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BackgroundAn international randomized clinical trial (RCT) on pre-exposure prophylaxis (PrEP) as an human immunodeficiency virus (HIV)-prevention intervention found that taken on a daily basis, PrEP was safe and effective among men who have sex with men (MSM) and male-to-female transgender women. Within the context of the HIV epidemic in the United States (US), MSM and transgender women are the most appropriate groups to target for PrEP implementation at the population level; however, their perspectives on evidenced-based biomedical research and the results of this large trial remain virtually unknown. In this study, we examined the acceptability of individual daily use of PrEP and assessed potential barriers to community uptake.MethodsWe conducted semi-structured interviews with an ethnoracially diverse sample of thirty HIV-negative and unknown status MSM (n = 24) and transgender women (n = 6) in three California metropolitan areas. Given the burden of disease among ethnoracial minorities in the US, we purposefully oversampled for these groups. Thematic coding and analysis of data was conducted utilizing an approach rooted in grounded theory.ResultsWhile participants expressed general interest in PrEP availability, results demonstrate: a lack of community awareness and confusion about PrEP; reservations about PrEP utilization, even when informed of efficacious RCT results; and concerns regarding equity and the manner in which a PrEP intervention could be packaged and marketed in their communities.ConclusionsIn order to effectively reduce HIV health disparities at the population level, PrEP implementation must take into account the uptake concerns of those groups who would actually access and use this biomedical intervention as a prevention strategy. Recommendations addressing these concerns are provided.

Objective: The study objective was to describe the effect of socioeconomic status (SES) on mortality among people with type 2 diabetes.Research Design and Methods: We used a population-based national electronic diabetes database for 35- to 84-year-olds in Scotland for 2001-2007 linked to mortality records. SES was derived from an area-based measure with Q5 and Q1 representing the most deprived and affluent quintiles, respectively. Poisson regression was used to estimate relative risks (RRs) for mortality among people with type 2 diabetes compared with the population without diabetes stratified by age (35-64 and 65-84 years), sex, duration of diabetes (< 2 and ≥ 2 years), and SES.Results: Complete data were available for 210,994 eligible individuals (99.4%), and there were 33,842 deaths. Absolute mortality from all causes among people with type 2 diabetes increased with increasing age and socioeconomic deprivation and was higher for men than women. RR for mortality associated with type 2 diabetes was highest for women aged 35-64 years in Q1 with diabetes duration < 2 years at 4.83 (95% CI 3.15-7.40) and lowest for men aged 65-84 years in Q5 with diabetes duration ≥ 2 years at 1.13 (1.03-1.24).Conclusions: SES modifies the association between type 2 diabetes and mortality so that RR for mortality is lower among more deprived populations. Age, sex, and duration of diabetes also interact with type 2 diabetes to influence RR of mortality. Differences in prevalence of comorbidities may explain these findings. [ABSTRACT FROM AUTHOR]

Presents evidence for the existence of a novel pregnancy-associated soluble variant of the vascular endothelial growth factor (VEGF) receptor, Flt-1. Purification of the VEGF-binding protein; Measurement of the extent of VEGF-binding sites; Presence of VEGF-binding activity in the amniotic fluid; Failure to detect additional RNA species by reverse transcriptase polymerase chain reaction.

Objectives: We aimed to compare a new primary care outcome measure-the Patient Enablement Instrument (PEI)-against two established satisfaction measures [the Medical Interview Satisfaction Scale (MISS) and the Consultation Satisfaction Questionnaire (CSQ)]. Specifically, we sought (i) to test whether enablement and satisfaction are related or separate concepts; and (ii) to assess whether the internal consistency of the PEI might be enhanced by the inclusion of items from the satisfaction instruments.Methods: Questionnaire forms containing the three instruments in a variety of combinations were distributed to a total of 818 patients attending for routine surgery consultations in three urban general practices of varying socio-economic mix. The main outcome measures were: scores on the PEI; scores on the CSQ, the MISS and their individual components; rank correlations between scores on the PEI and scores on the CSQ, the MISS and their component subscales; and Cronbach's alpha coefficient for the PEI.Results: Overall mean scores, expressed as percentages of maximum scores attainable, were 44.1% for the PEI, 76.9% for the CSQ and 77.6% for the MISS. Rank correlations between PEI scores and scores for the complete CSQ and MISS instruments were 0.48 (P < 0.01) and 0.47 (P < 0.01), respectively. Correlations of PEI scores with individual component scores on the CSQ were generally lower and ranged from 0.14 to 0.53; correlations of PEI scored with MISS component scores were also generally lower and ranged from 0.21 to 0.53. Internal consistency of the PEI items (assessed by Cronbach's alpha coefficient) was lowered when items from the CSQ or MISS were added.Conclusions: The study shows that 'enablement' is a primary care outcome measure which is related to but is different from general satisfaction. [ABSTRACT FROM AUTHOR]

