls in wheelchair and scooter users living with MS. Forty-four PwMS were recruited from research and medical centers in the United States and Asia. Participants completed a survey focusing on prevalence of falls, frequency of injurious falls, circumstances of the fall, and various quality of life indicators. A total of 44 individuals (32 females/11 males/1 not reported) aged 27 to 82 years (mean = 58 yrs) completed the survey. Seventy-five percent (n = 33) reported falling at least once in 6 months and 48% (n = 12) of those that fell sustained an injury. The majority (87.5%) of the falls occurred inside the home. Most individuals (76.7%; n = 33) reported concerns about falling and 65.9% (n = 29) limited their activities because of their concern of falling. Falls are prevalent in wheelchair and scooter users with MS. The observations highlight the need for interventions targeting this segment of the MS community.

Incidental findings in trauma patients: dedicated communication with the primary care physician ensures adequate follow-up.

BACKGROUND: Frequent use of computed tomography (CT) in trauma patients results in frequent detection of non-trauma-related incidental findings (IFs). Inpatient documentation and disclosure at discharge are infrequent, even when they are potentially serious. We aimed to not only identify the incidence of IFs but also to evaluate the effectiveness of an intervention to trigger follow-up. METHODS: In this before-after study, all trauma patients evaluated by the trauma surgery service who underwent CT were admitted for >24 h, had at least one IF requiring follow-up, and had a primary care physician (PCP) employed in our health care system were identified. The historical control period was from January 2006 to December 2008. The intervention period was from December 2011 to September 2012. Intervention consisted of notifying the PCP via email or postal letter. The outcome of interest-the rate of follow-up-was compared between both groups. RESULTS: During the historical period, 364 (20.5 %) of 1,774 eligible trauma patients had 434 IFs requiring follow-up. During the study period, 197 (26 %) of 692 trauma patients had 212 IFs requiring follow-up. Overall, 91 % of study patients with postdischarge PCP follow-up had documented follow-up of the IF. There was a significant improvement in the rate of follow-up in the study group compared to that of the control group (51 vs. 11 %; p < 0.0001). CONCLUSIONS: Detection of IFs is common in trauma patients. A dedicated effort of communicating the presence of an IF to the patient's PCP triggered a follow-up for 91 % of patients who saw their PCP after hospital discharge.

Prosody-syntax interactions in aging: event-related potentials reveal dissociations between on-line and off-line measures.

This study used ERPs to determine whether older adults use prosody in resolving early and late closure ambiguities comparably to young adults. Participants made off-line acceptability judgments on well-formed sentences or those containing prosody-syntax mismatches. Behaviorally, both groups identified mismatches, but older subjects accepted mismatches significantly more often than younger participants. ERP results demonstrate CPS components and garden-path effects (P600s) in both groups, however, older adults displayed no N400 and more anterior P600 components. The data provide the first electrophysiological evidence suggesting that older adults process and integrate prosodic information in real-time, despite off-line behavioral differences. Age-related differences in neurocognitive processing mechanisms likely contribute to this dissociation.

The effects of contextual strength on phonetic identification in younger and older listeners.

It has often been reported that older listeners have difficulty discriminating between phonetically similar items, but may rely on contextual cues as a compensatory mechanism. The present study examined the effects of different degrees of semantic bias on speech perception in groups of younger and older listeners. Stimuli from two /g/-/k/ voice onset time (VOT) continua were presented at the end of biasing and neutral sentences. Results indicated that context strongly influenced phonetic identification in older listeners; this was true for younger listeners only in the case of less-than-ideal stimuli. Findings are discussed in relation to theories concerning age-related changes in speech processing.

Images of sexual stereotypes in rap videos and the health of African American female adolescents.

OBJECTIVE: This study sought to determine whether perceiving portrayals of sexual stereotypes in rap music videos was associated with adverse health outcomes among African American adolescent females. METHODS: African American female adolescents (n = 522) were recruited from community venues. Adolescents completed a survey consisting of questions on sociodemographic characteristics, rap music video viewing habits, and a scale that assessed the primary predictor variable, portrayal of sexual stereotypes in rap music videos. Adolescents also completed an interview that assessed the health outcomes and provided urine for a marijuana screen. RESULTS: In logistic regression analyses, adolescents who perceived more portrayals of sexual stereotypes in rap music videos were more likely to engage in binge drinking (OR 3.8, 95% CI 1.32-11.04, p = 0.01), test positive for marijuana (OR 3.4, 95% CI 1.19-9.85, p = 0.02), have multiple sexual partners (OR 1.9, 95% CI 1.01-3.71, p = 0.04), and have a negative body image (OR 1.5, 95% CI 1.02-2.26, p = 0.04). This is one of the first studies quantitatively examining the relationship between cultural images of sexual stereotypes in rap music videos and a spectrum of adverse health outcomes in African American female adolescents. CONCLUSIONS: Greater attention to this social issue may improve the health of all adolescent females.

ERP effects of the processing of syntactic long-distance dependencies.

In behavioral studies on sentence comprehension, much evidence indicates that shorter dependencies are preferred over longer dependencies, and that longer dependencies incur a greater processing cost. However, it remains uncertain which of the various steps involved in the processing of long-distance dependencies is responsible for the increased cost of longer dependencies. Previous sentence comprehension studies using event-related potentials (ERPs) have revealed response components that reflect the construction [J. King, M. Kutas, Who did what and when? Using word- and clause-level ERPs to monitor working memory usage in reading. Journal of Cognitive Neuroscience, 7, (1995) 376-395.] and completion [E. Kaan, A. Harris, E. Gibson, P. Holcomb, The P600 as an index of syntactic integration difficulty. Language and Cognitive Processes, 5, (2000) 159-201.] of long-distance wh-dependencies. This article reports one off-line rating study and one ERP study that manipulated both the presence of wh-dependencies and the length of the dependencies (one clause vs. two clauses), with the aim of clarifying the locus of length-sensitivity and the functional role of associated ERP components. Results of the off-line study confirm that longer wh-dependencies incur greater processing cost. Results of the ERP study indicate that both a sustained anterior negativity that follows the initiation of the wh-dependency and also a late posterior positivity (P600) that marks the completion of the dependency are sensitive to the presence of a wh-dependency, but do not show amplitude variations reflecting the length of the dependency. However, the P600 is delayed when it marks the completion of a longer wh-dependency. This suggests that both the sustained negativity and the P600 reflect length-insensitive aspects of the construction of syntactic dependencies. In addition, an N400 component is elicited in the middle of the two clause wh-dependency, upon encountering a verb with an argument structure that prevents completion of the dependency.