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2.
J Adolesc Health ; 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38970606

ABSTRACT

PURPOSE: Although the harmful outcomes of peer bullying are well-established, the effects of bullying by teachers are less understood. Teacher bullying occurs when a teacher uses their authority to punish or disparage a student beyond appropriate discipline. METHODS: This study investigated the prevalence of teacher bullying and its relationship with student risk-taking behaviors in a sample of 106,865 high school students who completed a statewide school climate survey. Students were classified into four groups: no bullying (91%), only peer bullying (4%), only teacher bullying (4%), and both peer and teacher bullying (2%). RESULTS: Logistic regression results indicated that all victimization groups were more likely to participate in risk behaviors (substance use, weapon carrying, fighting, suicidal ideation, and attempts) than nonbullied peers, and students bullied by both peers and teachers were at greatest jeopardy of participation. DISCUSSION: These results support greater attention to teacher bullying in antibullying efforts.

3.
Article in English | MEDLINE | ID: mdl-38976407

ABSTRACT

OBJECTIVE: Cultural stress potently predicts mental health inequities, such as anxiety, among adult and adolescent immigrants in the United States. However, less work has focused on preadolescence, a period marked by neurodevelopmental and psychosocial changes that can exacerbate anxiety symptoms. Latina girls, who exhibit heightened levels of untreated anxiety, may be at elevated risk. The present study tests whether cultural stress predicts anxiety symptoms in Latina girls and their caregivers. METHOD: The primary caregivers of 161 predominantly Mexican-identifying Latina girls (Mage = 10.70, SD = 1.68) reported their exposure to racism, acculturative stress, and political hostility. They also reported their own and their daughter's anxiety severity. RESULTS: To index cultural stress, a principal component was extracted from composite scores of the racism, acculturative stress, and political hostility questionnaires. Hierarchical regression analyses then tested whether the multidetermined cultural stress component predicted caregiver and child anxiety, with child age, annual household income, and subjective socioeconomic status entered at the first step. Cultural stress positively predicted caregiver (ΔR² = .13, p < .001) and child (ΔR² = .15, p < .001) anxiety symptoms over and above the observed inverse effects of subjective socioeconomic status, such that higher levels of cultural stress were associated with elevated levels of caregiver (ß = .37, p < .001) and child (ß = .39, p < .001) anxiety symptoms. CONCLUSIONS: The results of this study highlight the role of racism, acculturative stress, and political hostility in escalating anxiety symptoms in Latinx families and identify cultural stress as a factor that likely contributes to the high rates of anxiety in Latina girls during a key developmental period. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

4.
Nat Biomed Eng ; 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38987629

ABSTRACT

Prime editing (PE) enables precise and versatile genome editing without requiring double-stranded DNA breaks. Here we describe the systematic optimization of PE systems to efficiently correct human cystic fibrosis (CF) transmembrane conductance regulator (CFTR) F508del, a three-nucleotide deletion that is the predominant cause of CF. By combining six efficiency optimizations for PE-engineered PE guide RNAs, the PEmax architecture, the transient expression of a dominant-negative mismatch repair protein, strategic silent edits, PE6 variants and proximal 'dead' single-guide RNAs-we increased correction efficiencies for CFTR F508del from less than 0.5% in HEK293T cells to 58% in immortalized bronchial epithelial cells (a 140-fold improvement) and to 25% in patient-derived airway epithelial cells. The optimizations also resulted in minimal off-target editing, in edit-to-indel ratios 3.5-fold greater than those achieved by nuclease-mediated homology-directed repair, and in the functional restoration of CFTR ion channels to over 50% of wild-type levels (similar to those achieved via combination treatment with elexacaftor, tezacaftor and ivacaftor) in primary airway cells. Our findings support the feasibility of a durable one-time treatment for CF.

