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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.
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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.
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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.
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Virus del Dengue , Dengue , Brotes de Enfermedades , Genoma Viral , Filogenia , Secuenciación Completa del Genoma , Nepal/epidemiología , Virus del Dengue/genética , Virus del Dengue/clasificación , Virus del Dengue/aislamiento & purificación , Humanos , Dengue/epidemiología , Dengue/virología , Secuenciación Completa del Genoma/métodos , Masculino , Adulto , Femenino , SerogrupoRESUMEN
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.
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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.
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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 CO2 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.
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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.
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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.
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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.
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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).
Independent validation study: 40-GEP identifies patients with cutaneous squamous cell carcinoma who would be most likely to benefit from adjuvant radiation therapy.
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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.
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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.
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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.
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Antihipertensivos , Tiempo de Tratamiento , Humanos , Femenino , Antihipertensivos/uso terapéutico , Masculino , Persona de Mediana Edad , Anciano , Tiempo de Tratamiento/estadística & datos numéricos , China/epidemiología , Hipertensión/tratamiento farmacológico , Hipertensión/complicaciones , Resultado del Tratamiento , Infarto Cerebral/tratamiento farmacológico , Factores de Tiempo , Accidente Cerebrovascular Isquémico/tratamiento farmacológicoRESUMEN
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.
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Mild stroke symptoms are cited as the reason for not using tissue-type plasminogen activator in 29-43% of time-eligible patients. Previous studies suggested that not all of these patients had a good recovery or even survival to hospital discharge. Since then, stroke guidelines worldwide recommended thrombolysis in minor but disabling strokes.Dual antiplatelet treatment with aspirin and clopidogrel was more effective than aspirin alone for reducing subsequent events in patients with minor stroke if started within 24 hours of onset in both CHANCE (Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events) and POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischaemic Stroke) trials. Recently, both PRISMS (The Potential of rtPA for Ischemic Strokes With Mild Symptoms) trial and TEMPO-2(The Potential of rtPA for Ischemic Strokes With Mild Symptoms) trial showed that treatment with thrombolysis versus antiplatelet did not increase the likelihood of favourable functional outcome at 90 days among patients with minor non-disabling acute ischaemic strokes. Therefore, a narrative review on thrombolysis for patients with minor strokes from published studies may help practicing clinicians.
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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).
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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.