27941 research outputs found
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Cardiovascular safety of fixed-dose extended-release naltrexone/bupropion in clinical practice
No full textBackground: The fixed-dose extended-release combination of naltrexone/bupropion (NB-ER) is indicated to treat overweight and obesity in adults as an adjunct to a reduced-calorie diet and increased physical activity. This study compared the rate of major adverse cardiovascular events (MACE) and its components (nonfatal acute myocardial infarction [AMI], nonfatal stroke, and cardiovascular death) between patients initiating NB-ER and those initiating lorcaserin (removed from US market in 2020; included as active comparator to minimize possible confounding by indication) in routine clinical practice.
Methods: This was a retrospective cohort study with a new-user, active-comparator design. Patients initiating NB-ER or lorcaserin were identified using Arcadia Data Research electronic health records, including insurance claims (June 2012-February 2020). Incidence rate ratios were estimated, and adjusted hazard ratios (aHRs) with 95 % confidence intervals (CIs) were estimated using a propensity score (PS)-weighted Cox proportional hazard model in an intention-to-treat analysis.
Results: Patients initiating NB-ER (n = 12 475) or lorcaserin (n = 12 171) were followed for a mean observation period of 4.7 years. After PS weighting, baseline comorbidities, concomitant medications, lifestyle factors, and clinical measures were balanced between cohorts. MACE incidence was 0.77/1000 person-years for NB-ER and 1.03/1000 person-years for lorcaserin. Compared to lorcaserin, patients initiating NB-ER had statistically similar rates of MACE (aHR, 0.76; 95 % CI, 0.48-1.22), nonfatal AMI (aHR, 0.74; 95 % CI, 0.45-1.23), and nonfatal stroke (aHR, 1.05; 95 % CI, 0.34-3.22). No deaths were observed within 30 days of an AMI or stroke.
Conclusion: Patients initiating NB-ER compared with lorcaserin were not at an increased risk of MACE or its components. Conclusions from this study must be interpreted in the context of certain assumptions related to PS methodology and use of lorcaserin as an active comparator. Causal interpretations for the cardiovascular safety of NB-ER should be evaluated further in a prospective, randomized, blinded, controlled clinical trial.No embarg
A Spatially Coordinated Keratinocyte-Fibroblast Circuit Recruits MMP9+ Myeloid Cells to Drive IFN-I-Driven Inflammation in Photosensitive Autoimmunity [preprint]
Get PDFThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Photosensitivity is central to cutaneous lupus erythematosus (CLE) and dermatomyositis (DM), but the mechanisms linking UVB exposure to tissue-specific autoimmunity are poorly defined. Using single-cell RNA sequencing, spatial transcriptomics, UVB provocation, and in vitro modeling, we identify MMP9⁺ CD14⁺ myeloid cells as critical mediators of photosensitivity. These cells expand significantly in lesional skin, produce IFN-b, and colocalize with cytotoxic CD4⁺ T cells at the dermal-epidermal junction. Keratinocytes activate fibroblasts in the superficial dermis, prompting them to release chemokines (CCL2, CCL19, CCL7, CCL8, CXCL12) that recruit MMP9⁺ CD14⁺ cells. IFN-I-primed keratinocytes exposed to UVB release cytokines activating dendritic cells, mirroring in vivo responses. UVB irradiation of non-lesional DM skin rapidly recruits these myeloid cells. In a clinical proof-of-concept study, anti-IFN-I treatment with anifrolumab prevented UVB-induced myeloid infiltration and reduced photosensitivity. Thus, targeting MMP9⁺ CD14⁺ cells may offer therapeutic potential for managing photosensitive autoimmune skin conditions.No embarg
Travel nurses' experience with ethical challenges in practice: A qualitative descriptive study