5.
Physiol Genomics ; 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38881429

ABSTRACT

The circadian timing system and integrated stress response (ISR) systems are fundamental regulatory mechanisms that maintain body homeostasis. The central circadian pacemaker in the suprachiasmatic nucleus (SCN) governs daily rhythms through interactions with peripheral oscillators via the hypothalamus-pituitary-adrenal (HPA) axis. On the other hand, ISR signaling is pivotal for preserving cellular homeostasis in response to physiological changes. Notably, disrupted circadian rhythms are observed in cases of impaired ISR signaling. In this work, we examine the potential interplay between the central circadian system and the ISR, mainly through the SCN and HPA axis. We introduce a semi-mechanistic mathematical model to delineate the suprachiasmatic nucleus (SCN)'s capacity for indirectly perceiving physiological stress through glucocorticoid-mediated feedback from the HPA axis and orchestrating a cellular response via the ISR mechanism. Key components of our investigation include evaluating general control nonderepressible 2 (GCN2) expression in the SCN, the effect of physiological stress stimuli on the HPA axis, and the interconnected feedback between the HPA and SCN. Simulation reveals a critical role for GCN2 in linking ISR with circadian rhythms. Experimental findings have demonstrated that a Gcn2 deletion in mice leads to rapid re-entrainment of the circadian clock following jetlag, as well as to an elongation of the circadian period. These.

6.
medRxiv ; 2024 May 22.
Article in English | MEDLINE | ID: mdl-38826433

ABSTRACT

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder where progressive neuron loss is driven by impaired brain bioenergetics, particularly mitochondrial dysfunction and disrupted cellular respiration. Terazosin (TZ), an α-1 adrenergic receptor antagonist with a known efficacy in treating benign prostatic hypertrophy and hypertension, has shown potential in addressing energy metabolism deficits associated with PD due to its action on phosphoglycerate kinase 1 (PGK1). This study aimed to investigate the safety, tolerability, bioenergetic target engagement, and optimal dose of TZ in neurologically healthy subjects. Methods: Eighteen healthy men and women (60 - 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels, 31 Phosphorous magnetic resonance spectroscopy for brain ATP levels, 18 F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics. Results: Our results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral 18 F-FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response. Conclusions: TZ at a dosage of 5 mg/day engages its metabolic targets effectively in both sexes without inducing significant adverse effects and provides a promising therapeutic avenue for mitigating energetic deficiencies. Further investigation via clinical trials to validate TZ's efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.

7.
Aust Health Rev ; 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38914419

ABSTRACT

ObjectivesThe aim of this study was to develop the Remote Health Value Framework to evaluate the models of healthcare provision for workers in the oil and gas sector, predominantly situated in rural and remote areas.MethodsThe framework was co-designed with the leadership team in one global oil and gas company using a multi-criteria decision analysis approach with a conjoint analysis component. This was used to elicit and understand preferences and trade-offs among different value domains that were important to the stakeholders with respect to the provision of healthcare for its workers. Preference elicitation and interviews were conducted with a mix of health, safety, and environment (HSE) team and non-HSE managers and leaders.ResultsOut of five presented value domains, participants considered the attribute 'Improving health outcomes of employees' the most important aspect for the model of healthcare which accounted for 37.3% of the total utility score. Alternatively, the 'Program cost' attribute was least important to the participants, accounting for only 11.0% of the total utility score. The marginal willingness-to-pay analysis found that participants would be willing to pay A$9090 per utile for an improvement in a particular value attribute.ConclusionsThis is the first value framework for healthcare delivery in the oil and gas industry, contextualised by its delivery within rural and remote locations. It provides a systematic and transparent method for creating value-based healthcare models. This approach facilitates the evaluation of healthcare investments, ensuring they align with value domains prioritised by the HSE and leadership teams.

