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No full textMy granddaughter, Jasmine Maya, an hour after birth.
New life, new hope: our work will make her world a healthier place to live in
Comparative Efficacy and Safety of Daridorexant, Lemborexant, and Suvorexant for Insomnia: A Systematic Review and Network Meta-Analysis
No full textBackground: In order to appraise the risk-benefit balance of the three available dual orexin receptor antagonists (DORAs; daridorexant, lemborexant, and suvorexant) for the management of adults with insomnia, we conducted a systematic review and random-effects model network meta-analysis. Methods: Included were all published double-blind, randomized, placebo-controlled trials of these agents. Outcomes included subjective time to sleep onset at month 1 (sTSO, primary), subjective total sleep time at month 1 (sTST, co-primary), subjective wake after sleep onset at month 1, Insomnia Severity Index scores at month 1, all-cause discontinuation, discontinuation due to adverse events, and the incidence of individual adverse events such as somnolence, dizziness, falls, headache, nasopharyngitis, and upper respiratory tract infection. Results: This meta-analysis included eight trials (5198 adults, average age = 56.33 years, 67.84% female). The treatment arms included daridorexant 25 mg/day (DAR25), daridorexant 50 mg/day (DAR50), lemborexant 5 mg/day (LEM5), lemborexant 10 mg/day (LEM10), suvorexant 20 mg/day (15 mg/day for people ≥65years, SUV20/15), and placebo. All active-treatments outperformed placebo in terms of all efficacy outcomes. The standardized mean difference (95% CI) in primary outcomes ranged from; sTSO: −0.430 (−0.568, −0.292) for LEM10 to −0.164 (−0.296, −0.031) for SUV20/15 and sTST: −0.475 (−0.593, −0.357) for DRA50 to −0.206 (−0.330, −0.082) for LEM5. An additional sensitivity analysis suggested that DRA25, LEM10, and SUV20/15 were associated with a higher incidence of somnolence compared to a placebo. Conclusions: Considering that there is no evidence that DORAs are associated with physiological tolerance, withdrawal symptoms, or rebound insomnia when abruptly discontinued, and that sleep architecture is not adversely affected, the DORAs appear to be a favorable choice in managing insomnia disorder in adults
Narrative Review of Electronic Health Record Systems in Anesthesia: Benefits, Risks, and Medico-Legal Considerations in the United States of America
No full textElectronic health records (EHRs) have transformed healthcare delivery and documentation by accurately capturing routine care and critical events through automated data recording. EHRs also enable clinical decision support, quality improvement initiatives, and large-scale research. A narrative review has been constructed using relevant research regarding medicolegal liability associated with EHRs, related to anesthesia care. EHRs have created new liability exposures through alert fatigue, system errors, and inappropriate use of functions such as copy-and-paste. Ethical issues and concerns with EHRs include privacy, informed consent, and secondary data uses. Metadata, data about the data , provides insight into record authenticity, clinician involvement in care, and communication between providers. However, EHR metadata is legally discoverable, and courts have compelled its release to plaintiffs despite hospital objections. This narrative review covers the benefits of EHRs in anesthesiology practice, discusses medicolegal liability and ethical concerns, and highlights a method for assessing medicolegal risks using the EHR
Response to “Two Cases of Ulcerative Dermatomyositis With Negative Antimelanoma Differentiation-Associated Gene 5 Antibody”
No full textImpact of Obesity on Orthopedic Injury and Fracture Patterns in Motor Vehicle Accidents
No full textPurpose: Obese trauma patients face a higher risk of mortality, prolonged ICU stays, and more complications than non-obese patients. However, some studies suggest that obesity might provide protective benefits in high-impact trauma situations through the “cushion effect”. This study will examine whether obesity influences fracture occurrence, injury severity, and clinical outcomes in motor vehicle accidents (MVA). Methods: A retrospective study of 555 adult patients who presented to a Level 1 Trauma Center following a MVA from 2010–2022. Patients with a Body Mass Index (BMI) greater than or equal to 30 kg/m2 were categorized as obese (178 patients, 32.6%), and those with a BMI less than 30 kg/m2 were classified as non-obese (377 patients, 67.4%). Incidence of bone fractures and injury severity were compared between both groups using injury severity score (ISS) and abbreviated injury scale (AIS). For variables significant on univariate analysis, binary logistic regression models were used to control age, gender, restraint use, and airbag deployment. Results: The mean number of fractures (0.62 vs 0.46, p=0.096) and ISS (4.55 vs 4.51, p=0.703) were similar between the obese and non-obese groups. However, obese patients were more likely to experience upper extremity fractures (7.3% vs 3.4%, p=0.045) and lower extremity fractures (7.3% vs 2.7%, p =0.01), particularly fractures of the tibia/fibula (5.6% vs 1.6%, p=0.008). No significant differences were found in the incidence of head, thoracolumbar, or pelvic fractures between the two groups. After controlling for age, gender, restraint use, and airbag deployment, obesity remained an independent predictor of lower extremity fracture (aOR) 2.62 (95% CI: 1.01–6.56), p = 0.04). Conclusion: Obesity is an independent predictor of lower extremity fractures following a MVA. Clinicians should acknowledge potential differences in fracture occurrence and patterns between obese and non-obese patients during triage
Epigenetic Modulation of the NLRP6 Inflammasome Sensor as a Therapeutic Modality to Reduce Necroptosis-Driven Gastrointestinal Mucosal Dysfunction in HIV/SIV Infection