Objective: To determine the relation between deprivation category, triage score and accident and emergency (A&E) attendance for children under the age of 13.Design: Retrospective study of all children attending an A&E department over one year.Setting: A paediatric teaching hospital in Edinburgh.Subjects: All children attending the A&E department who had a postcode and a triage score documented on attendance. The postcode was used to determine the deprivation category and the triage scored the severity of illness or injury.Main Outcome Measure: The relation between deprivation category, triage score and frequency of attendance.Results: There is a trend towards increased attendance in all triage categories for deprivation categories 6 and 7.Conclusions: Attendance at A&E is not only related to severity of injury but also to deprivation category. The reason why people from disadvantaged areas attend more frequently needs further evaluation. [ABSTRACT FROM AUTHOR]

Objectives: To explore the relationship between adult attention deficit hyperactivity disorder (ADHD) subtypes and neuropsychological functioning among U.S. soldiers.Methods: Deploying soldiers (N = 260) completed the World Health Organization Adult ADHD Self-Report Scale (ASRS) Screener. Cognitive tests, a deployment health-history questionnaire, and the post-traumatic stress disorder (PTSD) Checklist-Military Version were completed by subsamples of available participants.Results: The prevalence of positive ASRS screens was 10.4%. ASRS scores were correlated with PTSD avoidance (n = 63, p = 0.37, p = 0.003), hyperarousal (n = 63, p = 0.25, p = 0.047), and total PTSD scores (n = 62, p = 0.33, p = 0.009); and all six moods (e.g., anger, anxiety) scale scores (n = 110; p = -0.37 to 0.43). ASRS was also correlated with scores on the match-to-sample (n = 110, p = -0.23, p = 0.014) and emotional Stroop (n = 108, p = -0.23, p = 0.016) tasks. In addition, a differential pattern between subtypes of ADHD was noted with regard to cognitive functioning, mood, and combat stress symptomatology.Conclusions: Although the results are preliminary given the sample size, the prevalence and comorbidities of ADHD appear to be similar among military and nonmilitary populations. [ABSTRACT FROM AUTHOR]

The pituitary gland produces and secretes a variety of hormones that are essential to life, such as for the regulation of growth and development, metabolism, reproduction, and the stress response. This is achieved through an intricate signalling interplay between the brain and peripheral feedback signals that shape pituitary cell excitability by regulating the ion channel properties of these cells. In addition, endocrine anterior pituitary cells spontaneously fire action potentials to regulate the intracellular calcium ([Ca 2+ ] i ) level, an essential signalling conduit for hormonal secretion. To this end, pituitary cells must regulate their resting membrane potential (RMP) close to the firing threshold, but the molecular identity of the ionic mechanisms responsible for this remains largely unknown. Here, we revealed that the sodium leak channel NALCN, known to modulate neuronal excitability elsewhere in the brain, regulates excitability in the mouse anterior endocrine pituitary cells. Using viral transduction combined with powerful electrophysiology methods and calcium imaging, we show that NALCN forms the major Na + leak conductance in these cells, appropriately tuning cellular RMP for sustaining spontaneous firing activity. Genetic depletion of NALCN channel activity drastically hyperpolarised these cells, suppressing their firing and [Ca 2+ ] i oscillations. Remarkably, despite this profound function of NALCN conductance in controlling pituitary cell excitability, it represents a very small fraction of the total cell conductance. Because NALCN responds to hypothalamic hormones, our results also provide a plausible mechanism through which hormonal feedback signals from the brain and body could powerfully affect pituitary activity to influence hormonal function. KEY POINTS: Pituitary hormones are essential to life as they regulate important physiological processes, such as growth and development, metabolism, reproduction and the stress response. Pituitary hormonal secretion relies on the spontaneous electrical activity of pituitary cells and co-ordinated inputs from the brain and periphery. This appropriately regulates intracellular calcium signals in pituitary cells to trigger hormonal release. Using viral transduction in combination with electrophysiology and calcium imaging, we show that the activity of the background leak channel NALCN is a major controlling factor in eliciting spontaneous electrical activity and intracellular calcium signalling in pituitary cells. Remarkably, our results revealed that a minute change in NALCN activity could have a major influence on pituitary cell excitability. Our study provides a plausible mechanism through which the brain and body could intricately control pituitary activity to influence hormonal function., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Normal reproductive function and fertility rely on the rhythmic secretion of gonadotropin-releasing hormone (GnRH), which is driven by the hypothalamic GnRH pulse generator. A key regulator of the GnRH pulse generator is the posterodorsal subnucleus of the medial amygdala (MePD), a brain region that is involved in processing external environmental cues, including the effect of stress. However, the neuronal pathways enabling the dynamic, stress-triggered modulation of GnRH secretion remain largely unknown. Here, we employ in silico modelling in order to explore the impact of dynamic inputs on GnRH pulse generator activity. We introduce and analyse a mathematical model representing MePD neuronal circuits composed of GABAergic and glutamatergic neuronal populations, integrating it with our GnRH pulse generator model. Our analysis dissects the influence of excitatory and inhibitory MePD projections' outputs on the GnRH pulse generator's activity and reveals a functionally relevant MePD glutamatergic projection to the GnRH pulse generator, which we probe with in vivo optogenetics. Our study sheds light on how MePD neuronal dynamics affect the GnRH pulse generator activity and offers insights into stress-related dysregulation.