8.
Am J Surg ; : 115808, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38944622

ABSTRACT

BACKGROUND: There has been tremendous effort to improve quality following colorectal surgery, including the proliferation of minimally invasive techniques, enhanced recovery protocols, and surgical site infection prevention bundles. While these programs have demonstrated improved postoperative outcomes at the institutional level, it is unclear whether similar benefits are present on a national scale. METHODS: American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Targeted Colectomy data from 2012 to 2020 were used to identify patients undergoing minimally invasive surgery (MIS) or open partial colectomy (CPT 44140, 44204) or low anterior resection (CPT 44145, 44207). Chronological cohorts as well as annual trends in 30-day postoperative outcomes including surgical site infection, venous thromboembolism, and length of stay were assessed using both univariable and multivariable regression analyses. RESULTS: 261,301 patients, 135,876 (52 â€‹%) female, with a median age of 62 (IQR 53-72) were included. Across all years, MIS partial colectomy was the most common procedure (37 â€‹%), followed by MIS low anterior resection (27 â€‹%), open partial colectomy (24 â€‹%), and open low anterior resection (12 â€‹%). MIS increased from 59 â€‹% in 2012-2014 to 66 â€‹% in 2018-2020 (p â€‹< â€‹0.001). During this same period, postoperative length of stay decreased from a median of 5 days (IQR 4-7) in 2012-2014 to 4 days (IQR 3-6) in 2018-2020 (p â€‹< â€‹0.001). Superficial surgical site infections decreased from 5.5 â€‹% in 2012-2014 to 2.9 â€‹% in 2018-2020 (p â€‹< â€‹0.001). Deep surgical site infections similarly decreased from 1.1 â€‹% to 0.4 â€‹% between these periods (p â€‹< â€‹0.001). Pulmonary embolism also decreased from 0.6 â€‹% to 0.5 â€‹% between periods (p â€‹= â€‹0.02). 30-day mortality was unchanged at 1.7 â€‹% between 2012-2014 and 2018-2020 (p â€‹= â€‹0.40). After adjustment for ACS NSQIP estimated probability of morbidity and mortality, undergoing a colectomy in 2020 compared to 2012 was associated with a 14 â€‹% decrease in postoperative length of stay (p â€‹< â€‹0.001). CONCLUSIONS: Between 2012 and 2020, significant improvements in postoperative outcomes after colectomy were observed in the United States. These results support the positive impact that the widespread adoption of quality improvement initiatives is having on colorectal patient care nationally.

9.
bioRxiv ; 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38712202

ABSTRACT

The increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing toward vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct OUD behaviors while maintaining a uniform environment, an experimental design not easily achieved in humans. Furthermore, we used a novel non-linear network-based clustering approach to characterize rats based on OUD vulnerability to assess genetic variants associated with OUD susceptibility. Our findings confirm the heritability of several OUD-like behaviors, including OUD susceptibility. Additionally, several genetic variants associated with nociceptive threshold prior to heroin experience, heroin consumption, escalation of intake, and motivation to obtain heroin were identified. Tom1 , a microglial component, was implicated for nociception. Several genes involved in dopaminergic signaling, neuroplasticity and substance use disorders, including Brwd1 , Pcp4, Phb1l2 and Mmp15 were implicated for the heroin traits. Additionally, an OUD vulnerable phenotype was associated with genetic variants for consumption and break point, suggesting a specific genetic contribution for OUD-like traits contributing to vulnerability. Together, these findings identify novel genetic markers related to the susceptibility to OUD-relevant behaviors in HS rats.