No full textBackground: Gastrointestinal (GI) disease/dysfunction persists in people living with HIV (PLWH) receiving suppressive combination anti-retroviral therapy (ART) leading to epithelial barrier breakdown, microbial translocation and systemic inflammation that can drive non-AIDS associated comorbidities. Although epigenetic mechanisms are predicted to drive GI dysfunction, they remain unknown and unaddressed in HIV/SIV infection. The present study investigated genome-wide changes in DNA methylation, and gene expression exclusively in colon epithelial cells (CE) in response to simian immunodeficiency virus infection (SIV) and long-term low-dose delta-9-tetrahydrocannabinol (THC). Methods: Using reduced-representation bisulfite sequencing, we characterized DNA methylation changes in colonic epithelium (CE) of uninfected controls (n=5) and SIV-infected rhesus macaques (RMs) administered vehicle (VEH/SIV; n=7) or THC (THC/SIV; n=6). Intact jejunum resection segments (~5cm) were collected from sixteen ART treated SIV-infected RMs [(VEH/SIV/ART; n=8) and (THC/SIV/ART; n=8)] to confirm protein expression data identified in the colon of ART-naïve SIV-infected RMs. Transcriptomics data was used to confirm expression of differentially methylated genes. Protein expression of differentially methylated genes and their downstream targets was assessed using Immunofluorescence followed by HALO quantification. Results: SIV infection in ART-naïve RMs induced marked hypomethylation throughout promoter-associated CpG islands (paCGIs) in genes related to inflammatory response (NLRP6, cGAS), cellular adhesion (PCDH17, CDH7) and proliferation (WIF1, SFRP1, TERT, and HAND2) in CEs. Moreover, low-dose THC reduced NLRP6 protein expression in CE by hypermethylating the NLRP6 paCGI and blocked polyI:C induced NLRP6 upregulation in vitro. In ART suppressed SIV-infected RMs, significant NLRP6 protein upregulation during acute infection was unaffected by long-term ART administration during chronic infection despite successful plasma and tissue viral suppression. In this group, NLRP6 protein upregulation was associated with significantly increased expression of necroptosis-driving proteins; phosphorylated-RIPK3(Ser199), phosphorylated-MLKL(Thr357/Ser358), and HMGB1. Most strikingly, adding ART to THC-treated SIV-infected RMs effectively reduced NLRP6 and necroptosis-driving protein expression to pre-infection levels. Conclusions: We conclude that DNA hypomethylation-assisted NLRP6 upregulation can lead to its constitutively high expression resulting in the activation of necroptosis signaling via the RIPK3/p-MLKL pathway that can eventually drive intestinal epithelial loss/death. From a clinical standpoint, low-dose phytocannabinoids in combination with ART could safely and successfully reduce/reverse persistent GI inflammatory responses via modulating DNA methylation
12-Lipoxygenase Inhibition Improves Glycemia and Obesity-Associated Inflammation in Male Human Gene Replacement Mice
No full textObesity-associated inflammation is characterized by macrophage infiltration into peripheral tissues, contributing to the progression of prediabetes and type 2 diabetes. 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and promotes the migration of macrophages, yet its role in obesity-associated inflammation remains incompletely understood. Furthermore, differences between mouse and human orthologs of 12-LOX have limited efforts to study existing pharmacologic inhibitors of 12-LOX. In this study, we used a human gene replacement mouse model in which the gene encoding mouse 12-LOX (Alox15) is replaced by the human ALOX12 gene. As a model of obesity and dysglycemia, we administered male mice a high-fat diet. We subsequently investigated the effects of VLX-1005, a potent and selective small molecule inhibitor of human 12-LOX. Oral administration of VLX-1005 resulted in improved glucose homeostasis, decreased β-cell dedifferentiation, and reduced macrophage infiltration in islets and adipose tissue. Analysis of the stromal vascular fraction from adipose tissue showed a reduction in myeloid cells and cytokine expression with VLX-1005 treatment, indicating decreased adipose tissue inflammation. In a distinct mouse model in which Alox15 was selectively deleted in myeloid cells, we observed decreased β-cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and type 2 diabetes
Surrogates May Not Accurately Estimate Resilience and Spirituality in Neurologically Critically Ill Patients
No full textBackground: Surrogates often provide substituted judgement for neurologically critically ill patients. Resilience and spirituality are understudied constructs in this patient population. In this study we examine how accurately surrogates estimate measures of resilience and spirituality for neurologically critically ill patients. Methods: A convenience sample of English/Spanish speaking neurologically critically ill patient-surrogate dyads was enrolled from March 2016 to 2018. Questionnaires related to resilience (CD-RISC-10), spiritual wellbeing (positive Brief R-COPE), and spiritual turmoil (negative Brief R-cope) were completed by patients for themselves and surrogates on behalf of patients while in the Neurosciences Intensive Care Unit. Responses were evaluated by Spearman\u27s rank-order correlation, Bland-Altman analysis and Cohen\u27s weighted kappa. Results: 51 dyads were included. No correlation was found between patient and surrogate CD-RISC-10 (0.17, p = 0.238); moderate, positive correlations for positive (0.47, p \u3c 0.001) and negative (0.33, p = 0.021) Brief R-COPE. Mean differences between patient and surrogate scores were low for CD-RISC-10 (−1.0 point), positive R-COPE (− 0.14 point), and negative R-COPE (0.02 point) suggesting lack of bias towards over/under-estimation. Kappa scores demonstrate fair inter-rater agreement for positive/negative R-COPE and no agreement for CD-RISC-10. Conclusion: Surrogate evaluations lack systematic bias, but may not estimate resilience and spirituality reliably for neurologically critically ill patients