Search

In utero gene editing with mRNA-based therapeutics has the potential to revolutionize the treatment of neurodevelopmental disorders. However, a critical bottleneck in clinical application has been the lack of mRNA delivery vehicles that can efficiently transfect cells in the brain. In this report, we demonstrate that in utero intracerebroventricular (ICV) injection of densely PEGylated lipid nanoparticles (ADP-LNPs) containing an acid-degradable PEG-lipid can safely and effectively deliver mRNA for gene editing enzymes to the fetal mouse brain, resulting in successful transfection and editing of brain cells. ADP-LNPs containing Cre mRNA transfected 30% of the fetal brain cells in Ai9 mice and had no detectable adverse effects on fetal development and postnatal growth. In addition, ADP-LNPs efficiently transfected neural stem and progenitor cells in Ai9 mice with Cre mRNA, which subsequently proliferated and caused over 40% of the cortical neurons and 60% of the hippocampal neurons to be edited in treated mice 10 weeks after birth. Furthermore, using Angelman syndrome, a paradigmatic neurodevelopmental disorder, as a disease model, we demonstrate that ADP-LNPs carrying Cas9 mRNA and gRNA induced indels in 21% of brain cells within 7 days postpartum, underscoring the precision and potential of this approach. These findings demonstrate that LNP/mRNA complexes have the potential to be a transformative tool for in utero treatment of neurodevelopmental disorders and set the stage for a frontier in treating neurodevelopmental disorders that focuses on curing genetic diseases before birth.

Hyperpolarized Xenon MRI (HPG MRI) has been studied for its potential use in assessing lung function in patients with cystic fibrosis (CF) and in patients with asthma. We present a case of a man with overlapping cystic fibrosis and allergic asthma with severe obstructive lung disease in which spirometry and computed topography (CT) imaging was unable to determine the primary cause for his uncontrolled symptoms. HPG MRI was used to guide a tissue biopsy and determine the primary driver to be allergic asthma. After starting targeted therapy for severe asthma, his symptoms have greatly improved., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Our case highlights an atypical presentation of Coxiella burnetii endocarditis with acute ischaemic stroke in a male patient in his 60s. The patient had undergone a congenital bicuspid aortic valve replacement with a bioprosthetic valve and an ascending aortic root graft with a pacemaker. He experienced intermittent fevers, chills and malaise over 15 months leading up to his presentation. During our diagnostic process, we used the newly developed Karius test, which detects microbial cell-free DNA in the patient's serum. The patient was treated with doxycycline and hydroxychloroquine for 24 months along with surgical removal and replacement of his aortic valve and graft. Our case underscores the utility of the Karius test and the essential role of neurology in the multidisciplinary team., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. Nuclear factor κB (NF-κB) activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion equally derived from infiltrating monocytes and resident cells. Moreover, NF-κB-activated cells and macrophages undergo crosstalk; NF-κB +  cells recruit macrophages to inhibit regeneration and promote atrophy but, interestingly, also protect myofibers, while macrophages stimulate NF-κB +  cells to sustain an inflammatory feedforward loop. Together, we propose that NF-κB functions in multiple cells in the muscle microenvironment to stimulate macrophages that both promote and protect against muscle wasting in cancer., Competing Interests: Declaration of interests T.A.Z. is a scientific advisory board member of Emmyon, Inc. and PeleOS, LLC., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is a respiratory disease characterized by pulmonary and systemic inflammation. Inflammatory mediators show relationships with shortness of breath, exercise intolerance and health related quality of life. Pulmonary rehabilitation (PR), a comprehensive education and exercise training programme, is the most effective therapy for COPD and is associated with reduced exacerbation and hospitalization rates and increased survival. Exercise training, the primary physiological intervention within PR, is known to exert a beneficial anti-inflammatory effect in health and chronic diseases. The question of this review article is whether exercise training can also make such a beneficial anti-inflammatory effect in COPD. Experimental studies using smoke exposure mice models suggest that the response of the immune system to exercise training is favourably anti-inflammatory. However, the evidence about the response of most known inflammatory mediators (C-reactive protein, tumour necrosis factor α, interleukin 6, interleukin 10) to exercise training in COPD patients is inconsistent, making it difficult to conclude whether regular exercise training has an anti-inflammatory effect in COPD. It is also unclear whether COPD patients with more persistent inflammation are a subgroup that would benefit more from hypothesized immunomodulatory effects of exercise training (i.e., personalized treatment). Nevertheless, it seems that PR combined with maintenance exercise training (i.e., lifestyle change) might be more beneficial in controlling inflammation and slowing disease progress in COPD patients, specifically in those with early stages of disease., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: The 4 serotypes of dengue virus (DENV1-4) can each cause potentially deadly dengue disease, and are spreading globally from tropical and subtropical areas to more temperate ones. Nepal provides a microcosm of this global phenomenon, having met each of these grim benchmarks. To better understand DENV transmission dynamics and spread into new areas, we chose to study dengue in Nepal and, in so doing, to build the onsite infrastructure needed to manage future, larger studies., Methods and Results: During the 2022 dengue season, we enrolled 384 patients presenting at a hospital in Kathmandu with dengue-like symptoms; 79% of the study participants had active or recent DENV infection (NS1 antigen and IgM). To identify circulating serotypes, we screened serum from 50 of the NS1 + participants by RT-PCR and identified DENV1, 2, and 3 - with DENV1 and 3 codominant. We also performed whole-genome sequencing of DENV, for the first time in Nepal, using our new on-site capacity. Sequencing analysis demonstrated the DENV1 and 3 genomes clustered with sequences reported from India in 2019, and the DENV2 genome clustered with a sequence reported from China in 2018., Conclusion: These findings highlight DENV's geographic expansion from neighboring countries, identify China and India as the likely origin of the 2022 DENV cases in Nepal, and demonstrate the feasibility of building onsite capacity for more rapid genomic surveillance of circulating DENV. These ongoing efforts promise to protect populations in Nepal and beyond by informing the development and deployment of DENV drugs and vaccines in real time., (© 2024. The Author(s).)

