Bidirectional Associations Between Loneliness, Emotional Support, and Sleep in Daily Life.

OBJECTIVE: Evidence suggests a link between positive social relationship perceptions and improved sleep (e.g., quality, efficiency) across the life span. Less work has probed the directionality of these relationships. Here, we report findings from the first study to examine bidirectional between- and within-person associations between loneliness and emotional support with daily life measures of sleep. METHODS: Participants were 389 healthy adults aged 40 to 64 years (61% female) who completed hourly surveys assessing loneliness and perceptions of emotional support over the course of 4 days. Measures of actigraphy-assessed sleep and nightly sleep quality were also assessed for 7 to 10 days. RESULTS: Individuals with lower average daily loneliness showed higher sleep quality and efficiency than individuals with higher loneliness (r = -0.19, p < .001; r = -0.14, p = .008, respectively), and greater average emotional support was likewise linked with better sleep quality (r = 0.18, p < .001). Controlling for neuroticism attenuated the effects of average loneliness on sleep. Within-person analyses showed unexpected bidirectional effects. Specifically, days in which people felt relatively lonelier were followed by nights with greater sleep efficiency (γ = 1.08, p = .015), and nights when people reported relatively poorer sleep quality were followed by days with greater emotional support (γ = -0.04, p = .013). These unexpected findings are probed in exploratory analyses. CONCLUSIONS: Individuals with higher loneliness and lower emotional support report poorer sleep quality and efficiency, on average. Day-to-day fluctuations in perceptions of social relationships may affect the following night's sleep, and vice versa.

Behavioral-Social Rhythms and Cardiovascular Disease Risk in Retired Night Shift Workers and Retired Day Workers.

OBJECTIVE: Stability in the timing of key daily routine behaviors such as working/doing housework, sleeping, eating, and engaging in social interactions (i.e., behavioral-social rhythms) contributes to health. This study examined whether behavioral-social rhythms were associated with cardiovascular disease (CVD) risk factors in retired night shift workers and retired day workers and explored whether past night shift work exposure moderated this association. METHODS: A total of 154 retired older adults participated in this study. Multiple logistic regression models were used to examine associations between behavioral-social rhythms and CVD risk factors. Independent variables included Social Rhythm Metric (SRM)-5 score and actigraphy rest-activity rhythm intradaily variability (IV) and interdaily stability (IS). Dependent variables were metabolic syndrome prevalence and its five individual components. RESULTS: More regular behavioral-social rhythms were associated with lower odds of prevalent metabolic syndrome (SRM: odds ratio [OR] = 0.57, 95% confidence interval [CI] = 0.35-0.88; IV: OR = 4.00, 95% CI = 1.86-8.58; IS: OR = 0.42, 95% CI = 0.24-0.73) and two of its individual components: body mass index (SRM: OR = 0.56, 95% CI = 0.37-0.85; IV: OR = 2.84, 95% CI = 1.59-5.07; IS: OR = 0.42, 95% CI = 0.26-0.68) and high-density lipoprotein cholesterol (SRM: OR = 0.49, 95% CI = 0.30-0.80; IV: OR = 2.49, 95% CI = 1.25-4.96; IS: OR = 0.35, 95% CI = 0.19-0.66). Past shift work history did not moderate the association between behavioral-social rhythms and metabolic syndrome. CONCLUSIONS: Behavioral-social rhythms were related to CVD risk factors in retired adults regardless of prior night shift work exposure. Older retired workers may benefit from education and interventions aiming to increase behavioral-social rhythm regularity.

Improving community antibiotic prescribing to keep antibiotics working in Aotearoa New Zealand.

Antibiotic resistance, principally a consequence of the human use of antibiotics dispensed in the community, is a relentlessly growing threat to human health in Aotearoa New Zealand. Reducing the prescription of antibiotics for conditions in which they confer no benefit is the most effective method of slowing the spread of antibiotic resistance. In Aotearoa New Zealand, as in many other nations, antibiotic "treatment" of acute respiratory tract infections is the most important component of unnecessary antibiotic use. Because of the ethnic inequities in the incidence and consequences of infectious diseases in Aotearoa New Zealand, Maori and Pacific patients should receive antibiotic treatment more frequently than patients of other ethnicities. However, Maori and Pacific people who present to their doctor with conditions that do not require antibiotic treatment deserve the same excellent treatment as anyone else and should not be prescribed an antibiotic when it will provide no benefit. Setting annual goals for reductions in community antibiotic dispensing has been an effective method to encourage sustained improvements in antibiotic prescribing in other nations, and may help to quickly reduce inappropriate antibiotic prescribing in Aotearoa New Zealand.