Hematologic emergencies are bleeding or clotting disorders that are hereditary or acquired and must be treated emergently to avoid significant morbidity or mortality. Patients experiencing a hematologic emergency may present with spontaneous bleeding, jaundice, petechiae, or purpura. Initial diagnostic testing should include a complete blood count. Patients who have bleeding associated with a hereditary disorder should receive clotting factor replacement before diagnostic testing. Acute chest syndrome is an uncommon but serious complication of sickle cell disease. Hemolysis caused by autoimmune disorders or iatrogenic errors from blood product transfusions has a distinct clinical presentation and requires immediate action. Severe thrombocytopenia presenting as immune or thrombotic thrombocytopenic purpura should be differentiated and treated appropriately. Disseminated intravascular coagulation and trauma coagulopathy are sometimes confused with each other, but both can cause serious injury and require unique treatments. Primary care physicians should promptly recognize patients who require emergent referral to a hematologic specialist.

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder. Besides major deficits in motor coordination, patients may also display sensory and cognitive impairments, which are often overlooked despite being inherently part of the PD symptomatology. Amongst those symptoms, respiration, a key mechanism involved in the regulation of multiple physiological and neuronal processes, appears to be altered. Importantly, breathing patterns are highly correlated with the animal's behavioral states. This raises the question of the potential impact of behavioral state on respiration deficits in PD. To answer this question, we first characterized the respiratory parameters in a neurotoxin-induced rat model of PD (6-OHDA) across three different vigilance states: sleep, quiet waking and exploration. We noted a significantly higher respiratory frequency in 6-OHDA rats during quiet waking compared to Sham rats. A higher respiratory amplitude was also observed in 6-OHDA rats during both quiet waking and exploration. No effect of the treatment was noted during sleep. Given the relation between respiration and olfaction and the presence of olfactory deficits in PD patients, we then investigated the odor-evoked sniffing response in PD rats, using an odor habituation/cross-habituation paradigm. No substantial differences were observed in olfactory abilities between the two groups, as assessed through sniffing frequency. These results corroborate the hypothesis that respiratory impairments in 6-OHDA rats are vigilance-dependent. Our results also shed light on the importance of considering the behavioral state as an impacting factor when analyzing respiration., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Anxiety in pregnancy and after giving birth (the perinatal period) is highly prevalent but under-recognised. Robust methods of assessing perinatal anxiety are essential for services to identify and treat women appropriately., Aims: To determine which assessment measures are most psychometrically robust and effective at identifying women with perinatal anxiety (primary objective) and depression (secondary objective)., Method: We conducted a prospective longitudinal cohort study of 2243 women who completed five measures of anxiety and depression (Generalized Anxiety Disorder scale (GAD) two- and seven-item versions; Whooley questions; Clinical Outcomes in Routine Evaluation (CORE-10); and Stirling Antenatal Anxiety Scale (SAAS)) during pregnancy (15 weeks, 22 weeks and 31 weeks) and after birth (6 weeks). To assess diagnostic accuracy a sample of 403 participants completed modules of the Mini-International Neuropsychiatric Interview (MINI)., Results: The best diagnostic accuracy for anxiety was shown by the CORE-10 and SAAS. The best diagnostic accuracy for depression was shown by the CORE-10, SAAS and Whooley questions, although the SAAS had lower specificity. The same cut-off scores for each measure were optimal for identifying anxiety or depression (SAAS ≥9; CORE-10 ≥9; Whooley ≥1). All measures were psychometrically robust, with good internal consistency, convergent validity and unidimensional factor structure., Conclusions: This study identified robust and effective methods of assessing perinatal anxiety and depression. We recommend using the CORE-10 or SAAS to assess perinatal anxiety and the CORE-10 or Whooley questions to assess depression. The GAD-2 and GAD-7 did not perform as well as other measures and optimal cut-offs were lower than currently recommended.