Objective: To evaluate the impact of a nationally available continuing education online curriculum on Emergency Medical Services (EMS) clinician confidence and knowledge in caring for end-of-life (EOL) patients., Methods: This is a prospective observational study of EMS clinicians (emergency medical technicians [EMTs], advanced EMTs [AEMTs], and paramedics). EMS clinicians and physicians with both EMS and palliative care expertise developed two 20-min modules regarding: (1) communication skills (including death notification) and (2) hospice knowledge. EMS clinicians' subject confidence (modified Likert-scale) and knowledge were assessed electronically immediately before and after each module. Data analysis compared before and after module improvements in knowledge and confidence. Linear regressions analyzed baseline EOL skill confidence scores based on EMS agency, level of certification, and years of experience., Results: We analyzed completed datasets for 1825 EMS clinicians (979 EMTs, 112 AEMTs, and 734 paramedics) representing a heterogeneous cohort across different EMS agencies (617 private, 545 fire-based, 298 hospital-based, 61 third service, and 304 other) and all 50 states and the District of Columbia. After the communication module, the number of EMS clinicians who reported confidence in delivering bad news increased from 62% (1131/1825) to 80% (1468/1825) ( p  < 0.001). After the hospice module, the number of EMS clinicians who reported confidence in knowing what services hospice provides increased from 51% (925/1825) to 75% (1375/1825) ( p  < 0.001) and confidence in knowing what active dying patients look like from 57% (1033/1825) to 78% (1429/1835) ( p  < 0.001) in knowing what active dying patients look like. Linear regression demonstrated that before modules, EMS clinicians with more monthly EOL calls, those with more years of experience, and paramedics were more confident in their EOL skills than their peers. After module completion, those with the fewest years of experience (0-3 years) and EMTs gained significantly more confidence in communication skills than their peers., Conclusion: Asynchronous, online continuing education improves EMS clinician knowledge and confidence in caring for patients near the EOL. The greatest benefit in improved confidence was for EMTs and those with the fewest years of EMS experience., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (© 2024 The Author(s). Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

A patient with fever presented to the referral infectious disease hospital in Kathmandu, Nepal. Metagenomic sequencing of the patient's serum recovered a near-complete genome of human immunodeficiency virus-1 (HIV-1), distinct from previous HIV-1 genomes from Nepal in GenBank. It shared 92.48% nucleotide identity with an HIV-1 subtype C isolate from India.

Visible and microwave satellite measurements can provide the global whitecap fraction. The bubble clouds are three-dimensional structures, and a space-based lidar can provide complementary observations of the bubble depth. Here, we use lidar measurements of the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) satellite to quantify global bubble depth from the depolarization. The relationship between CALIPSO bubble depth and wind speed from the Advanced Microwave Scanning Radiometer for EOS (AMSR-E) and AMSR2 is similar to a recently derived relationship based on buoy measurements. The CALIPSO-based bubble depth data show global distributions and seasonal variations consistent with the high wind speed (> 7 m/s) but with some variance. We also found similarities between the CALIPSO bubble depth and the whitecap fraction from AMSR2 and WindSat. Our findings support the use of spaceborne lidar measurements for advancing the understanding of the 3D bubble properties, and the ocean physics at high wind speeds., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Most approaches to advance simplified physiology-based precision medicine strategies for obstructive sleep apnea (OSA) focus on sleep parameters (i.e., OSA endotypes). However, wakefulness physiology measures can also provide prediction insight for certain OSA therapies yet their relationship with sleep parameters has not been extensively investigated. This study aimed to investigate potential relationships between awake ventilatory control parameters and sleep OSA endotypes and their potential to predict changes in OSA severity with morphine. Data were acquired from a randomised, cross-over trial that investigated effects of morphine versus placebo on OSA severity and underlying mechanisms. Here, awake ventilatory chemoreflex testing prior to overnight polysomnography was compared with direct measures of sleep respiratory control (e.g., hypercapnic ventilatory responses and loop gain) and OSA endotypes during a separate overnight physiology study (pharyngeal critical closure pressure-Pcrit, muscle responsiveness via genioglossus intramuscular electromyography and arousal threshold via epiglottic pressure catheter to transient continuous positive airway pressure reductions). Twenty-one men with OSA completed both study arms. During placebo, 1) awake chemosensitivity correlated with Pcrit (r=0.726, p=0.001), 2) arousal threshold correlated with awake CO 2 ventilatory response threshold (r=-0.467, p=0.047) and basal ventilation (r=-0.500, p=0.029). Awake chemosensitivity and Pcrit also correlated with the apnea-hypopnea index (p<0.001) during placebo. Awake chemosensitivity was predictive of changes in OSA severity with morphine(r=-0.535, p=0.013). In conclusion, awake measures of respiratory control are related to physiological endotypes such as airway collapsibility and arousal threshold during sleep and OSA severity. Awake ventilatory chemosensitivity has the best potential to predict changes in OSA severity with morphine.

Background/Objectives: Nephrolithiasis (kidney stones) is a frequently occurring urologic condition resulting in significant patient morbidity and healthcare costs. Despite the higher prevalence of metabolic risk factors for nephrolithiasis among Black women, there have been few epidemiologic studies of kidney stones focusing on this group. Methods: We describe demographic and health characteristics, diagnostics, and metabolic profiles of US Black women with self-reported kidney stones. The women were participants in the Black Women's Health Study (BWHS), a large prospective cohort of US Black women (median age 38 years) begun in 1995. Results: Among the 2750 BWHS participants who completed an online supplemental questionnaire assessing urologic health, 201 women reported nephrolithiasis. Of this number, 62% had completed ≥ 16 years of education, and 82% reported access to health care. Overall, 39% reported experiencing ≥ 2 stones in their lifetime, and 29% required surgery to treat the condition. Thirty-two percent reported having completed a metabolic evaluation, while 70% had undergone a CT scan to diagnose nephrolithiasis. The frequency of metabolic evaluation increased with the number of metabolic components reported: 3% (0 components) to 43% (3-4 components). Conclusions: Our findings are consistent with reports of lower rates of metabolic evaluation among Black patients despite their having multiple risk factors for nephrolithiasis. Further study is needed to identify the barriers and facilitators of metabolic and diagnostic workup of nephrolithiasis in Black women.

Hunger and thirst are two fundamental drives for maintaining homeostasis, and elicit distinct food- and water-seeking behaviors essential for survival. For neonatal mammals, however, both hunger and thirst are sated by consuming milk from their mother. While distinct neural circuits underlying hunger and thirst drives in the adult brain have been characterized, it is unclear when these distinctions emerge in neonates and what processes may affect their development. Here we show that hypothalamic hunger and thirst regions already exhibit specific responses to starvation and dehydration well before a neonatal mouse can seek food and water separately. At this early age, hunger drives feeding behaviors more than does thirst. Within neonatal regions that respond to both hunger and thirst, subpopulations of neurons respond distinctly to one or the other need. Combining food and water into a liquid diet throughout the animal's life does not alter the distinct representations of hunger and thirst in the adult brain. Thus, neural representations of hunger and thirst become distinct before food- and water-seeking behaviors mature and are robust to environmental changes in food and water sources.

