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Abstract Inappropriate and chronic activation of the cytosolic NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first‐in‐human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150–1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC‐2394, a small‐molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC‐2394 and its CYP3A4 induction potential in food‐effect (FE) and drug–drug interaction (DDI) stages, respectively. Although GDC‐2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug‐induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC‐2394 was rapidly absorbed; exposure increased in an approximately dose‐proportional manner with low‐to‐moderate intersubject variability. The mean terminal half‐life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high‐fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC‐2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole‐blood stimulation assays showed rapid, reversible, and near‐complete inhibition of the selected PD biomarkers, IL‐1β and IL‐18, across all tested doses. Despite favorable PK and target engagement PD, the GDC‐2394 safety profile precludes its further development.

Trait introgression requires universal markers, but cross-species transferability of current SNP markers can be as low as 2%. Here, the authors use an AmpSeq haplotype strategy targeting the collinear core genome for marker development and show transferability increases to 91.4% in the Vitis genus.

Piscidin 3 (P3), a peptide produced by fish, and a hexyl ester-modified sophorolipid (SL-HE), have individually shown promise as antimicrobial and anticancer drugs. A recent report by our team revealed that combining P3 with SL-HE in a 1:8 molar ratio resulted in an 8-fold enhancement in peptide activity, while SL-HE improved by 25-fold its antimicrobial activity against the Gram-positive microorganism Bacillus cereus . Extending these findings, the same P3/SL-HE combination was assessed on two breast cancer cell lines: BT-474, a hormonally positive cell line, and MDA-MB-231, an aggressive triple-negative cell line. The results demonstrated that the 1:8 molar ratio of P3/SL-HE synergistically enhances the anticancer effects against both tumorigenic breast cell lines. Mechanistic studies indicate the activation of an intrinsic apoptotic cell death mechanism through an increase in reactive oxygen species and mitochondrial dysfunction and a secondary programmed necrotic pathway that involves pore formation in the plasma membrane. When a fibroblast cell line, CCD1065SK HDF, was utilized to determine selectivity, the synergistic SL-HE/P3 combination exhibited a protective property compared to the use of SL-HE alone and therefore afforded vastly improved selectivity indices. Given the promising results reported herein, the synergistic combination of P3/SL-HE constitutes a novel strategy that merits further study for the treatment of breast cancer., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Isolated vaginal bleeding before the onset of puberty is a rare presentation of isosexual precocity. In most cases, isolated vaginal bleeding without an abnormal genital examination is self-limited with resolution usually within 1 to 3 episodes. Watchful waiting is appropriate in most patients who do not have persistent bleeding, other signs of puberty, or signs/symptoms of an underlying etiology. Workup for patients with concerning features may include puberty hormone levels and/or transabdominal and transperineal ultrasound., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Acne is a common skin condition in adolescent patients but much less common in childhood. Pediatric providers should be familiar with the varying presentations in the pediatric population and recognize when additional physical signs of hyperandrogenism are present. This article details the pathogenesis and presentation of acne in infancy, mid-childhood, and preadolescence. The differential diagnosis is discussed and recommendations for initial workup, referral, and treatment are provided. [ Pediatr Ann . 2024;53(4):e115-e120.] .

