Citations

Abstract Human β-defensin 1 (hBD-1) is a small, disulfide-constrained antimicrobial peptide produced predominantly in the kidney and urogenital tract, where it contributes to epithelial innate defense. Genetic variation in the gene encoding hBD-1 has been associated with altered expression levels and susceptibility to infections, including infection following solid organ transplantation, yet the molecular consequences of coding substitutions in the active, mature form remain largely undefined. Here, we integrate conventional genomics, protein bioinformatics, structural modeling, and molecular dynamics to investigate the molecular consequences of 93 human-observed hBD-1 missense variants. Evaluation of hBD-1 missense variants across sequence-, structure-, and dynamics-based dimensions reveals variant-specific molecular perturbation signatures that complement conventional and static biophysical predictions. By treating naturally occurring substitutions as a perturbation series across a compact defensin scaffold, this study identifies multiple molecular routes through which sequence variation can remodel an endogenous antimicrobial peptide and prioritizes variants for direct structure-function testing. These findings provide a mechanistic framework for investigating how naturally occurring hBD-1 variation may influence peptide behavior and, ultimately, antimicrobial function.

Background Native American (NA) patients experience persistent inequities in advance care planning (ACP) and often present to tertiary centers with critical illness; culturally respectful serious-illness communication is therefore essential in emergency and intensive care settings. Intervention We developed and implemented a nursing-led, multidisciplinary educational initiative at a large academic medical center serving patients from >50 tribal nations. Informed by a literature review, local practice needs, and expert input from a Native American Patient Experience Ambassador, we created (1) an “Honoring Your Choices” (HYC) communication card with culturally sensitive prompts for serious illness conversations and (2) a quick reference guide (QRG) outlining key cultural considerations and unit-specific resources. Tools were disseminated to seven intensive care units and the emergency department through nurse leader engagement, unit rounding, and staff education, and the initiative was presented at departmental Grand Rounds/didactics with pre/post surveys to assess impact. Results Twenty-seven pre-session and twenty-four post-session surveys were collected from clinicians and trainees. Prior to the session, >80% of respondents reported being not or only slightly confident discussing end-of-life issues with NA patients/families; post-session surveys demonstrated increased self-reported confidence in recognizing when cultural beliefs may influence care and in conducting end-of-life discussions. Conclusions This initiative demonstrates how culturally congruent approaches to serious illness conversations may support more meaningful engagement with NA patients and families. Our experience suggests that developing and evaluating a brief, point-of-care communication tool like Honoring Your Choices may be accomplished with existing interdisciplinary partnerships, offering a practical model that other institutions can readily mirror.

Background Sarcopenia is associated with worse outcomes in pancreatic cancer patients, but longitudinal body composition changes during neoadjuvant therapy remain poorly understood. Methods A retrospective review identified patients who underwent pancreatectomy, either upfront or after neoadjuvant therapy, for pancreatic adenocarcinoma between 2011 and 2021. Skeletal muscle area, index, and mean attenuation were calculated from CT images throughout the treatment course to assess sarcopenia. Multivariable generalized linear and logistic regression models were used to assess associations between sarcopenia, neoadjuvant therapy, and postoperative outcomes. Results A total of 72 patients were included: 32 who underwent neoadjuvant therapy and 40 who underwent upfront surgery. Forty-one (57%) patients had sarcopenia at diagnosis (65% upfront surgery vs 47% neoadjuvant, P = 0.154). Post-neoadjuvant therapy, 15.6% developed and 18.8% resolved sarcopenia. Median skeletal muscle mean attenuation increased by 2.4 HU after neoadjuvant therapy ( P = 0.02). Patients receiving neoadjuvant therapy were more likely to undergo nutrition consultation prior to surgery (61% vs 7%, P = 0.003). Neoadjuvant therapy was also associated with higher postoperative albumin levels (β = 0.244; 95% CI 0.041-0.446). Baseline sarcopenia diagnosed by skeletal muscle area was associated with increased postoperative complications (OR 13.696; 95% CI 2.537-73.921), while neoadjuvant therapy did not significantly impact complications (OR 0.384; 95% CI 0.12-1.226). Conclusions Patients who completed neoadjuvant therapy and underwent resection did not have increased rates of sarcopenia and were more likely to receive preoperative nutrition consultation and have higher postoperative albumin levels. The neoadjuvant period may represent an opportunity for sarcopenia assessment, nutritional optimization, and multimodal prehabilitation prior to pancreatectomy.