Background: A subset of females with breast implants have reported a myriad of nonspecific systemic symptoms collectively termed systemic symptoms associated with breast implants (SSBI). SSBI symptoms are similar to manifestations associated with autoimmune and connective tissue disorders. Breast tissue is rich in adipose cells, comprised of lipids. Insertion of an implant creates an oxidative environment leading to lipid oxidation. Oxylipins can influence immune responses and inflammatory processes., Objectives: In this study we explored the abundance of a spectrum of oxylipins in the periprosthetic tissue surrounding the breast implant. Because oxylipins are immunogenic, we sought to determine if they were associated with the SSBI patients. We have also attempted to determine if the common manifestations exhibited by such patients have any association with oxylipin abundance., Methods: The study included 120 patients divided into 3 cohorts. We analyzed 46 patients with breast implants exhibiting manifestations associated with SSBI; 29 patients with breast implants not exhibiting manifestations associated with SSBI (control cohort I, non-SSBI); and 45 patients without implants (control cohort II, no-implant tissue). Lipid extraction and oxylipin quantification were performed with liquid chromatography mass spectrometry (LC-MS/MS). LC-MS/MS targeted analysis of the breast adipose tissue was performed., Results: Of the 15 oxylipins analyzed, 5 exhibited increased abundance in the SSBI cohort when compared to the non-SSBI and no-implant cohorts., Conclusions: The study documents the association of the oxylipins with each manifestation reported by the patient. This study provides an objective assessment of the subjective questionnaire, highlighting which symptoms may be more relevant than the others., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Aesthetic Society.)

Aim: To independently confirm that the 40-gene expression profile (40-GEP) test can identify patients with high-risk cutaneous squamous cell carcinoma who are more or less likely to benefit from adjuvant radiation therapy (ART). Materials & methods: Primary cutaneous squamous cell carcinoma tumors from two academic centers received retrospective 40-GEP testing and were analyzed for 5-year metastasis-free survival and projected time to event. Results: Random sampling of matched patient pairs ( n  = 52 ART-treated; 371 no ART) showed a median 50% decrease in 5-year progression rate for ART-treated patients (vs no ART) with 40-GEP Class 2B. Class 2A was associated with a modest ART benefit, but not Class 1. Conclusion: The 40-GEP identified patients most likely to benefit from ART (Class 2B) and those that can consider deferring treatment (Class 1).

Neuronal activity plays a critical role in the maturation of circuits that propagate sensory information into the brain. How widely does early activity regulate circuit maturation across the developing brain? Here, we used targeted recombination in active populations (TRAP) to perform a brain-wide survey for prenatally active neurons in mice and identified the piriform cortex as an abundantly TRAPed region. Whole-cell recordings in neonatal slices revealed preferential interconnectivity within embryonically TRAPed piriform neurons and their enhanced synaptic connectivity with other piriform neurons. In vivo Neuropixels recordings in neonates demonstrated that embryonically TRAPed piriform neurons exhibit broad functional connectivity within piriform and lead spontaneous synchronized population activity during a transient neonatal period, when recurrent connectivity is strengthening. Selectively activating or silencing these neurons in neonates enhanced or suppressed recurrent synaptic strength, respectively. Thus, embryonically TRAPed piriform neurons represent an interconnected hub-like population whose activity promotes recurrent connectivity in early development., Competing Interests: Declaration of interests L.L. is a member of Neuron’s advisory board., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have identified thousands of putative disease causing variants with unknown regulatory effects. Efforts to connect these variants with splicing quantitative trait loci (sQTLs) have provided functional insights, yet sQTLs reported by existing methods cannot explain many GWAS signals. We show current sQTL modeling approaches can be improved by considering alternative splicing representation, model calibration, and covariate integration. We then introduce MAJIQTL, a new pipeline for sQTL discovery. MAJIQTL includes two new statistical methods: a weighted multiple testing approach for sGene discovery and a model for sQTL effect size inference to improve variant prioritization. By applying MAJIQTL to GTEx, we find significantly more sGenes harboring sQTLs with functional significance. Notably, our analysis implicates the novel variant rs582283 in Alzheimer's disease. Using antisense oligonucleotides, we validate this variant's effect by blocking the implicated YBX3 binding site, leading to exon skipping in the gene MS4A3., Competing Interests: Competing Interests: The authors declare that they have no competing interests.

Purpose: To determine the bioavailability, safety, and tolerability of a single dose of oral docetaxel plus encequidar (oDox + E) and compare its pharmacokinetic exposure with current standard of care IV docetaxel., Introduction: Docetaxel is a taxane widely used as an anti-neoplastic agent. Due to low oral bioavailability secondary to gut P-glycoprotein (P-gp) efflux, its current use is limited to intravenous administration. Oral docetaxel may provide a less resource intensive, more convenient, and tolerable alternative. Encequidar is a first in class, minimally absorbed, oral gut-specific P-gp inhibitor. We tested whether oDox + E can achieve comparable pharmacokinetic exposure to IV docetaxel., Methods: A multicentre, phase I open-label, pharmacokinetic trial was undertaken to determine the bioavailability, safety, and tolerability of a single dose of oDox + E (at 75 mg/m2 + 15 mg, 150 mg/m2 + 15 mg, and 300 mg/m2 + 15 mg) in metastatic prostate cancer (mPC) patients compared to standard of care IV docetaxel as prescribed by their oncologists. The 15 mg of Encequidar at each dose level was given one hour prior to oral docetaxel., Results: 11 patients were enrolled; 9 patients completed the study. Oral docetaxel exposure increased with dose, achieving the highest at 300 mg/m2 oDox + E (with AUC 0 - infinity of 1343.3 ± 443.0 ng.h/mL compared to the IV docetaxel AUC 0 - infinity of 2000 ± 325 ng.h/mL) and became non-linear at 300 mg/m 2 . The mean absolute bioavailability of oDox + E across all 3 dose levels was 16.14% (range: 8.19-25.09%). No patient deaths, dose limiting toxicity, treatment-related serious adverse event or grade 4 toxicity were observed. Maximal tolerated dose was not reached., Conclusion: oDox + E has a safe and tolerable adverse event profile in patients with metastatic prostate cancer. The increase in oral bioavailability of oDox + E suggests a multi-dose oDox + E regimen could theoretically achieve exposures comparable with standard of care IV docetaxel. Further development to examine the optimal multiple dose regimen of oDox + E is warranted., Trial Registration Number: U1111-1173-5473., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: Conflicts of interest None disclosed.