Fundamental Sex Differences in Cocaine-Induced Plasticity of Dopamine D1 Receptor- and D2 Receptor-Expressing Medium Spiny Neurons in the Mouse Nucleus Accumbens Shell.

Background: Cocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in dopamine D1 receptor-expressing medium spiny neurons (D1R-MSNs), with little if any impact on dopamine D2 receptor-expressing medium spiny neurons (D2R-MSNs). In females, the effect of cocaine on accumbens shell D1R- and D2R-MSN neurophysiology has yet to be reported, nor have estrous cycle effects been accounted for. Methods: We used a 5-day locomotor sensitization paradigm followed by a 10- to 14-day drug-free abstinence period. We then obtained ex vivo whole-cell recordings from fluorescently labeled D1R-MSNs and D2R-MSNs in the nucleus accumbens shell of male and female mice during estrus and diestrus. We examined accumbens shell neuronal excitability as well as miniature excitatory postsynaptic currents (mEPSCs). Results: In females, we observed alterations in D1R-MSN excitability across the estrous cycle similar in magnitude to the effects of cocaine in males. Furthermore, cocaine shifted estrous cycle-dependent plasticity from intrinsic excitability changes in D1R-MSNs to D2R-MSNs. In males, cocaine treatment produced the anticipated drop in D1R-MSN excitability with no effect on D2R-MSN excitability. Cocaine increased mEPSC frequencies and amplitudes in D2R-MSNs from females in estrus and mEPSC amplitudes of D2R-MSNs from females in diestrus. In males, cocaine increased both D1R- and D2R-MSN mEPSC amplitudes with no effect on mEPSC frequencies. Conclusions: Overall, while there are similar cocaine-induced disparities regarding the relative excitability of D1R-MSNs versus D2R-MSNs between the sexes, this is mediated through reduced D1R-MSN excitability in males, whereas it is due to heightened D2R-MSN excitability in females.

The nucleus accumbens shell (NAcSh) is a key brain region involved in motivation and reward. It is primarily composed of dopamine D₁ and D₂ receptor­expressing medium spiny neurons (D1R and D2R neurons). Previous studies in males demonstrated that D1R neurons undergo intrinsic plasticity following cocaine exposure, believed to underlie aspects of drug addiction. We confirmed this effect. It has also been generally assumed that females would show similar responses. However, this does not appear to be true, and our data indicate 2 novel findings. First, under baseline conditions, the estrous cycle produces recurring changes in D1R neuron excitability, with no changes observed in D2R neurons. Second, following cocaine exposure, D1R neuron plasticity is arrested, and D2R neurons begin to show estrous cycle effects on intrinsic excitability. These results indicate profound sex differences in the neurophysiological underpinnings of motivational behaviors including drug addiction.

Impact of antiplatelet therapy on microvascular thrombosis during ST-elevation myocardial infarction.

During an acute coronary syndrome, atherosclerotic plaque rupture triggers platelet activation and thrombus formation, which may completely occlude a coronary artery leading to ST-elevation myocardial infarction (STEMI). Although emergency percutaneous coronary intervention (PCI) is effective in re-opening the main coronary arteries, the downstream microvasculature can become obstructed by embolised plaque material and thrombus. Dual antiplatelet therapy is recommended by guidelines and used routinely for the management of STEMI to reduce the risk of recurrent atherothrombotic events. However it is unclear to what extent antiplatelet therapy reduces microvascular thrombosis, largely because most tools to assess microvascular thrombosis only became available after antiplatelet therapy was already used in the majority of patients. Platelets play a central role in key aspects of microvascular thrombosis, such as atherosclerotic plaque-induced thrombus development, inflammation and microvascular dysfunction, making them a potential target for novel therapeutic interventions. Currently, more potent antiplatelet agents like GPIIb/IIIa inhibitors may be administered during PCI directly into coronary arteries with high thrombus burden but it is not well-established whether this reduces microvascular thrombosis and they significantly increase the risk of bleeding. In this review article we discuss the role of platelets in microvascular thrombosis, describe how microvascular thrombosis and obstruction can be assessed clinically and explore potential new antiplatelet treatments for this. In particular, we highlight novel antiplatelet drugs targeting the platelet receptor GPVI, as well as PAR4, GPIb-IX-V and 5HT2A receptors. We also discuss the potential benefit of P-selectin inhibitors as they have proven to be effective in reducing microvascular thrombosis in sickle-cell disease which could translate into potential benefits in acute coronary syndrome.