Purpose: Low physical activity in the academic workplace may increase the risk of cardiometabolic disease. This randomised controlled trial investigated the effect of 14 weeks of concurrent exercise training (CT) on components of metabolic syndrome, body composition, insulin resistance, and markers of systemic inflammation in inactive academics., Methods: 59 inactive academics were randomised into a CT (n = 29) or wait-list control group (n = 30). CT performed supervised training at an onsite facility 3 times per week for 14 weeks and cardiometabolic health was assessed pre- and post-intervention. Aerobic capacity was measured via a metabolic cart. Dual-Energy X-ray Absorptiometry measured fat mass, lean mass, and central adiposity. Fasting blood samples were analysed for interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), glucose, and lipid profile., Results: Following the intervention, there was a decrease in fat mass (mean ± SD;  - 1.3 ± 1.4%), android fat mass (median (IQR);  - 0.06 (0.27) kg), and visceral adipose tissue (median (IQR);  - 66 (110) cm 3 ) in CT, but not control. Lean mass (median (IQR); 1.35 (1.86) kg) and aerobic capacity (mean ± SD; 4.0 ± 3.1 mL/kg/min) increased in CT, but not in control. There were no changes in IL-6, TNF-a, HOMA-IR, glucose, or lipid profile in response to the intervention (P > 0.05). Changes in insulin resistance were positively associated with IL-6 in the control group only (coefficients [95%CI]; 5.957 [2.961, 8.953])., Conclusion: Implementing combined aerobic and resistance exercise training programs in academic institutions may be an appropriate intervention to increase physical activity and reduce risk factors associated with cardiometabolic disease., Trial Registration: The study was registered with the Australian New Zealand Clinical Trials Registry on the  23rd  of April, 2019 (ACTRN12619000608167)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In the course of legal investigations, law enforcement officers may enlist emergency department (ED) personnel to gather information or forensic evidence, often with the intent of building cases against a patient. These situations create ethical conflicts between the emergency physician's obligations to the patient and society. This paper provides an overview of the ethical and legal considerations in ED forensic evidence collection and the general principles that emergency physicians should apply in these situations., (© 2023 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Differences of sex development (DSD) refer to rare conditions in which an individual's sex development is different from typical male or female development. The neonatologist is often the first health care provider to interact with parents of newborns with DSD and must be familiar with the approach to patients with DSD. In this article, we discuss definition of DSD, initial workup of the patient with DSD, terminology, and controversies in care., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to evaluate the differences between the vaginal microbiome of reproductive-aged women with overweight and obesity (Ow/Ob) compared with healthy weight (HW)., Methods: In this case-control study, a cohort of 367 nonpregnant women (18 to 40 years) with Ow/Ob (BMI ≥25 kg/m 2 ) was case-matched with 367 women with HW (BMI 18.0 to 24.9 kg/m 2 ). The study was a secondary analysis of 16S rRNA vaginal microbiome surveys through the Vaginal Human Microbiome Study (VaHMP). Groups were matched on age, race/ethnicity, income, and nulliparity status., Results: Mean age and BMI of Ow/Ob and HW groups were 26.8 versus 26.7 years and 37.0 versus 22.1 kg/m 2 , respectively. The overall vaginal microbiome composition differed between groups (PERMANOVA, p = 0.035). Women with Ow/Ob had higher alpha diversity compared with women with HW (Wilcoxon test, Shannon index p = 0.025; inverse Simpson index p = 0.026). Lactobacillus dominance (≥30% proportional abundance) was observed in a greater proportion of women with HW (48.7%) compared with Ow/Ob (40.1%; p = 0.026)., Conclusions: The vaginal microbiome differs in reproductive-aged women with Ow/Ob compared with women with HW, with increased alpha diversity and decreased predominance of Lactobacillus. Observed differences in the vaginal microbiome may partially explain differences in preterm birth and bacterial vaginosis risk between these populations., (© 2021 The Obesity Society.)