Purpose: The aim of this study was to examine demographic and surgical factors that influence patient-reported knee function in patients who undergo anterior crucial ligament reconstruction (ACLR) with concurrent bucket-handle meniscal tear (BHMT) procedures. We hypothesized that repair of BHMT in the setting of concomitant ACLR and shorter time from injury to surgery would lead to improved patient-reported outcomes., Methods: Forty-one patients (mean age: 28.0 ± 9.8 years, 72% male) with BHMT at the time of ACLR completed the International Knee Documentation Committee Subjective Knee Form (IKDC-SKF) via online survey at an average of 15.2 months postop. Patient demographics and surgical characteristics, including time from injury to surgery, were compared between repair ( n  = 22) and meniscectomy ( n  = 19) groups using one-way analysis of variances; distributions of sex, graft source, BHMT compartment and zone were compared between groups using χ 2 tests. The association between IKDC-SKF score, demographics and surgical characteristics was evaluated using multivariable linear regression. A priori alpha level was p  < 0.05., Results: Meniscal repair and meniscectomy groups differed based on graft source and BHMT zone but not IKDC-SKF score ( p  = 0.085). Patients undergoing ACLR with autograft ( p  = 0.003) and with red-red zone BHMT ( p  < 0.001) more often underwent meniscal repair. The regression model demonstrated longer time from injury to surgery ( p  = 0.049), red-red tear zone ( p  = 0.04) and meniscectomy ( p  = 0.008); these were predictive of poorer IKDC-SKF scores., Conclusion: BHMT repair was more likely performed in ACL autograft and on red-red zone tears. Longer time from injury to surgery is an indicator of poorer IKDC-SKF score, as this may increase the risk of concomitant pathologies. White-white zone BHMTs are associated with better IKDC-SKF scores than red-red zone BHMTs, which may be due to the smaller volume of tissue removed during meniscectomy of white-white zone tears and the avoidance of iatrogenic complications of meniscal repair., Level of Evidence: Level III, therapeutic study., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Objectives: Balloon-assisted maturation (BAM) is a well-established technique for maturation of inadequate arteriovenous fistulas (AVF). The objective of this study was to evaluate outcomes of initial BAM using large-diameter angioplasty balloons., Methods: Charts of patients who underwent BAM between 2018 and 2021 at a single academic institution were reviewed. AVF maturation rate was the primary outcome. Secondary outcomes included procedural complications, re-intervention rates, post-procedure vein diameter, and time to catheter-free hemodialysis (HD). Outcomes of patients that underwent initial BAM with ⩾7 mm diameter balloons (Group I) were compared to those of patients that had initial BAM with <7 mm balloons (Group II)., Results: Group I ( n  = 149) was a significantly younger cohort and had more men compared to Group II ( n  = 90). There were no significant differences associated with procedural details and complication rates. Median vein diameter was larger (5.9 mm, IQR: 5-6.4) in Group I compared to Group II (5.1 mm, IQR: 4.2-5.9; p  = 0.03) on post-procedure Duplex ultrasound. There was also a higher incidence of vein stenosis in Group II. The overall maturation rate was higher in Group I (97% vs 88%, p  = 0.003), and a larger proportion of patients in Group II required more than one BAM to achieve maturation (33% vs 16%, p  = 0.002). The median time to catheter-free HD after first BAM was 29 days (IQR: 19-47) in Group I and 42 days (IQR: 24-75) in Group II ( p  = 0.002). At 60 days after first BAM, the incidence of catheter-free HD was 83% in Group I versus 67% in Group II ( p  = 0.001)., Conclusions: Our study demonstrates that the ability to utilize large angioplasty balloons during initial BAM is associated with higher rates of AVF maturation with fewer re-interventions and shorter time to catheter-free dialysis. AVFs that can tolerate this procedure often have more favorable baseline characteristics., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

SARS-CoV-2 molecular testing coupled with whole-genome sequencing is instrumental for real-time genomic surveillance. Genomic surveillance is critical for monitoring the spread of variants of concern (VOCs) as well as discovery of novel variants. Since the beginning of the pandemic, millions of SARS-CoV-2 genomes have been deposited into public sequence databases. This is the result of efforts of both national and regional diagnostic laboratories. In this study, we describe the results of SARS-CoV-2 genomic surveillance from February 2021 to June 2022 at a metropolitan hospital in the United States. We demonstrate that consistent daily sampling is sufficient to track the regional prevalence and emergence of VOCs and recapitulate national trends. Similar sampling efforts should be considered a viable option for local SARS-CoV-2 genomic surveillance at other regional laboratories., Importance: In our manuscript, we describe the results of SARS-CoV-2 genomic surveillance from February 2021 to June 2022 at a metropolitan hospital in the United States. We demonstrate that consistent daily sampling is sufficient to track the regional prevalence and emergence of variants of concern (VOCs). Similar sampling efforts should be considered a viable option for local SARS-CoV-2 genomic surveillance at other regional laboratories. While the SARS-CoV-2 pandemic has evolved into a more endemic form, we still believe that additional real-world information about sampling, procedures, and data interpretation is valuable for ongoing as well as future genomic surveillance efforts. Our study should be of substantial interest to clinical virologists., Competing Interests: The authors declare no conflict of interest.

Importance: The China Antihypertensive Trial in Acute Ischemic Stroke II (CATIS-2) suggests that early antihypertensive treatment did not reduce the risk of dependency or death in acute ischemic stroke (AIS), compared with delayed treatment. Single subcortical infarction (SSI) is an important stroke subtype, and the association of antihypertensive timing with clinical outcomes is unclear., Objective: To investigate the association of early vs delayed antihypertensive treatment with clinical outcomes in patients with SSI, stratified by the presence of parent artery disease (PAD) stenosis., Design, Setting, and Participants: This secondary analysis of the CATIS-2 randomized clinical trial included 106 hospitals in China between June 2018 and July 2022. In CATIS-2, patients with AIS within 24 to 48 hours of symptoms onset and elevated systolic blood pressure were eligible. Patients with SSI detected in diffusion-weighted imaging were included in the current post hoc subgroup analysis. Patients were grouped into (1) SSI with PAD stenosis and (2) SSI without PAD stenosis. Statistical analysis was performed from July 2023 to May 2024., Exposures: Early (immediate) vs delayed (starting on day 8) antihypertensive therapy., Main Outcome and Measure: Primary outcome was the combination of functional dependency or death (modified Rankin Scale score ≥3) at 90 days., Results: Among 997 patients with SSI in CATIS-2 (mean [SD] age, 62.4 [9.8] years; 612 [61.4%] men), 116 (11.6%) had SSI with PAD and 881 (88.4%) had SSI without PAD. There was no significant difference in the primary outcome between early and delayed antihypertensive treatment groups among all patients with SSI (8.8% vs 7.1%; OR, 1.25 [95% CI, 0.79-1.99]; P = .34). Among patients with SSI with PAD, early antihypertensive treatment was associated with increased risk of the primary outcome compared with delayed treatment (23.4% vs 7.7%; OR, 3.67 [95% CI, 1.14-11.86]; P = .03); this finding was not observed in patients with SSI without PAD (6.6% vs 7.1%; OR, 0.93 [95% CI, 0.55-1.57]; P = .77). Significant interaction with treatment and presence of PAD stenosis was detected for the primary outcome (P for interaction = .04)., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, early antihypertensive treatment was associated with an increased risk of functional dependency or death at 90 days among patients with SSI and coexisting PAD stenosis, compared with delayed antihypertensive treatment. Further studies are warranted for individualized BP management in patients with SSI by the presence of PAD., Trial Registration: ClinicalTrials.gov Identifier: NCT03479554.