GPVI as an effective antithrombotic target.

Glycoprotein (GP) VI plays a major role in thrombosis but not haemostasis, making it a promising antithrombotic target. The primary role of GPVI on the surface of platelets is a signalling receptor for collagen, which is one of the most potent thrombotic sub-endothelial components that is exposed by atherosclerotic plaque rupture. Inhibition of GPVI has therefore been investigated as a strategy for treatment and prevention of atherothrombosis, such as during stroke and acute coronary syndromes. A range of specific GPVI inhibitors have been characterised and 2 of these inhibitors, glenzocimab and revacept, have completed phase II clinical trials in ischemic stroke. In this review, we summarise mechanisms of GPVI activation and the latest progress of clinically tested GPVI inhibitors, including their mechanisms of action. By focussing on what is known about GPVI activation, we also discuss whether alternate strategies could also be used to target GPVI.

Same sleep disorder but different sleep patterns: individual differences in sleep health and depressive symptomatology in veterans with obstructive sleep apnea.

PURPOSE: Poor sleep health, a composite measure of key sleep characteristics, may relate to increased depressive symptoms among individuals treated for obstructive sleep apnea. The current investigation examined the association between sleep health and depressive symptomatology. METHODS: In a pilot sample of 13 symptomatic OSA military Veterans with adequate CPAP adherence (mean age = 54.8, 76.9% male, 100% White), empirically validated cutoffs were applied to actigraphy-derived sleep variables: duration, efficiency, timing, and regularity. RESULTS: Participants with zero optimal sleep scores had significantly higher depressive scores (M = 19.0, SD = 3.0) than participants with 1 or 2 (M = 9.8. SD = 4.3, p = .016) and 3 or more optimal sleep scores (M = 11.3, SD = 4.9, p = .038). CONCLUSIONS: These preliminary findings suggest that better sleep health was associated with lower depressive symptomatology. Future work should replicate these preliminary findings in a larger sample.

Identification of a system for hydroxamate xenosiderophore-mediated iron transport in Burkholderia cenocepacia.

One of the mechanisms employed by the opportunistic pathogen Burkholderia cenocepacia to acquire the essential element iron is the production and release of two ferric iron chelating compounds (siderophores), ornibactin and pyochelin. Here we show that B. cenocepacia is also able to take advantage of a range of siderophores produced by other bacteria and fungi ('xenosiderophores') that chelate iron exclusively by means of hydroxamate groups. These include the tris-hydroxamate siderophores ferrioxamine B, ferrichrome, ferricrocin and triacetylfusarinine C, the bis-hydroxamates alcaligin and rhodotorulic acid, and the monohydroxamate siderophore cepabactin. We also show that of the 24 TonB-dependent transporters encoded by the B. cenocepacia genome, two (FhuA and FeuA) are involved in the uptake of hydroxamate xenosiderophores, with FhuA serving as the exclusive transporter of iron-loaded ferrioxamine B, triacetylfusarinine C, alcaligin and rhodotorulic acid, while both FhuA and FeuA are able to translocate ferrichrome-type siderophores across the outer membrane. Finally, we identified FhuB, a putative cytoplasmic membrane-anchored ferric-siderophore reductase, as being obligatory for utilization of all of the tested bis- and tris-hydroxamate xenosiderophores apart from alcaligin.

Fabry-specific treatment in Australia: time to align eligibility criteria with international best practices.