Undocumented immigrants with end-stage renal disease in the United States are uniquely disadvantaged in their ability to access dialysis. This article examines the unique circumstances of the medical condition and healthcare system, including the relevant legal and regulatory influences that largely relegate undocumented immigrants to relying on emergency-only dialysis through a hospital's Emergency Medical Treatment and Labor Act obligations. We explore the ethical implications of this current state, emphasizing the adverse effects on patients and staff alike. We also review necessary actions that range from the actions an individual emergency physician to changes needed in federal policy., Competing Interests: The authors declare no conflicts of interest., (© 2021 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Purpose of Review: In this review, we outline the usage and formulations of gonadotropin-releasing hormone analogs (GnRHas) in central precocious puberty (CPP), short stature, and gender diverse individuals, as well as adverse effects, long-term outcomes, and monitoring of therapy. There is a particular focus on citing references published within the last 24 months., Recent Findings: Long-acting formulations of GnRHa now include Federal Drug Administration approval for subcutaneous injections. Significant adverse events continue to be rarely reported; extremely rare events include arterial hypertension and pseudotumor cerebri. There continue to be no significant long-term consequences including the impact upon body mass index and bone mineral density, which appear to be transient. GnRHas have been used in differences of sexual development (DSD) and increasingly in the treatment of adolescent transgender individuals., Summary: GnRHas remain as the only fully efficacious therapy for CPP and effectively suppress pubertal hormones in other situations. The use of GnRHa therapy in gender incongruent individuals has proven beneficial and has become a standard of care, whereas use in those with DSDs should still be considered experimental., Video Abstract: http://links.lww.com/MOP/A62., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This study examined the effects of high-intensity interval training (HIIT; 30 s sprint, 4-5 min passive recovery) and prolonged intermittent sprint training (PIST; 10 s sprint, 2-3 min moderate exercise) on the systemic inflammatory markers C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α), aerobic capacity, and anthropometry in a middle-aged, sedentary population., Methods: Fifty-five sedentary adults (age 49.2 ± 6.1 years) were randomised into HIIT (n = 20), PIST (n = 21), or a sedentary control group (CTRL n = 14). HIIT and PIST performed three training sessions per week for 9 weeks on a cycle ergometer, matched for total high-intensity time, while CTRL continued normal sedentary behaviours. Pre- and post-intervention testing involved measures of anthropometry, peak oxygen consumption (VO 2peak ), and venous blood collection for analyses of CRP and TNF-α., Results: HIIT and PIST increased VO 2peak compared to CTRL (+3.66 ± 2.23 and 3.74 ± 2.62 mL kg min -1 ). A group × time interaction (p = 0.042) and main effect of time (p = 0.026) were evident for waist girth, with only HIIT showing a significant reduction compared to CTRL (-2.1 ± 2.8 cm). TNF-α and CRP showed no group × time interaction or time effect (p > 0.05)., Conclusions: In sedentary individuals, 9 weeks of HIIT or PIST were effective to improve aerobic capacity; however, only HIIT significantly reduced waist girth and WHR compared to CTRL. Markers of systemic inflammation remained unchanged across all groups. Accordingly, for inflammation and VO2 peak , the distribution of sprints and the active or passive recovery periods are inconsequential provided that total duration of high-intensity efforts is similar.

There is little guidance on what clinicians should do when advance directives (or living wills, specifically) are challenged, particularly when surrogate decision-makers' interpretations of patients' wishes conflict with the living will. In our commentary, we make a controversial argument suggesting that overriding living wills can be ethically preferable to the alternative of strictly adhering to them. We propose four ethical considerations for determining whether it is ethically supportable to override living wills., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The care of patients with a psychiatric emergency is fraught with ethical challenges. Applying ethical reasoning to clinical challenges may help to improve care. Emergency providers should assess decision-making capacity using 4 criteria: communication, understanding, appreciation, and reasoning. Maintaining patient confidentiality is a strong imperative for emergency physicians and should be protected unless compelling additional concerns take precedence. The goal of involuntary treatment should be to protect patients from harm that they would not be exposed to were they capable of autonomous decision making, not dangerous, or not impaired by their psychiatric illness using the least restrictive means possible., (Copyright © 2015 Elsevier Inc. All rights reserved.)

While valuable work has been done addressing clinical ethics within established healthcare systems, we anticipate that the projected growth in acquisitions of community hospitals and facilities by large tertiary hospitals will impact the field of clinical ethics and the day-to-day responsibilities of clinical ethicists in ways that have yet to be explored. Toward the goal of providing clinical ethicists guidance on a range of issues that they may encounter in the systematization process, we discuss key considerations and potential challenges in implementing system-wide ethics consultation services. Specifically, we identify four models for organizing, developing, and enhancing ethics consultation activities within a system created through acquisitions: (1) train-the-trainer, (2) local capacity-building, (3) circuit-riding, and (4) consolidated accountability. We note each model's benefits and challenges. To our knowledge, this is the first paper to consider the broader landscape of issues affected by consolidation. We anticipate that clinical ethicists, volunteer consultants, and hospital administrators will benefit from our recommendations.

The use of mechanical circulatory support (MCS) devices has increased sixfold since 2006. Although there is an established legal and ethical consensus that patients have the right to withdraw and withhold life-sustaining interventions when burdens exceed benefits, this consensus arose prior to the widespread use of MCS technology and is not uniformly accepted in these cases. There are unique ethical and clinical considerations regarding MCS deactivation. Our center recently encountered the challenge of an awake and functionally improving patient with a total artificial heart (TAH) who requested its deactivation. We present a narrative description of this case with discussion of the following questions: (1) Is it ethically permissible to deactivate this particular device, the TAH? (2) Are there any particular factors in this case that are ethical contraindications to proceeding with deactivation? (3) What are the specific processes necessary to ensure a compassionate and respectful deactivation? (4) What proactive practices could have been implemented to lessen the intensity of this case's challenges? We close with a list of recommendations for managing similar cases.