The development of optimized dosing regimens plays a crucial role in oncology drug development. This study focused on the population pharmacokinetic modelling and simulation of docetaxel, comparing the pharmacokinetic exposure of oral docetaxel plus encequidar (oDox + E) with the standard of care intravenous (IV) docetaxel regimen. The aim was to evaluate the feasibility of oDox + E as a potential alternative to IV docetaxel. The article demonstrates an approach which aligns with the FDA's Project Optimus which aims to improve oncology drug development through model informed drug development (MIDD). The key question answered by this study was whether a feasible regimen of oDox + E existed. The purpose of this question was to provide an early GO / NO-GO decision point to guide drug development and improve development efficiency., Methods:  A stepwise approach was employed to develop a population pharmacokinetic model for total and unbound docetaxel plasma concentrations after IV docetaxel and oDox + E administration. Simulations were performed from the final model to assess the probability of target attainment (PTA) for different oDox + E dose regimens (including multiple dose regimens) in relation to IV docetaxel using AUC over effective concentration (AUCOEC) metric across a range of effective concentrations (EC). A Go / No-Go framework was defined-the first part of the framework assessed whether a feasible oDox + E regimen existed (i.e., a PTA ≥ 80%), and the second part defined the conditions to proceed with a Go decision., Results:  The overall population pharmacokinetic model consisted of a 3-compartment model with linear elimination, constant bioavailability, constant binding mechanics, and a combined error model. Simulations revealed that single dose oDox + E regimens did not achieve a PTA greater than 80%. However, two- and three-dose regimens at 600 mg achieved PTAs exceeding 80% for certain EC levels., Conclusion:  The study demonstrates the benefits of MIDD using oDox + E as a motivating example. A population pharmacokinetic model was developed for the total and unbound concentration in plasma of docetaxel after administration of IV docetaxel and oDox + E. The model was used to simulate oDox + E dose regimens which were compared to the current standard of care IV docetaxel regimen. A GO / NO-GO framework was applied to determine whether oDox + E should progress to the next phase of drug development and whether any conditions should apply. A two or three-dose regimen of oDox + E at 600 mg was able to achieve non-inferior pharmacokinetic exposure to current standard of care IV docetaxel in simulations. A Conditional GO decision was made based on this result and further quantification of the "effective concentration" would improve the ability to optimise the dose regimen., (© 2024. The Author(s).)

Acute encephalitis syndrome (AES) causes significant morbidity and mortality worldwide. In Nepal, Japanese encephalitis virus (JEV) accounts for ~5-20% of AES cases, but ~75% of AES cases are of unknown etiology. We identified a gemykibivirus in CSF collected in 2020 from an 8-year-old male patient with AES using metagenomic next-generation sequencing. Gemykibiviruses are single stranded, circular DNA viruses in the family Genomoviridae . The complete genome of 2,211 nucleotides was sequenced, which shared 98.69% nucleotide identity to its closest relative, Human associated gemykibivirus 2 isolate SAfia-449D. Two real-time PCR assays were designed, and screening of 337 cerebrospinal fluid (CSF) and 164 serum samples from AES patients in Nepal collected in 2020 and 2022 yielded 11 CSF and 1 serum sample that were positive in both PCR assays. Complete genomes of seven of the positives were sequenced. These results identify a potential candidate etiologic agent of encephalitis in Nepal., Importance: Viral encephalitis is a devastating disease, but unfortunately, worldwide, the causative virus in many cases is unknown. Therefore, it is important to identify viruses that could be responsible for cases of human encephalitis. Here, using metagenomic sequencing of CSF, we identified a gemykibivirus in a male child from Nepal with acute encephalitis syndrome (AES). We subsequently detected gemykibivirus DNA in CSF or serum of 12 more encephalitis patients by real-time PCR. The virus genomes we identified are highly similar to gemykibiviruses previously detected in CSF of three encephalitis patients from Sri Lanka. These results raise the possibility that gemykibivirus could be an underrecognized human pathogen., Competing Interests: The authors declare no conflict of interest.

Objective: The present study explored rates of burnout and racial trauma among 182 Black mental health professionals (BMHPs) and utilized racial-cultural theory to explore potential protective factors against burnout and racial trauma., Method: We collected data from 182 Black psychologists and counselors who were active mental health professionals during 2020. Descriptive statistics, multivariate analyses of variance, follow-up univariate analyses of variance, bivariate correlations, and multiple regression analyses were used., Results: Both burnout and racial trauma were considerably higher among BMHPs than has been reported across general samples of helping professionals and across a sample of Black participants across the United States. Differences among rates of burnout and racial trauma existed across genders and specialties (i.e., counseling and psychology). Higher levels of social support and an external locus of control significantly predicted lower levels of burnout and racial trauma. In addition, higher levels of resilient coping predicted lower levels of burnout. Last, more frequent meetings with a mentor significantly predicted lower levels of racial trauma., Conclusions: Results from this study suggest that BMHPs may be more susceptible to burnout and race-based traumatic stress as a result of their work. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A key feature distinguishing high-grade glioma (HG) from low-grade glioma (LG) is the extensive neovascularization and endothelial hyperproliferation. Prior work has shown that tumor-associated vasculature from HG is molecularly and functionally distinct from normal brain vasculature and expresses higher levels of protumorigenic factors that promote glioma growth and progression. However, it remains unclear whether vessels from LG also express protumorigenic factors, and to what extent they functionally contribute to glioma growth. Here, we profile the transcriptomes of glioma-associated vascular cells (GVC) from IDH-mutant (mIDH) LG and IDH-wild-type (wIDH) HG and show that they exhibit significant molecular and functional differences. LG-GVC show enrichment of extracellular matrix-related gene sets and sensitivity to antiangiogenic drugs, whereas HG-GVC display an increase in immune response-related gene sets and antiangiogenic resistance. Strikingly, conditioned media from LG-GVC inhibits the growth of wIDH glioblastoma cells, whereas HG-GVC promotes growth. In vivo cotransplantation of LG-GVC with tumor cells reduces growth, whereas HG-GVC enhances tumor growth in orthotopic xenografts. We identify ASPORIN (ASPN), a small leucine-rich repeat proteoglycan, highly enriched in LG-GVC as a growth suppressor of wIDH glioblastoma cells in vitro and in vivo. Together, these findings indicate that GVC from LG and HG are molecularly and functionally distinct and differentially regulate tumor growth. Implications: This study demonstrated that vascular cells from IDH-mutant LG and IDH-wild-type HG exhibit distinct molecular signatures and have differential effects on tumor growth via regulation of ASPN-TGFβ1-GPM6A signaling., (©2024 The Authors; Published by the American Association for Cancer Research.)