BACKGROUND: Disease-specific therapy aims to improve symptoms, stabilise current disease and delay progression in patients with Fabry disease. In Australia, treatment access is subject to eligibility criteria initially established in 2004. Patients and their clinicians question why these criteria have remained unchanged despite significant progress in disease understanding. AIMS: Appraise the clinical quality of the Australian treatment access criteria. METHODS: The Fabry Australia Medical Advisory Committee (N = 6) used the Appraisal of Guidelines for REsearch and Evaluation Global Rating Scale (AGREE II GRS) to assess the clinical quality of the current treatment eligibility criteria. They reviewed the literature, developed 17 clinical statements to help guide reforms of the eligibility criteria and achieved consensus (achievement of ≥75% agreement in the range 5-7 on a 7-point Likert scale) through anonymous voting. The findings were applied to develop proposals for revised classification and treatment initiation criteria. RESULTS: The current treatment eligibility criteria underperformed on the AGREE II GRS. They are pragmatic but out-of-step with contemporary data. Consensus was achieved on all 17 proposed clinical statements. There was strong agreement to differentiate classical male Fabry patients to facilitate timelier access to Fabry-specific treatment. There was also agreement on the value of adopting relevant organ involvement criteria in classical female patients and patients with non-classical disease. CONCLUSIONS: Australian access criteria are misaligned with current clinical evidence. The clinical statements and proposed classification and initiation criteria should prompt discussions to support more equitable access to treatment and better align Australian practice with contemporary evidence and international guidelines.

Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell medium spiny neurons via NMDAR activation in a sex-dependent manner.

Recent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4 g/kg) to acetic acid in vivo to guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males > females). Ex vivo electrophysiology recordings of NAcSh medium spiny neurons (MSN) in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh MSN excitability in both sexes. N-methyl-D-aspartate receptor (NMDAR) antagonists, AP5 and memantine, robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males and were not estrous cycle dependent. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain from ethanol consumption. Furthermore, these findings also highlight a specific sex-dependent sensitivity in females to acetic acid-NMDAR interactions. This may underlie their more rapid advancement to alcohol use disorder and increased risk of alcohol related neurodegeneration compared to males.

Relative bioavailability of fedratinib through various alternative oral administration methods in healthy adults.

Fedratinib is an oral Janus kinase 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis; however, some patients have difficulty with oral dosing. This randomized, phase 1, open-label, 2-part crossover study evaluated the relative bioavailability, safety, tolerability, taste, and palatability of fedratinib resulting from various alternative oral administration methods in healthy adults. Participants could receive fedratinib 400 mg orally as intact capsules along with a nutritional supplement; as contents of capsules dispersed in a nutritional supplement, delivered via nasogastric tube; or as a divided dose of 200 mg orally twice daily as intact capsules with a nutritional supplement. Fifty-eight participants received treatment. Total exposure to fedratinib was similar after oral administration of intact capsules or when dispersed in a nutritional supplement (area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration geometric mean ratio [AUC0-t GMR] [90% CI], 1.007 [0.929-1.092]). Total exposure to fedratinib was slightly reduced following nasogastric administration (AUC0-t GMR 0.850 [0.802-0.901]) and as a divided dose (AUC0-t GMR 0.836 [0.789-0.886]). No new safety signals were identified for fedratinib, and most participants found the taste and palatability acceptable when dispersed in a nutritional supplement. Overall, results suggest no clinically meaningful differences in total exposure to fedratinib between the tested oral administration methods. These findings may facilitate administration of fedratinib to patients who are intolerant of swallowing the capsule dosage form. (ClinicalTrials.gov: NCT05051553).

Sex differences in mouse infralimbic cortex projections to the nucleus accumbens shell.