No full textBackgroundNursing turnover rates are among the highest measured in recent years, contributing to financial and staffing challenges in the healthcare industry. Citing ethical challenges and subsequent moral distress, nurses have increasingly turned to travel nurse positions. Current literature regarding moral distress and ethical challenges has largely focused on staff nurses, and it is unknown how travel nurses experience ethical challenges and any associated moral distress.AimTo explore travel nurses' experiences with ethical challenges, inclusive of how they respond and feel or mitigate moral distress related to these challenges. Sources of support will be identified, with a focus on personal and organizational resources.Research designA qualitative descriptive study conducted through individual interviews. Participants were recruited with a purposive sampling strategy through flyers and social media. The data was analyzed using inductive and deductive content analysis. Participants and research context: Nurses ( = 15) working as travel nurses in the United States of America. Data was collected between August 2024 and February 2025.Ethical considerationsThis study received approval by the Institutional Review Board at the UMass Chan Medical School and Baystate Medical Center.FindingsThree themes described the participants' experience of ethical challenges. Strategies that travel nurses use to address and cope with ethical challenges include reflective thought, formation of a support network, and contemplation of action strategies.DiscussionTravel nurses' experience with ethical challenges has some unique qualities, and coping strategies have some distinctions from recommended strategies to avoid and mitigate moral distress.ConclusionThis study will inform practice models of travel nursing and strategies to support all nurses encountering ethical challenges in their practice. Nursing leaders should foster strategies for feedback from travel nurses, including ways to improve the ethical environment.No embarg
Advancing the APRN and PA professions through medical staff membership: An organizational case study
No full textGranting medical staff membership to advanced practice registered nurses (APRNs) and physician associates (PAs) is a national trend endorsed by The Joint Commission in 1983 and by the Centers for Medicare & Medicaid Services in 2012. APRNs and PAs must participate in the system in which medical care policies are made and communicated. Medical staff privileges enable these clinicians to help develop and implement hospital and medical staff policies that improve the quality and appropriateness of patient care. Medical staff membership also encourages a culture that promotes interprofessional and collaborative practice, enhancing and strengthening clinician relationships. Through education and by updating bylaws, rules, and regulations, APRNs and PAs at our facility can now admit patients, and they have a voice and vote in medical staff governance committees that affect their practice.No embarg
Brown Fat Citrate Carrier (SLC25A1) and ATP-Citrate Lyase (ACLY) Link Carbohydrate Availability to Thermogenesis and Guard Against Metabolic Stress
No full textBrown adipose tissue (BAT) in mammals performs non-shivering thermogenesis. This function is mainly thought to be carried out by uncoupling protein 1(UCP1), an inner mitochondrial membrane protein that dissipates proton gradient as heat. Active BAT in humans correlates with improved metabolic health. Thus, there is interest in therapeutically stimulating BAT to combat obesity. A conventional view is that active BAT catabolizes glucose and fatty acids to fuel the tricarboxylic acid (TCA) cycle, which provides the electron donors to drive the mitochondrial membrane potential and UCP1-mediated uncoupling. However, during cold exposure, the TCA intermediate citrate is exported from the mitochondria into the cytosol, where it is converted to acetyl- CoA, which fuels de novo lipid synthesis. A portion of these lipids are then immediately catabolized through beta-oxidation, resulting in simultaneous fatty acid synthesis (FAS) and fatty acid oxidation (FAO). Why this paradox occurs during thermogenesis has long been a mystery. To test this, we generated several brown fat-specific knockout models in the de novo lipid synthesis pathway. Using these models, we have shown that SLC25A1, mitochondrial citrate carrier, and ATP citrate lyase (ACLY), the enzyme that cleaves citrate into acetyl-CoA, are essential for mitochondrial/thermogenic program in the brown fat, and they allow citrate exit from mitochondria and thus mitigate mitochondrial stress under carbohydrate-rich conditions. Overall, we propose a model in which FAS-FAO cycling is crucial and can relieve mitochondrial stress, generate important metabolites for thermogenesis, contribute to heat production through multiple ATP hydrolysis steps, and dissipate energy excess, which can be utilized therapeutically.Interdisciplinary Graduate Program2 years2027-04-1
Dissecting the Molecular Mechanisms of Human Pharyngeal Endoderm Development in Human Pluripotent Stem Cell Differentation