Quercetin, an essential flavonoid compound, exhibits diverse biological activities including anti-inflammatory and antioxidant effects. Nevertheless, due to its inadequate solubility in water and vulnerability to degradation, pure quercetin is constrainedly utilized in pharmaceutical formulations and functional foods. Considering the existing scarcity of nanoparticles consisted of zein and hydrophobic biopolymers, this study developed a quercetin-loaded nanoencapsulation based on zein, shellac, and chitosan (QZSC). When the mass ratio of zein to chitosan was 4:1, the encapsulation efficiency of QZSC reached 74.95%. The ability of QZSC for scavenging DPPH radicals and ABTS radicals increased from 59.2% to 75.4% and from 47.0% to 70.2%, respectively, compared to Quercetin. For QZSC, the maximum release amount of quercetin reached 59.62% in simulated gastric fluid and 81.64% in simulated intestinal fluid, achieving controlled and regulated release in vitro. In summary, this study offers a highly promising encapsulation strategy for hydrophobic bioactive substances that are prone to instability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To report a novel anatomical pattern of autoimmune encephalitis characterized by strictly unilateral cortical inflammation and a clinical picture overlapping with late-onset Rasmussen's encephalitis., Methods: We retrospectively gathered data of patients identified at two tertiary referral academic centers who met inclusion criteria., Results: We identified twelve cases (average age 65, +/- 19.8 years, 58% female). All patients had unilateral cortical inflammation manifesting with focal seizures, cognitive decline, hemicortical deficits, and unilateral MRI and/or EEG changes. Six cases were idiopathic, two paraneoplastic, two iatrogenic (in the setting of immune checkpoint inhibitors), and two post-COVID-19. Serologically, ten patients were seronegative, one had high titer anti-GAD65, and one had anti-NMDAR. Five patients met Rasmussen's encephalitis criteria, and six did not fully meet the criteria but had symptoms significantly overlapping with the condition. Most patients had significant improvement with immunotherapy., Discussion: Unilateral cortical AE seems to be more prevalent in the elderly and more frequently idiopathic and seronegative. Patients with this anatomical variant of autoimmune encephalitis have overlapping features with late-onset Rasmussen's encephalitis but are more responsive to immunotherapy. In cases refractory to immunotherapy, interventions used in refractory Rasmussen's encephalitis may be considered, such as functional hemispherectomy., Competing Interests: Declaration of competing interest CS reports salary support given to NYU for work provided to the following entities: Alterity, Baergic, Biogen, BioXcel, Cerebral, Cerevel, Eliem, Equilibre, Janssen, Longboard, Lundbeck, Marinus, NeuCyte, Neurocrine, Neuroelectrics, Ono, SK Life Science, and UCB. CS also receives grants from NINDS, NORD, UCB and Parekh Centre for Interdisciplinary Neurology outside the submitted work. HA is a consultant and speaker for Biogen, Genentech, BMS, Horizon, and Alexion, receives research support from Genentech, BMS, Novartis, Sanofi, and the Guthy-Jackson Charitable Foundation, and serves as an Assistant Editor for the Neurology Journal. All other authors have nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The transmission bottleneck, defined as the number of viruses that transmit from one host to infect another, is an important determinant of the rate of virus evolution and the level of immunity required to protect against virus transmission. Despite its importance, SARS-CoV-2's transmission bottleneck remains poorly characterized, in part due to a lack of quantitative measurement tools. To address this, we adapted a SARS-CoV-2 reverse genetics system to generate a pool of >200 isogenic SARS-CoV-2 viruses harboring specific 6-nucleotide barcodes inserted in ORF10, a non-translated ORF. We directly inoculated donor Syrian hamsters intranasally with this barcoded virus pool and exposed a paired naïve contact hamster to each donor. Following exposure, the nasal turbinates, trachea, and lungs were collected, viral titers were measured, and the number of barcodes in each tissue were enumerated to quantify the transmission bottleneck. The duration and route (airborne, direct contact, and fomite) of exposure were varied to assess their impact on the transmission bottleneck. In airborne-exposed hamsters, the transmission bottleneck increased with longer exposure durations. We found that direct contact exposure produced the largest transmission bottleneck (average 27 BCs), followed by airborne exposure (average 16 BCs) then fomite exposure (average 8 BCs). Interestingly, we detected unique BCs in both the upper and lower respiratory tract of contact animals from all routes of exposure, suggesting that SARS-CoV-2 can directly infect hamster lungs. Altogether, these findings highlight the utility of barcoded viruses as tools to rigorously study virus transmission. In the future, barcoded SARS-CoV-2 will strengthen studies of immune factors that influence virus transmission., Competing Interests: The Boon laboratory has received unrelated funding support in sponsored research agreements from AI Therapeutics, GreenLight Biosciences Inc., and Nano targeting & Therapy Biopharma Inc. The Boon laboratory has received funding support from AbbVie Inc., for the commercial development of SARS-CoV-2 mAb.

Background: Lower socioeconomic status and public insurance lead to a longer delay to surgery and a higher likelihood of concomitant pathology before undergoing anterior cruciate ligament reconstruction (ACLR). However, few studies have examined the influence of community deprivation on ACLR timing and outcomes., Purpose/hypothesis: The primary aim of this study was to define the effect of the area deprivation index (ADI) and insurance classification on access to orthopaedic care after an ACL rupture, and the secondary aim was to determine whether these variables were associated with a second ACL injury after primary ACLR. It was hypothesized that patients with a greater national ADI percentile and Medicaid insurance would experience longer delays to care and an increased risk of reinjury after ACLR., Study Design: Cohort study; Level of evidence, 3., Methods: A retrospective study was performed to evaluate patients undergoing primary ACLR between 2016 and 2019. The national ADI percentile was obtained utilizing the Neighborhood Atlas website. The relationship between national ADI percentile and care characteristics (eg, time to specialized care) was investigated using the Spearman rho correlation coefficient ( r ). The association between patient and care characteristics and second ACL injury after the index procedure (ie, graft rerupture or contralateral ACL rupture) was investigated using binary logistic regression., Results: A total of 197 patients met the inclusion criteria. Longer times from injury to surgery ( r = 0.238; P < .001) and from specialized care to surgery ( r = 0.217; P = .002) were associated with a greater national ADI percentile. The second injury group reported significantly greater national ADI ( P = .026) and included a greater percentage of patients with Medicaid insurance (31.3%) compared with the no second injury group. Patients experienced 5.1% greater odds of a second ACL injury for each additional month between evaluation and surgery., Conclusion: Greater national ADI percentile and Medicaid insurance status were associated with adverse ACLR timing and outcomes. Patients with a greater national ADI percentile took significantly longer to obtain surgery after ACL injury. Those who sustained a second ACL injury after ACLR had an overall higher mean national ADI percentile and included a greater proportion of patients with Medicaid compared with those who did not sustain a second ACL injury. Future studies should critically investigate the underlying factors of these associations to reach equity in orthopaedic care., Competing Interests: The authors declared that they have the following conflicts of interest: A.J.C. has received education payments from Arthrex, Medwest Associates, Mid-Atlantic Surgical Systems LLC, Smith+Nephew, and Supreme Orthopedic Systems LLC; hospitality payments from Stryker; and a grant from Arthrex. B.M.B. has received education payments from Conetic Solutions, Arthrex, Smith+Nephew, and Medwest Associates; hospitality payments from Stryker, Smith+Nephew, Conetic Solutions, and Medical Device Business Services; honoraria from Encore Medical LP; and a grant from Arthrex. C.M.C. has received education payments from Liberty Surgical and hospitality payments from Medical Device Business Services. E.S.C. has received consulting fees from Avanos Medical; education payments from Arthrex and Supreme Orthopedic Systems LLC; and hospitality payments from Arthrex. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. Ethical approval for this study was obtained from the Western Institutional Review Board-Copernicus Group (ref No. 20216925)., (© The Author(s) 2024.)