10.
Sci Rep ; 14(1): 11834, 2024 05 23.
Article in English | MEDLINE | ID: mdl-38783150

ABSTRACT

Human adipose-derived stem cell (ASC) grafts have emerged as a powerful tool in regenerative medicine. However, ASC therapeutic potential is hindered by stressors throughout their use. Here we demonstrate the transgenic expression of the tardigrade-derived mitochondrial abundant heat soluble (MAHS) protein for improved ASC resistance to metabolic, mitochondrial, and injection shear stress. In vitro, MAHS-expressing ASCs demonstrate up to 61% increased cell survival following 72 h of incubation in phosphate buffered saline containing 20% media. Following up to 3.5% DMSO exposure for up to 72 h, a 14-49% increase in MAHS-expressing ASC survival was observed. Further, MAHS expression in ASCs is associated with up to 39% improved cell viability following injection through clinically relevant 27-, 32-, and 34-gauge needles. Our results reveal that MAHS expression in ASCs supports survival in response to a variety of common stressors associated with regenerative therapies, thereby motivating further investigation into MAHS as an agent for stem cell stress resistance. However, differentiation capacity in MAHS-expressing ASCs appears to be skewed in favor of osteogenesis over adipogenesis. Specifically, activity of the early bone formation marker alkaline phosphatase is increased by 74% in MAHS-expressing ASCs following 14 days in osteogenic media. Conversely, positive area of the neutral lipid droplet marker BODIPY is decreased by up to 10% in MAHS-transgenic ASCs following 14 days in adipogenic media. Interestingly, media supplementation with up to 40 mM glucose is sufficient to restore adipogenic differentiation within 14 days, prompting further analysis of mechanisms underlying interference between MAHS and differentiation processes.


Subject(s)
Cell Differentiation , Cell Survival , Stem Cells , Tardigrada , Animals , Humans , Cell Survival/drug effects , Stem Cells/metabolism , Stem Cells/cytology , Tardigrada/metabolism , Adipose Tissue/cytology , Adipose Tissue/metabolism , Mitochondrial Proteins/metabolism , Mitochondrial Proteins/genetics , Mitochondria/metabolism , Adipogenesis , Cells, Cultured , Stress, Physiological
11.
Eur Phys J E Soft Matter ; 47(5): 36, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38802588

ABSTRACT

Fibrous networks such as collagen are common in biological systems. Recent theoretical and experimental efforts have shed light on the mechanics of single component networks. Most real biopolymer networks, however, are composites made of elements with different rigidity. For instance, the extracellular matrix in mammalian tissues consists of stiff collagen fibers in a background matrix of flexible polymers such as hyaluronic acid (HA). The interplay between different biopolymer components in such composite networks remains unclear. In this work, we use 2D coarse-grained models to study the nonlinear strain-stiffening behavior of composites. We introduce a local volume constraint to model the incompressibility of HA. We also perform rheology experiments on composites of collagen with HA. Theoretically and experimentally, we demonstrate that the linear shear modulus of composite networks can be increased by approximately an order of magnitude above the corresponding moduli of the pure components. Our model shows that this synergistic effect can be understood in terms of the local incompressibility of HA, which acts to suppress density fluctuations of the collagen matrix with which it is entangled.

12.
Clin Nephrol ; 2024 May 03.
Article in English | MEDLINE | ID: mdl-38699984

ABSTRACT

Controversy exists as to the optimal observational time (OT) after outpatient percutaneous kidney biopsy. Further, there is some uncertainty about the benefit of smaller (18-gauge) vs. larger (16-gauge) biopsy needles. At our institution, we have been lowering the OT after outpatient kidney biopsies. Initially in 2015, we were monitoring for 6 hours and gradually began to decrease the OT over time. From 2020, we have adopted an OT of less than 4 hours. During this time period (in 2018), we also began using a smaller gauge needle (18 gauge). We reviewed all outpatient kidney biopsies performed by the nephrology division at our institution since 2015. There were 137 biopsies reviewed. 63 had OT of 4 - 6 hours, and 74 had OT < 4 hours. There was a total of 4 significant complications (2.9%). Two complications, symptomatic retroperitoneal bleeds, were detected in less than 3 hours. The other 2 complications were seen at 9 hours (clot retention) and 72 hours (retroperitoneal bleed after anticoagulation restarted). 63% of the biopsies were done using 18-gauge needles with 1 complication in this group vs. 3 in the 16-gauge group. All cases had adequate tissue for interpretation based on the ability to make a kidney diagnosis. The number of glomeruli obtained in the 18-gauge group was 29 ± 13 glomeruli, and in the 16-gauge group was 25 ± 10, which did not differ between groups. In summary, in an outpatient population, all significant post-biopsy complications were evident either within the first 3 hours or after 9 hours, and this suggests the feasibility of using shorter than standard OT in outpatient kidney biopsies. Furthermore, an 18-gauge needle may lower the risk of complications and obtain adequate tissue.