No full textThe human pharyngeal foregut endoderm (PFE) is the embryonic precursor to many important tissues and organs, including Eustachian tube, palatine tonsils, thymus, and parathyroid glands. Defects in human PFE development can give rise to severe genetic disorders, such as DiGeorge syndrome, Barakat syndrome, and branchio-oto-renal syndrome. The development of human PFE is regulated by a sophisticated network of signaling pathways and transcription factors (TFs). To investigate the molecular mechanisms of human PFE development, we first employed a state-of-the-art human pluripotent stem cell (hPSC) differentiation protocol to recapitulate human PFE development stepwise in vitro. We refined temporal and dose parameters for retinoic acid signaling, and examined the resulting cell populations at cellular and molecular level. To dissect the molecular roles of key TFs in human PFE development, we performed a Perturb-Seq screen that revealed key genes involved in human PFE maturation. Using single-cell multi-omic analysis, we discovered that GATA3 knock-out was significantly enriched in the immature population. To further probe GATA3 function, we generated a clonal GATA3 knock-out hPSC line and compared the gene expression profile, chromatin accessibility and epigenetic landscape between knock-out and wild-type in human PFE differentiation. We found that GATA3 controls the gene expression of various downstream targets by interacting with different enhancer regions at different timepoints. In conclusion, this dissertation defines the retinoic acid signaling requirements in human PFE differentiation, uncovers new roles of GATA3 during human PFE development, and sheds light on potential disease mechanisms of pharyngeal defects in patients with congenital GATA3 mutation.Translational Science2 years2027-10-0
Investigating Host-Pathogen Interaction to Discover a Novel Therapeutic Target for SARS-CoV-2
No full textSARS-CoV-2 is a positive-stranded RNA virus that caused the COVID-19 epidemic, which left a huge impact not only in the scientific community but also in global economics and politics. Preparing for these crises require exploration of various methods of antiviral applications. In response to the epidemic, we sought to discover antiviral strategies by focusing on possible therapeutic targets in SARS-CoV-2 replication cycle. The first approach we applied is repurposing a known influenza A virus treatment. We tested amantadine and its variants against SARS-CoV-2 infection in cultured cells and in vivo in mouse and hamster models. We concluded that amantadine and its closely related chemicals only have a mild antiviral effect in SARS-CoV-2 infection. We next examined host factors that could be involved in SARS-CoV-2 replication. Scavenger receptor type 1, class B (SR-B1) is a cholesterol receptor that receives cholesteryl esters by attaching to high-density lipoproteins at cell surface. When SR-B1 is inhibited or knocked out of the cell, we discovered that SARS-CoV-2 replication is diminished. To elucidate the role for SR-B1in SARS-CoV-2 replication, we used its inhibitors and SR-B1 knockout cell lines in binding assays as well as pH-indicating assays. We find that SR-B1 promotes acidification of the endolysosomal compartment and its inhibition or absence results in SARS-CoV-2 entrapment. We believe that these findings can lead to developing novel therapeutic targets against SARS-CoV-2 as well as that of other enveloped viruses.Biochemistry and Molecular BiotechnologyNo embarg
Patient and Health Care Provider Experiences With Suicide-Related Tele-Mental Health Evaluations in the Emergency Department: Multiphase Qualitative Study
Get PDFBackground: Suicide is one of the most pressing public health issues in the United States, inflicting a devastating toll on families, communities, and society. Individuals with suicide risk often visit emergency departments (EDs), but the setting has chronic shortages in psychiatric care staffing, which results in gaps in best practices, prolonged length of stay for patients, and unnecessary inpatient admissions. To improve behavioral health care and suicide prevention practices, we implemented telehealth-based mental health evaluations with enhanced suicide care at 2 EDs in Massachusetts. Little is known about patient experiences and perceptions toward the appropriateness of telehealth for emergency mental health evaluations in the context of suicide prevention.