BACKGROUND: The nucleus accumbens (NAc) is an important region in motivation and reward. Glutamatergic inputs from the infralimbic cortex (ILC) to the shell region of the NAc (NAcSh) have been implicated in driving the motivation to seek reward through repeated action-based behavior. While this has primarily been studied in males, observed sex differences in motivational circuitry and behavior suggest that females may be more sensitive to rewarding stimuli. These differences have been implicated for the observed vulnerability in women to substance use disorders. METHODS: We used an optogenetic self-stimulation task in addition to ex vivo electrophysiological recordings of NAcSh neurons in mouse brain slices to investigate potential sex differences in ILC-NAcSh circuitry in reward-seeking behavior. Glutamatergic neurons in the ILC were infected with an AAV delivering DNA encoding for channelrhodopsin. Entering the designated active corner of an open field arena resulted in photostimulation of the ILC terminals in the NAcSh. Self-stimulation occurred during two consecutive days of testing over three consecutive weeks: first for 10 Hz, then 20 Hz, then 30 Hz. Whole-cell recordings of medium spiny neurons in the NAcSh assessed both optogenetically evoked local field potentials and intrinsic excitability. RESULTS: Although both sexes learned to seek the active zone, within the first day, females entered the zone more than males, resulting in a greater amount of photostimulation. Increasing the frequency of optogenetic stimulation amplified female reward-seeking behavior. Males were less sensitive to ILC stimulation, with higher frequencies and repeated days required to increase male reward-seeking behavior. Unexpectedly, ex vivo optogenetic local field potentials in the NAcSh were greater in slices from male animals. In contrast, female medium-spiny neurons (MSNs) displayed significantly greater intrinsic neuronal excitability. CONCLUSIONS: Taken together, these data indicate that there are sex differences in the motivated behavior driven by glutamate within the ILC-NAcSh circuit. Though glutamatergic signaling was greater in males, heightened intrinsic excitability in females appears to drive this sex difference.

The shell region of the nucleus accumbens (NAcSh) is involved in motivation and reward. It receives excitatory glutamatergic inputs from multiple brain regions. One specific region is the infralimbic cortex (ILC), which when activated, influences reward-seeking behavior. While previous research has focused on males, there are inherent sex differences in reward circuitry and reward-seeking behavior. Using an optogenetic self-stimulation task, in addition to ex vivo electrophysiological recordings, we found inherent sex differences in the ILC-NAcSh circuit in behavioral output, synaptic strength, and intrinsic neurophysiology. Female mice showed more robust reward-seeking behavior. Increasing the frequency of stimulation intensified this behavior in females, while males required higher frequencies and repeated testing days to increase their reward-seeking behavior. Surprisingly, optogenetically stimulating the ILC terminals in the NAcSh in brain slices resulted in stronger responses in males. More consistent with the behavioral data, female MSNs displayed higher intrinsic excitability. Our results suggest that there are sex differences in motivated behavior, driven by glutamatergic signaling in the ILC-NAc circuit. Despite stronger ILC-based glutamatergic signaling in males, heightened intrinsic excitability of MSNs in females seems to be the driving force behind this sex difference in reward-seeking behavior. These findings contribute to our understanding of the neural mechanisms behind sex-based differences in motivation and their potential implications for substance use disorders.

Clinical Characteristics and Outcomes of Drug-Induced Acute Kidney Injury Cases.

Introduction: Drug-induced acute kidney injury (DI-AKI) is a frequent adverse event. The identification of DI-AKI is challenged by competing etiologies, clinical heterogeneity among patients, and a lack of accurate diagnostic tools. Our research aims to describe the clinical characteristics and predictive variables of DI-AKI. Methods: We analyzed data from the Drug-Induced Renal Injury Consortium (DIRECT) study (NCT02159209), an international, multicenter, observational cohort study of enriched clinically adjudicated DI-AKI cases. Cases met the primary inclusion criteria if the patient was exposed to at least 1 nephrotoxic drug for a minimum of 24 hours prior to AKI onset. Cases were clinically adjudicated, and inter-rater reliability (IRR) was measured using Krippendorff's alpha. Variables associated with DI-AKI were identified using L1 regularized multivariable logistic regression. Model performance was assessed using the area under the receiver operating characteristic curve (ROC AUC). Results: A total of 314 AKI cases met the eligibility criteria for this analysis, and 271 (86%) cases were adjudicated as DI-AKI. The majority of the AKI cases were recruited from the United States (68%). The most frequent causal nephrotoxic drugs were vancomycin (48.7%), nonsteroidal antiinflammatory drugs (18.2%), and piperacillin/tazobactam (17.8%). The IRR for DI-AKI adjudication was 0.309. The multivariable model identified age, vascular capacity, hyperglycemia, infections, pyuria, serum creatinine (SCr) trends, and contrast media as significant predictors of DI-AKI with good performance (ROC AUC 0.86). Conclusion: The identification of DI-AKI is challenging even with comprehensive adjudication by experienced nephrologists. Our analysis identified key clinical characteristics and outcomes of DI-AKI compared to other AKI etiologies.