13.
Front Hum Neurosci ; 18: 1383714, 2024.
Article in English | MEDLINE | ID: mdl-38812472

ABSTRACT

The purpose of this article is to review the scientific literature concerning speech in Parkinson's disease (PD) with reference to the DIVA/GODIVA neurocomputational modeling framework. Within this theoretical view, the basal ganglia (BG) contribute to several different aspects of speech motor learning and execution. First, the BG are posited to play a role in the initiation and scaling of speech movements. Within the DIVA/GODIVA framework, initiation and scaling are carried out by initiation map nodes in the supplementary motor area acting in concert with the BG. Reduced support of the initiation map from the BG in PD would result in reduced movement intensity as well as susceptibility to early termination of movement. A second proposed role concerns the learning of common speech sequences, such as phoneme sequences comprising words; this view receives support from the animal literature as well as studies identifying speech sequence learning deficits in PD. Third, the BG may play a role in the temporary buffering and sequencing of longer speech utterances such as phrases during conversational speech. Although the literature does not support a critical role for the BG in representing sequence order (since incorrectly ordered speech is not characteristic of PD), the BG are posited to contribute to the scaling of individual movements in the sequence, including increasing movement intensity for emphatic stress on key words. Therapeutic interventions for PD have inconsistent effects on speech. In contrast to dopaminergic treatments, which typically either leave speech unchanged or lead to minor improvements, deep brain stimulation (DBS) can degrade speech in some cases and improve it in others. However, cases of degradation may be due to unintended stimulation of efferent motor projections to the speech articulators. Findings of spared speech after bilateral pallidotomy appear to indicate that any role played by the BG in adult speech must be supplementary rather than mandatory, with the sequential order of well-learned sequences apparently represented elsewhere (e.g., in cortico-cortical projections).

14.
Dermatol Online J ; 30(1)2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38762855

ABSTRACT

Superficial granulomatous pyoderma gangrenosum is a rare, superficial, vegetating form of pyoderma gangrenosum that tends to occur as a single lesion, most commonly on the trunk. Herein, we report a clinically confounding case of disseminated superficial granulomatous pyoderma gangrenosum in a patient with a 5-year history of painful and chronic ulcerations of the bilateral upper extremities and face in a sun exposed distribution. This was a diagnostically challenging case due to the treatment-refractory nature of our patient's skin lesions and the atypical clinical and histologic presentations encountered. We review our clinical decision process and acknowledge other entities that were considered during the clinical course of this case. Additionally, we discuss the lack of responsiveness to various treatment options with eventual successful clearance of this patient's active skin disease with initiation of adalimumab.


Subject(s)
Adalimumab , Pyoderma Gangrenosum , Humans , Pyoderma Gangrenosum/pathology , Pyoderma Gangrenosum/diagnosis , Pyoderma Gangrenosum/drug therapy , Adalimumab/therapeutic use , Female , Male , Granuloma/pathology , Middle Aged , Suppuration , Dermatitis/pathology , Dermatitis/diagnosis
15.
J Invest Dermatol ; 2024 May 17.
Article in English | MEDLINE | ID: mdl-38763174