Objective: The goal of our qualitative study was to understand patient and health care provider experiences with the Telehealth to Improve Prevention of Suicide (TIPS) program and to gain insight into aspects of the implementation process.
Methods: We conducted 25 semistructured qualitative interviews with 10 patients who received a tele-mental health evaluation and 12 clinicians, including behavioral health and ED providers, whose clinical workflows included the new telehealth implementation. We used methods for rapid qualitative analysis and were guided by key implementation of a priori domains outlined in the Practical, Robust Implementation and Sustainability Model framework.
Results: Patients and health care providers reported their perceptions of the patient care experiences and recommendations related to implementation. Patients' perspectives were highly varied, with several factors and priorities contributing to their views on tele-mental health in this setting. Overall, patients valued transparency and informed decision-making, which extended to having the option to choose between an in-person or telehealth evaluation. Health care providers generally felt that in-person evaluations were preferable; however, given the long wait times and staffing concerns, telehealth evaluations offered a strong alternative. Both patients and health care providers reported several recommendations for future implementation efforts, including increased support and information, communication throughout the process, and improving overall psychiatric care in the ED.
Conclusions: Given current shortages in behavioral health care, emergency tele-mental health evaluations could provide an opportunity to reduce wait times and support the delivery of best practice suicide-related care. However, their implementation has the potential to exacerbate existing issues related to patient autonomy, therapeutic alliance, and care transitions. Our study contributes to filling a gap in knowledge related to patient and health care provider experiences of this telehealth service and describes factors that impact implementation, which may inform future care advances by clinicians and administrators.No embarg
Impact of Asynchronous Training on Student's Confidence and Attitudes Regarding Patients With Opioid Use Disorders
No full textBackground: The American opioid use disorder (OUD) and overdose epidemic require physicians and advanced care providers to be prepared to care for patients with this life-threatening condition. Learning to identify, engage, and treat patients with OUD with medications is an essential skill for providers, as is developing requisite confidence and therapeutic attitudes regarding the care of patients with OUD (CP-OUD). To address the need for improved OUD treatment education, our team built and implemented a 12-module asynchronous course entitled, "Care of Patients with Opioid Use Disorder", in 3 Doctor of Medicine (MD) programs and a Graduate School of Nursing (GSN) program.
Methods: Students self-reported their attitudes and confidence regarding the CP-OUD before and after each module. Twelve questions assessed confidence, and 12 questions assessed attitude. Students' change in confidence and attitudes before and after training was calculated.
Results: Responses were collected between January 2021 and November 2024. The number of students completing each module ranged from 552 to 967 MD students and 81 to 149 GSN students. Students reported improved confidence after completing each of the 12 modules (<0.0001). Students reported improved attitudes after completing 10 of the 12 modules (<0.0001). Differences ranging from small to medium size were observed between MD and GSN student's baseline confidence for 4 modules, and baseline attitudes for 6 modules.
Conclusions: Asynchronous learning modules can be effectively implemented in medical and nursing education to improve confidence and attitudes regarding the CP-OUD. The use of asynchronous training modules allows for flexible deployment, as evidenced by their use in 3 MD programs and a GSN program. Future research should investigate whether improved confidence and attitudes during medical and nursing education result in more graduates caring for patients with OUD post-training.No embarg
BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease
No full textClassic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the branched-chain α-ketoacid dehydrogenase E1α (BCKDHA), E1β (BCKDHB), or dihydrolipoamide branched-chain transacylase (DBT) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.hA-BiP-hB) to the liver, muscle, heart, and brain. rAAV9.hA-BiP-hB restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in BCKDHA-/- HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 1014 vector genomes per kilogram. In two models of severe MSUD (Bckdha-/- and Bckdhb-/- mice) and a newborn calf homozygous for BCKDHA c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.No embarg