Abstract Disruption of the intestinal microbiota increases susceptibility to Clostridioides difficile infection (CDI), creating an opportunity for prophylactic interventions before symptomatic disease develops. We investigated whether Escherichia coli Nissle 1917 (EcN) engineered to express the bacteriophage-derived endolysin CD27L could enhance pathogen inhibition and attenuate CDI. Using a plasmid-cured EcN chassis and pMUT2-derived vectors, we generated strains expressing CD27L under constitutive or anaerobically regulated promoter control. The constitutive strain, BioEcN1, reduced viable C. difficile recovery relative to parental EcN and was selected for animal studies. BioEcN1 remained recoverable from monoassociated mice without in vivo antibiotic selection, with similar recovery on selective and nonselective media supporting construct retention. Prophylactic administration reduced clinical disease, body-weight loss, and intestinal histopathological injury in germ-free mice. Observed survival was 100% in BioEcN1-treated challenged mice versus 50% in untreated challenged mice during the monitored period. Protection was accompanied by lower fecal and cecal pathogen burdens. In mice harboring a human-derived dysbiotic microbiota, prophylactic BioEcN1 also reduced clinical and stool-consistency scores, with lower early fecal pathogen recovery and less colon shortening. These findings establish preclinical proof of concept for prophylactic administration of an endolysin-expressing probiotic to attenuate CDI.

Abstract Reliable extraction of trial characteristics and outcomes is essential for systematic reviews, yet incorrect values can alter evidence synthesis and are difficult to detect without clear source evidence. We evaluate EviSearch, a clinical evidence-curation system that links extracted values to source passages, independently verifies cited evidence, and prioritizes higher-risk cells for review. Using ten trial publications, a 133-column schema, reference annotations, and consistent scoring across model families, we assess answer quality, inter-reading agreement, evidence reproduction, targeted review, and evidence modality. In the Qwen evaluation, EviSearch achieved 91.70% accuracy, cited 100.0% of admitted values, and reproduced 98.9% independently. Reviewing 15.6% of cells increased accuracy to 95.22%.

Cardiovascular disease (CVD) remains the leading cause of death worldwide and is a major driver of critical illness, resulting in admission to cardiac intensive care units (CICUs). Patients with acute, life-threatening CVD often experience episodes of acute decompensation characterized by high symptom burden that may portend progressive loss of function, significantly impair quality of life (QOL), and involve high-intensity, technologically advanced therapies to sustain life. Despite these advances, up to 30% of patients die during CICU hospitalizations, and those who survive may subsequently face persistent functional impairment and psychosocial distress. During critical CVD (CCVD), patients often endure prognostic uncertainty and face complex decisions regarding life-sustaining therapies alongside refractory symptoms. Thus, care that focuses exclusively on disease-directed or life-prolonging therapies is often insufficient to address the full spectrum of patient and caregiver needs. When integrated alongside intensive cardiovascular care, palliative care (PC) offers a complementary and essential approach to the management of CCVD to inform therapeutic decisions, improve QOL, and address psychosocial and spiritual well-being. In this article, a multidisciplinary team featuring PC clinicians (physicians, nurse practitioners, social worker, psychologist, and chaplain), cardiologists, cardiac surgeons, cardiothoracic anesthesiologists, and intensivists present evidence-based guidance in a “Top Ten Tips” format to support PC clinicians caring for CICU patients and their caregivers.