ABSTRACT

Gene editing nucleases, base editors, and prime editors are potential locus specific genetic treatment strategies for recessive dystrophic epidermolysis bullosa (RDEB); however, many RDEB COL7A1 mutations are unique, making the development of personalized editing reagents challenging. 270 of the ∼320 COL7A1 EB mutations reside in exons that can be skipped, and antisense oligonucleotides (ASO) and gene editing nucleases have been used to create in-frame deletions. ASOs are transient and nucleases generate deleterious double stranded DNA breaks (DSB) and uncontrolled mixtures of allele products. We developed a twin prime editing (twinPE) strategy using the PEmax and recently evolved PE6 prime editors and dual prime editing guide RNAs flanking COL7A1 exon five. Prime editing-mediated deletion of exon 5 with a homozygous premature stop codon was achieved in RDEB fibroblasts, keratinocytes, and iPSC with minimal DSBs, and collagen type VII (C7) protein was restored. TwinPE can replace the target exon with recombinase attachment sequences, and we exploited this to re-insert a normal copy of exon 5 using the Bxb1 recombinase. These findings demonstrate that twinPE can facilitate locus-specific, predictable, in-frame deletions and sequence replacement with few DSBs as a strategy that may enable a single therapeutic agent to treat multiple RDEB patient cohorts.

16.
J Bodyw Mov Ther ; 38: 155-157, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38763555

ABSTRACT

A 34-year-old male with a 9+ year history of right sided abdominal pain, associated diarrhea and a diagnosis of irritable bowel syndrome was referred for physical therapy and chiropractic care at a multidisciplinary primary care clinic. Multiple evaluations by various providers resulted in multiple tests and numerous medications without substantial relief in symptoms. Five physical therapy visits and three sessions of chiropractic care resulted in 90% improvement in subjective pain report and 60-70% reduction in diarrhea frequency. At a 6 month follow up phone visit, his symptoms had continued to decrease. While limited as a case study, this report may illustrate a potential somatovisceral relationship and subsequent reduction in gastrointestinal symptoms that can be addressed with conservative care.


Subject(s)
Abdominal Pain , Diarrhea , Exercise Therapy , Irritable Bowel Syndrome , Humans , Male , Adult , Diarrhea/therapy , Abdominal Pain/therapy , Abdominal Pain/etiology , Irritable Bowel Syndrome/therapy , Exercise Therapy/methods , Manipulation, Chiropractic/methods , Musculoskeletal Manipulations/methods , Chronic Disease
17.
bioRxiv ; 2024 May 05.
Article in English | MEDLINE | ID: mdl-38746397

ABSTRACT

The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit non-redundant functions in basal and pathological contexts. Here, we report the development of a bifunctional small molecule, MC-1, capable of selectively degrading EP300 over CREBBP. Using a potent aminopyridine-based inhibitor of the EP300/CREBBP catalytic domain in combination with a VHL ligand, we demonstrate that MC-1 preferentially degrades EP300 in a proteasome-dependent manner. Mechanistic studies reveal that selective degradation cannot be predicted solely by target engagement or ternary complex formation, suggesting additional factors govern paralogue-specific degradation. MC-1 inhibits cell proliferation in a subset of cancer cell lines and provides a new tool to investigate the non-catalytic functions of EP300 and CREBBP. Our findings expand the repertoire of EP300/CREBBP-targeting chemical probes and offer insights into the determinants of selective degradation of highly homologous proteins.

18.
Cell Rep ; 43(4): 114057, 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38583149

ABSTRACT

Pain that persists beyond the time required for tissue healing and pain that arises in the absence of tissue injury, collectively referred to as nociplastic pain, are poorly understood phenomena mediated by plasticity within the central nervous system. The parabrachial nucleus (PBN) is a hub that relays aversive sensory information and appears to play a role in nociplasticity. Here, by preventing PBN Calca neurons from releasing neurotransmitters, we demonstrate that activation of Calca neurons is necessary for the manifestation and maintenance of chronic pain. Additionally, by directly stimulating Calca neurons, we demonstrate that Calca neuron activity is sufficient to drive nociplasticity. Aversive stimuli of multiple sensory modalities, such as exposure to nitroglycerin, cisplatin, or lithium chloride, can drive nociplasticity in a Calca-neuron-dependent manner. Aversive events drive nociplasticity in Calca neurons in the form of increased activity and excitability; however, neuroplasticity also appears to occur in downstream circuitry.