Sleep onset insomnia is a pervasive problem that contributes significantly to the poor health outcomes associated with insufficient sleep. Auditory stimuli phase-locked to slow-wave sleep oscillations have been shown to augment deep sleep, but it is unknown whether a similar approach can be used to accelerate sleep onset. The present randomized controlled crossover trial enrolled adults with objectively verified sleep onset latencies (SOLs) greater than 30 min to test the effect of auditory stimuli delivered at specific phases of participants' alpha oscillations prior to sleep onset. During the intervention week, participants wore an electroencephalogram (EEG)-enabled headband that delivered acoustic pulses timed to arrive anti-phase with alpha for 30 min (Stimulation). During the Sham week, the headband silently recorded EEG. The primary outcome was SOL determined by blinded scoring of EEG records. For the 21 subjects included in the analyses, stimulation had a significant effect on SOL according to a linear mixed effects model (p = 0.0019), and weekly average SOL decreased by 10.5 ± 15.9 min (29.3 ± 44.4%). These data suggest that phase-locked acoustic stimulation can be a viable alternative to pharmaceuticals to accelerate sleep onset in individuals with prolonged sleep onset latencies. Trial Registration: This trial was first registered on clinicaltrials.gov on 24/02/2023 under the name Sounds Locked to ElectroEncephalogram Phase For the Acceleration of Sleep Onset Time (SLEEPFAST), and assigned registry number NCT05743114., (© 2024. The Author(s).)

Background: The 4 serotypes of dengue virus (DENV1-4) can each cause potentially deadly dengue disease, and are spreading globally from tropical and subtropical areas to more temperate ones. Nepal provides a microcosm of this global phenomenon, having met each of these grim benchmarks. To better understand DENV transmission dynamics and spread into new areas, we chose to study dengue in Nepal and, in so doing, to build the onsite infrastructure needed to manage future, larger studies., Methods and Results: During the 2022 dengue season, we enrolled 384 patients presenting at a hospital in Kathmandu with dengue-like symptoms; 79% of the study participants had active or recent DENV infection (NS1 antigen and IgM). To identify circulating serotypes, we screened serum from 50 of the NS1 + participants by RT-PCR and identified DENV1, 2, and 3 - with DENV1 and 3 codominant. We also performed whole-genome sequencing of DENV, for the first time in Nepal, using our new on-site capacity. Sequencing analysis demonstrated the DENV1 and 3 genomes clustered with sequences reported from India in 2019, and the DENV2 genome clustered with a sequence reported from China in 2018., Conclusion: These findings highlight DENV's geographic expansion from neighboring countries, identify China and India as the likely origin of the 2022 DENV cases in Nepal, and demonstrate the feasibility of building onsite capacity for more rapid genomic surveillance of circulating DENV. These ongoing efforts promise to protect populations in Nepal and beyond by informing the development and deployment of DENV drugs and vaccines in real time.

The angular gyrus (AG) and posterior cingulate cortex (PCC) demonstrate extensive structural and functional connectivity with the hippocampus and other core recollection network regions. Consequently, recent studies have explored neuromodulation targeting these and other regions as a potential strategy for restoring function in memory disorders such as Alzheimer's Disease. However, determining the optimal approach for neuromodulatory devices requires understanding how parameters like selected stimulation site, cognitive state during modulation, and stimulation duration influence the effects of deep brain stimulation (DBS) on electrophysiological features relevant to episodic memory. We report experimental data examining the effects of high-frequency stimulation delivered to the AG or PCC on hippocampal theta oscillations during the memory encoding (study) or retrieval (test) phases of an episodic memory task. Results showed selective enhancement of anterior hippocampal slow theta oscillations with stimulation of the AG preferentially during memory retrieval. Conversely, stimulation of the PCC attenuated slow theta oscillations. We did not observe significant behavioral effects in this (open-loop) stimulation experiment, suggesting that neuromodulation strategies targeting episodic memory performance may require more temporally precise stimulation approaches., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Summary: Delayed or missed diagnosis of perilunate or lunate dislocations can lead to significant morbidity. Advances in computer vision provide an opportunity to improve diagnostic performance. In this study, a deep learning algorithm was used for detection of perilunate and lunate dislocations on lateral wrist radiographs. A total of 435 lateral wrist radiographs were labeled as normal or pathologic (perilunate or lunate dislocation). The lunate in each radiograph was segmented with a rectangular bounding box. Images were partitioned into training and test sets. Two neural networks, consisting of an object detector followed by an image classifier, were applied in series. First, the object detection module was used to localize the lunate. Next, the image classifier performed a binary classification for normal or pathologic. The accuracy, sensitivity, and specificity of the overall system were evaluated. A receiver operating characteristic curve and the associated area under the curve were used to demonstrate the overall performance of the computer vision algorithm. The lunate object detector was 97.0% accurate at identifying the lunate. Accuracy was 98.7% among the subgroup of normal wrist radiographs and 91.3% among the subgroup of wrist radiographs with perilunate/lunate dislocations. The perilunate/lunate dislocation classifier had a sensitivity (recall) of 93.8%, a specificity of 93.3%, and an accuracy of 93.4%. The area under the curve was 0.986. The authors have developed a proof-of-concept computer vision system for diagnosis of perilunate/lunate dislocations on lateral wrist radiographs. This novel deep learning algorithm has potential to improve clinical sensitivity to ultimately prevent delayed or missed diagnosis of these injuries., (Copyright © 2023 by the American Society of Plastic Surgeons.)

When advance care plans are not communicated or goals are in conflict, significant family and clinician distress may result. The distress is especially high when potentially nongoal concordant care is expected by surrogates in the emergency department (ED). To demonstrate the effect of off-hour, phone consultations by palliative care clinicians in reducing the family and clinician distress when nongoal concordant care is expected in the ED. A partnership between palliative care and emergency medicine can decrease the burden of decision making and provide opportunities for modeling a goals-of-care discussion by experts in this important procedure.