Modelling clinical narrative as computable knowledge: The NICE computable implementation guidance project.

Introduction: Translating narrative clinical guidelines to computable knowledge is a long-standing challenge that has seen a diverse range of approaches. The UK National Institute for Health and Care Excellence (NICE) Content Advisory Board (CAB) aims ultimately to (1) guide clinical decision support and other software developers to increase traceability, fidelity and consistency in supporting clinical use of NICE recommendations, (2) guide local practice audit and intervention to reduce unwarranted variation, (3) provide feedback to NICE on how future recommendations should be developed. Objectives: The first phase of work was to explore a range of technical approaches to transition NICE toward the production of natively digital content. Methods: Following an initial 'collaborathon' in November 2022, the NICE Computable Implementation Guidance project (NCIG) was established. We held a series of workstream calls approximately fortnightly, focusing on (1) user stories and trigger events, (2) information model and definitions, (3) horizon-scanning and output format. A second collaborathon was held in March 2023 to consolidate progress across the workstreams and agree residual actions to complete. Results: While we initially focussed on technical implementation standards, we decided that an intermediate logical model was a more achievable first step in the journey from narrative to fully computable representation. NCIG adopted the WHO Digital Adaptation Kit (DAK) as a technology-agnostic method to model user scenarios, personae, processes and workflow, core data elements and decision-support logic. Further work will address indicators, such as prescribing compliance, and implementation in document templates for primary care patient record systems. Conclusions: The project has shown that the WHO DAK, with some modification, is a promising approach to build technology-neutral logical specifications of NICE recommendations. Implementation of concurrent computable modelling by multidisciplinary teams during guideline development poses methodological and cultural questions that are complex but tractable given suitable will and leadership.

Which computable biomedical knowledge objects will be regulated? Results of a UK workshop discussing the regulation of knowledge libraries and software as a medical device.

Introduction: To understand when knowledge objects in a computable biomedical knowledge library are likely to be subject to regulation as a medical device in the United Kingdom. Methods: A briefing paper was circulated to a multi-disciplinary group of 25 including regulators, lawyers and others with insights into device regulation. A 1-day workshop was convened to discuss questions relating to our aim. A discussion paper was drafted by lead authors and circulated to other authors for their comments and contributions. Results: This article reports on those deliberations and describes how UK device regulators are likely to treat the different kinds of knowledge objects that may be stored in computable biomedical knowledge libraries. While our focus is the likely approach of UK regulators, our analogies and analysis will also be relevant to the approaches taken by regulators elsewhere. We include a table examining the implications for each of the four knowledge levels described by Boxwala in 2011 and propose an additional level. Conclusions: If a knowledge object is described as directly executable for a medical purpose to provide decision support, it will generally be in scope of UK regulation as "software as a medical device." However, if the knowledge object consists of an algorithm, a ruleset, pseudocode or some other representation that is not directly executable and whose developers make no claim that it can be used for a medical purpose, it is not likely to be subject to regulation. We expect similar reasoning to be applied by regulators in other countries.

Benchmarking of human Y-chromosomal haplogroup classifiers with whole-genome and whole-exome sequence data.

In anthropological, medical, and forensic studies, the nonrecombinant region of the human Y chromosome (NRY) enables accurate reconstruction of pedigree relationships and retrieval of ancestral information. Using high-throughput sequencing (HTS) data, we present a benchmarking analysis of command-line tools for NRY haplogroup classification. The evaluation was performed using paired Illumina data from whole-genome sequencing (WGS) and whole-exome sequencing (WES) experiments from 50 unrelated donors. Additionally, as a validation, we also used paired WGS/WES datasets of 54 individuals from the 1000 Genomes Project. Finally, we evaluated the tools on data from third-generation HTS obtained from a subset of donors and one reference sample. Our results show that WES, despite typically offering less genealogical resolution than WGS, is an effective method for determining the NRY haplogroup. Y-LineageTracker and Yleaf showed the highest accuracy for WGS data, classifying precisely 98% and 96% of the samples, respectively. Yleaf outperforms all benchmarked tools in the WES data, classifying approximately 90% of the samples. Yleaf, Y-LineageTracker, and pathPhynder can correctly classify most samples (88%) sequenced with third-generation HTS. As a result, Yleaf provides the best performance for applications that use WGS and WES. Overall, our study offers researchers with a guide that allows them to select the most appropriate tool to analyze the NRY region using both second- and third-generation HTS data.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Amplified inhibition of atherosclerotic plaque-induced platelet activation by glenzocimab with dual antiplatelet therapy.