Subject(s)
Neurons , Parabrachial Nucleus , Animals , Parabrachial Nucleus/physiology , Parabrachial Nucleus/drug effects , Neurons/metabolism , Neurons/drug effects , Mice , Neuronal Plasticity/physiology , Male , Mice, Inbred C57BL
19.
Am J Hum Genet ; 111(5): 979-989, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38604166

ABSTRACT

Genotype imputation is now fundamental for genome-wide association studies but lacks fairness due to the underrepresentation of references from non-European ancestries. The state-of-the-art imputation reference panel released by the Trans-Omics for Precision Medicine (TOPMed) initiative improved the imputation of admixed African-ancestry and Hispanic/Latino samples, but imputation for populations primarily residing outside of North America may still fall short in performance due to persisting underrepresentation. To illustrate this point, we imputed the genotypes of over 43,000 individuals across 123 populations around the world and identified numerous populations where imputation accuracy paled in comparison to that of European-ancestry populations. For instance, the mean imputation r-squared (Rsq) for variants with minor allele frequencies between 1% and 5% in Saudi Arabians (n = 1,061), Vietnamese (n = 1,264), Thai (n = 2,435), and Papua New Guineans (n = 776) were 0.79, 0.78, 0.76, and 0.62, respectively, compared to 0.90-0.93 for comparable European populations matched in sample size and SNP array content. Outside of Africa and Latin America, Rsq appeared to decrease as genetic distances to European-ancestry reference increased, as predicted. Using sequencing data as ground truth, we also showed that Rsq may over-estimate imputation accuracy for non-European populations more than European populations, suggesting further disparity in accuracy between populations. Using 1,496 sequenced individuals from Taiwan Biobank as a second reference panel to TOPMed, we also assessed a strategy to improve imputation for non-European populations with meta-imputation, but this design did not improve accuracy across frequency spectra. Taken together, our analyses suggest that we must ultimately strive to increase diversity and size to promote equity within genetics research.


Subject(s)
Gene Frequency , Genetics, Population , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Humans , Genome, Human , Genotype , White People/genetics , European People , Hispanic or Latino , African People , Black People
20.
J Pharm Pract ; : 8971900241247932, 2024 Apr 21.
Article in English | MEDLINE | ID: mdl-38644362

ABSTRACT

Background: Limited data exists to evaluate the optimal management of outpatient beta blocker therapy when patients with heart failure with reduced ejection fraction (HFrEF) are admitted for acute decompensated heart failure (ADHF). Objective: This study aimed to compare the effects of holding or decreasing the dose of outpatient beta blocker therapy vs continuation of therapy on rates of tachyarrhythmias during admission for ADHF. Methods: This single-center, retrospective cohort study divided patients with HFrEF (left ventricular ejection fraction less than or equal to 40%) admitted for ADHF into two cohorts: one that had their outpatient beta blocker continued at the same dose upon admission and one that had it held or dose decreased. The primary outcome was a composite of non-sustained or sustained ventricular tachycardia, ventricular fibrillation, or atrial fibrillation or flutter with rapid ventricular response during the hospitalization. Secondary outcomes included the individual tachyarrhythmias in the primary outcome, in-hospital mortality, and 90-day re-admission for heart failure. Results: Of the 137 patients included, 82 were in the continuation cohort and 55 in the discontinuation/reduction cohort. The median length of stay was 5.3 days (interquartile range, 3.8-7.6). No significant difference in the primary composite outcome was found between the discontinuation/reduction and continuation cohorts (29.1% vs 22.0%; relative risk [95% confidence interval], 1.33 [.74-2.37]; P = .420). No significant differences were seen between the two cohorts for any of the secondary outcomes. Conclusion: Beta blocker therapy adjustment on admission for ADHF may not affect the occurrence of tachyarrhythmias in patients with HFrEF.

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