The coronavirus disease 2019 (COVID-19) pandemic and associated shelter-in-place ordinances passed in the first year of the pandemic rapidly limited access to in-person social interactions, raising concerns of diminishing social support and community cohesion while psychological stressors increased. For LGBTQIA+ people, connectedness to the LGBTQIA+ community is known to buffer against the harmful effects of stressors and decrease risks for poor psychological and behavioral health outcomes. The current study uses qualitative cross-sectional and trajectory analysis methods to characterize how LGBTQIA+ people's perceptions of community connectedness shifted during the first year of the pandemic. A convenience sample of LGBTQIA+-identified people in the U.S. completed an initial online survey in September 2020 ( n = 298 and a follow-up survey in September 2021 ( n = 129). The survey included changes in connectedness to the LGBTQIA+ community since the pandemic's beginning. Thus, we used both cross-sectional (between-person analyses) and longitudinal trajectory (within-person analyses) qualitative approaches to understanding changes in LGBTQIA+ people's sense of connection to the LGBTQIA+ community across the first two years of the COVID-19 pandemic. Eight cross-cutting themes (related to identity shifts/exploration, disconnection, online connections, and increased awareness of social justice issues) were identified and then organized within each level of the Social-Ecological Model of LGBTQIA+ wellbeing (i.e., the individual-, couple-, interpersonal-, organizational-, community-, and chronosystem- level). Given the importance of social support for LGBTQIA+ wellbeing, more longitudinal research is needed to determine whether these changes persist after the resolution of the acute phase of the pandemic.

Background: Leadership of clinical trials confers national recognition and promotes academic advancement. We hypothesized that women would be underrepresented among principal investigators (PIs) of hip and knee arthroplasty clinical trials in the United States., Methods: A query of hip and knee arthroplasty clinical trials from 2015 to 2021 was performed on ClinicalTrials.gov. Clinical trials were included if they involved a U.S.-based orthopaedic-surgeon PI. We analyzed the sex representation of arthroplasty PIs among junior-level (assistant professor) and senior-level (associate or full professor) faculty. Participation-to-prevalence ratios (PPRs) were calculated by comparing the sex representation among arthroplasty PIs with that among academic arthroplasty faculty at institutions conducting hip and knee arthroplasty clinical trials. A PPR of <0.8 indicated underrepresentation and a PPR of >1.2 indicated overrepresentation., Results: A total of 157 clinical trials involving 192 arthroplasty PIs were included. Of these PIs, only 2 (1.0%) were women. PIs were mostly funded by academic institutions (66%) and industry (33%). U.S. federal sources funded a minority (1%) of PIs. Of the 243 male arthroplasty faculty who were eligible, 190 men (78.2%) served as PIs. In contrast, of the 17 female arthroplasty faculty who were eligible, only 2 women (11.8%) served as PIs (p < 0.001). Across the entire cohort of arthroplasty PIs, women were underrepresented (PPR = 0.16), whereas men were equitably represented (PPR = 1.06). Women were underrepresented at the assistant professor (PPR = 0.0), associate professor (PPR = 0.52), and full professor (PPR = 0.58) levels., Conclusions: Women were underrepresented among PIs of hip and knee arthroplasty clinical trials, which may lead to disparities in academic promotion and advancement. More research is needed to understand the potential barriers to female leadership of clinical trials. Greater awareness and engagement are needed to create sex equity in clinical trial leadership for hip and knee arthroplasty research., Clinical Relevance: The underrepresentation of women among arthroplasty PIs may lead to fewer options in surgical providers for patients and may limit access to musculoskeletal care for certain patient populations. A diverse arthroplasty workforce can promote attention to issues that disproportionately affect historically underrepresented and vulnerable patient populations., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H580 )., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)