BACKGROUND: Aspirin and platelet P2Y12 inhibitors, such as ticagrelor, suboptimally inhibit microvascular thrombosis during ST-elevation myocardial infarction. Glycoprotein (GP) IIb/IIIa inhibitors may further inhibit this but cause excessive bleeding. OBJECTIVES: We investigated whether combination of glenzocimab, a GPVI inhibitor, with aspirin and ticagrelor provides additional antithrombotic effects, as GPVI has a critical role in atherothrombosis but minimal involvement in hemostasis. METHODS: We investigated the effects of glenzocimab (monoclonal antibody Fab fragment) using blood from healthy donors and patients with acute coronary syndrome treated with aspirin and ticagrelor. Platelets were stimulated with multiple agonists, including atherosclerotic plaque, from patients undergoing carotid endarterectomy. RESULTS: Aspirin and ticagrelor partially inhibited atherosclerotic plaque-induced platelet aggregation by 48% compared with control (34 ± 3 vs 65 ± 4 U; P < .001). Plaque-induced platelet aggregation, adhesion, secretion, and activation were critically dependent on GPVI activation. Glenzocimab alone reduced plaque-induced aggregation by 75% compared with control (16 ± 4 vs 65 ± 4 U; P < .001) and by >95% when combined with aspirin and ticagrelor (3 ± 1 vs 65 ± 4 U; P < .001). Glenzocimab reduced platelet aggregation, adhesion, and thrombin generation when added to blood of aspirin- and ticagrelor-treated patients with acute coronary syndrome. Glenzocimab shared several antithrombotic effects with the GPIIb/IIIa inhibitor eptifibatide with less effect on general hemostasis assessed by rotational thromboelastometry. In a murine intravital model of ST-elevation myocardial infarction, genetic depletion of GPVI reduced microvascular thrombosis. CONCLUSION: Addition of glenzocimab to aspirin and ticagrelor enhances platelet inhibition via multiple mechanisms of atherothrombosis. Compared with a GPIIb/IIIa inhibitor, glenzocimab shares multiple antithrombotic effects, with less inhibition of mechanisms involved in general hemostasis.

Deep Brain Stimulation for Substance Use Disorders? An Exploratory Qualitative Study of Perspectives of People Currently in Treatment.

OBJECTIVE: Although previous studies have discussed the promise of deep brain stimulation (DBS) as a possible treatment for substance use disorders (SUDs) and collected researcher perspectives on possible ethical issues surrounding it, none have consulted people with SUDs themselves. We addressed this gap by interviewing people with SUDs. METHODS: Participants viewed a short video introducing DBS, followed by a 1.5-hour semistructured interview on their experiences with SUDs and their perspective on DBS as a possible treatment option. Interviews were analyzed by multiple coders who iteratively identified salient themes. RESULTS: We interviewed 20 people in 12-step-based, inpatient treatment programs (10 [50%] White/Caucasian, 7 Black/African American [35%], 2 Asian [10%], 1 Hispanic/Latino [5%], and 1 [5%] Alaska Native/American Indian; 9 women [45%], 11 men [55%]). Interviewees described a variety of barriers they currently faced through the course of their disease that mirrored barriers often associated with DBS (stigma, invasiveness, maintenance burdens, privacy risks) and thus made them more open to the possibility of DBS as a future treatment option. CONCLUSIONS: Individuals with SUDs gave relatively less weight to surgical risks and clinical burdens associated with DBS than previous surveys of provider attitudes anticipated. These differences derived largely from their experiences living with an often-fatal disease and encountering limitations of current treatment options. These findings support the study of DBS as a treatment option for SUDs, with extensive input from people with SUDs and advocates.