The consistency of energy landscape theory predictions with available experimental data, as well as direct evidence from molecular simulations, have shown that protein folding mechanisms are largely determined by the contacts present in the native structure. As expected, native contacts are generally energetically favorable. However, there are usually at least as many energetically favorable nonnative pairs owing to the greater number of possible nonnative interactions. This apparent frustration must therefore be reduced by the greater cooperativity of native interactions. In this work, we analyze the statistics of contacts in the unbiased all-atom folding trajectories obtained by Shaw and coworkers, focusing on the unfolded state. By computing mutual cooperativities between contacts formed in the unfolded state, we show that native contacts form the most cooperative pairs, while cooperativities among nonnative or between native and nonnative contacts are typically much less favorable or even anticooperative. Furthermore, we show that the largest network of cooperative interactions observed in the unfolded state consists mainly of native contacts, suggesting that this set of mutually reinforcing interactions has evolved to stabilize the native state., Competing Interests: Competing interests statement:The authors declare no competing interest.

The Baeyer-Villiger oxidation of ketones is a crucial oxygen atom transfer (OAT) process used for ester production. Traditionally, Baeyer-Villiger oxidation is accomplished by thermally oxidizing the OAT from stoichiometric peroxides, which are often difficult to handle. Electrochemical methods hold promise for breaking the limitation of using water as the oxygen atom source. Nevertheless, existing demonstrations of electrochemical Baeyer-Villiger oxidation face the challenges of low selectivity. We report in this study a strategy to overcome this challenge. By employing a well-known water oxidation catalyst, Fe 2 O 3 , we achieved nearly perfect selectivity for the electrochemical Baeyer-Villiger oxidation of cyclohexanone. Mechanistic studies suggest that it is essential to produce surface hydroperoxo intermediates (M-OOH, where M represents a metal center) that promote the nucleophilic attack on ketone substrates. By confining the reactions to the catalyst surfaces, competing reactions (e.g., dehydrogenation, carboxylic acid cation rearrangements, and hydroxylation) are greatly limited, thereby offering high selectivity. The surface-initiated nature of the reaction is confirmed by kinetic studies and spectroelectrochemical characterizations. This discovery adds nucleophilic oxidation to the toolbox of electrochemical organic synthesis.

Electroencephalogram (EEG) alpha-band oscillations may reflect executive and processing function in patients with cerebral small vessel disease (CSVD). We aimed to assess such association and its relationship with CSVD severity, and to identify specific alpha-band parameters and the cut-off values for cognitive screening. We analysed the dispersion of amplitude-frequency characteristics of EEG alpha-band and different alpha-band parameters (PFα , ΔPFα , PPα , NCL) in different brain locations. We also assessed patients' executive and processing functions using verbal fluency test (VFT) and color trails test (CTT), and CSVD severity using total burden and Fazekas scores. 129 patients were recruited in the study. After adjusting for age, gender and education, PFα(F3), PFα(F4) and NCL were significantly associated with VFT-composite performance ( p <  0.05). CTT-1 time and error were associated with PFα(F3), PFα(F4), ΔPFα(O1;F3) and CSVD severity ( p <  0.05), whereas CTT-2 time was only associated with CSVD severity. Moreover, the correlations between alpha-band oscillations and cognitive function were higher in low than in high disease-severity group (ρ: -0.58 vs. -0.38, p <  0.05). The AUC of selected alpha-band parameters were higher than 0.8 for VFT and CTT. Specific alpha-band parameters in the frontal lobe were identified to correspond to executive and processing function. Assessing EEG alpha-band oscillations may assist in screening cognitive impairment., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Achieving virtual elimination of HIV transmission in Australia requires a combination of high treatment rates and high testing coverage among individuals at risk of acquiring HIV. HIV self-testing (HIVST) is an additional testing approach for key populations., Objective: We aimed to examine the knowledge, attitudes, and practices of HIVST among Asian-born gay, bisexual and other men who have sex with men (GBMSM)., Methods: This qualitative study used semi-structured interviews of overseas-born GBMSM of Asian background in Australia. Participants were recruited from personal networks, social media platforms, snowballing, and the Melbourne Sexual Health Centre. Twenty-five participants were purposively sampled with a range of ages and previous levels of experience with HIVST. Interview transcripts were imported into Nvivo 12 for data management., Results: The age of the participants ranged from 19 to 44 years, with a median of 30 years. Most were unaware of HIVST before the interview, and only a few had ever used one. All had limited sexual health knowledge (i.e., HIV testing, PrEP) before they arrived in Australia. Upon learning about HIVST during the interview, many expressed willingness to use HIVST, but in limited circumstances, such as traveling overseas, interim testing while taking on-demand PrEP, and point-of-sex testing. Almost all were open to distributing HIVST to their casual partners or friends, especially those they knew who engaged in high-risk sexual practice (i.e., condomless anal sex) and were not engaged in sexual healthcare. About half still preferred conventional serology testing because of regular HIV testing as part of PrEP prescription and the need for testing for other sexually transmitted infections., Conclusion: HIVST may be an acceptable additional testing approach for HIV testing among Asian-born GBMSM. Peer education and secondary distribution may help raise HIVST awareness and use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zhang, Chow, Sudarto, Wang, Stoove, Medland, O'Donnell, Keen, Ong and Phillips.)

Introduction: In this retrospective database review, the objective was to investigate the ethnic composition of urology applicants and residents in recent years and assess whether any advancements have been made in enhancing the recruitment of candidates from historically underrepresented groups in medicine., Methods: A retrospective database review was conducted on self-reported data on the ethnicity of urology applicants from academic year 2016 to 2017 (AY2016) to AY2021 and urology residents from AY2011 to AY2021. Applicant data were collected from the Association of American Medical Colleges, and resident data were collected from the Accreditation Council for Graduate Medical Education. The ethnic proportions of applicants and residents within cohorts were analyzed using χ 2 tests, and differences between cohorts were analyzed using Z tests., Results: There was a statistically significant decrease in the proportion of White applicants from 61.4% to 50.5% from AY2016 to AY2021 and a statistically significant increase in the proportion of applicants of multiple race/ethnicity from 4.7% to 12.0% from AY2016 to AY2021. There were disproportionately more Hispanic/Latino residents than applicants and disproportionately fewer residents of multiple race/ethnicity than applicants in the 2 cycles analyzed. There were disproportionately fewer Black residents than applicants only in the comparison of AY2016 to AY2020 applicants to AY2020 residents., Conclusions: There continues to be a lack of ethnic representation among applicants and residents in urology from underrepresented groups in medicine, despite some measurable improvement over the years. This deficit highlights the important need for new and ongoing efforts to diversify the field.

In this segment of the emergency department (ED) palliative care (PC) case series, we discuss a patient on hospice who presented to the ED for the management of acute symptoms and potential procedural intervention. Hospice patients frequently visit the ED and can challenge typical ED paradigms of care that often include resuscitative efforts and broad workups. Our patient had a history of advanced liver cancer, and his ED presentation was prompted by worsening abdominal pain from ascites requiring serial paracentesis. PC consultation was requested to help address the patient's symptoms and create a plan of care. The PC clinician played an important role in supporting aggressive symptom management, re-evaluating goals of care, addressing concerns about hospice, and facilitating changes in code status requested for a procedure.