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Purpose Immune checkpoint inhibitors (ICIs) are integral to first-line treatment of metastatic non–small cell lung cancer (NSCLC). Circadian biology may influence antitumor immunity, raising the hypothesis that time-of-day of ICI administration could affect outcomes. We evaluated the association between initial and cumulative ICI administration time-of-day and clinical outcomes in metastatic NSCLC. Materials and Methods We conducted a retrospective cohort study of 778 patients with metastatic NSCLC treated with first-line ICI-containing therapy across Mayo Clinic sites between January 2021 and March 2024. Patients were stratified by time-of-day of first ICI administration: early (0700-1200) versus late (1201-2400). Primary end points were overall survival (OS) and progression-free survival (PFS); the secondary end point was immune-related toxicity. Multivariable Cox proportional hazards models adjusted for clinically relevant covariates. Exploratory analyses evaluated cumulative infusion time-of-day and alternative administration-time thresholds using spline and cut-point analyses. Results Of 778 patients, 277 received early and 501 received late initial ICI administration. Median OS was 1.33 versus 1.48 versus years and median PFS was 0.65 versus 0.67 years in the late and early groups, respectively. Time-of-day of initial ICI administration was not associated with OS (HR, 1.01 [95% CI, 0.85 to 1.20]) or PFS (HR, 1.03 [95% CI, 0.88 to 1.21]). Findings were unchanged after multivariable adjustment. Immune-related toxicity occurred in 26.9% and 24.2% of patients in the late and early groups, respectively ( P = .40). Cumulative infusion time-of-day was not associated with OS or PFS, and spline analyses identified no significant administration-time threshold associated with outcomes. Conclusion In this large real-world cohort of patients with metastatic NSCLC, neither initial nor cumulative ICI administration time-of-day was associated with survival or immune-related toxicity. Prospective studies incorporating chronotype and circadian biomarkers are warranted to further define the role of chronotherapy in immuno-oncology.

Background Menopause-related symptoms are common but undertreated. Digital tools that support symptom assessment and patient education may improve engagement. Objective To assess whether a previsit digital menopause symptom assessment and education tool increased treatment initiation and patient engagement compared to an educational pamphlet. Design Women aged 45–55 years with upcoming primary care appointments were invited to participate. Those with a total Menopause Rating Scale (MRS) score ≥5 indicating bothersome menopause symptoms were included. Participants were randomized to a digital menopause symptom assessment tool or a digital educational pamphlet and completed a post-visit survey (NCT06919887). Participants Of the 14,726 women invited to participate between May 12, 2025, and December 5, 2025, there were 653 (4.4%) enrolled that met eligibility criteria. Interventions Randomized to an mHealth app called emmii or a standard digital menopause educational pamphlet. Main measures Menopause treatment initiation within 30 days of the clinical visit was assessed by electronic health data. Baseline and post-visit surveys were collected assessing patient experience, engagement, and perceived usefulness. Rates of menopause hormone therapy (HT) prescribing were compared with a reference population of nonparticipants aged 45–55 who had a primary care appointment at Mayo Clinic during the same period and received no study education materials. Key results Of 653 participants enrolled and randomized, 383 completed both the baseline and post-surveys (171 intervention and 212 control). HT initiation among study participants was significantly higher than in the reference population of women (9.3% vs. 4.4%, p < 0.001). There was no difference in HT initiation between the intervention (9.1%) and control groups (9.6%) ( p = 0.83). Initiation rates were 3.8% and 4.5%, respectively ( p = 0.64) for nonhormone therapies. Conclusions Among women with bothersome menopause symptoms, those who underwent previsit symptom screening and received educational materials had higher rates of HT initiation than women who did not participate in the study. These findings suggest that structured menopause education may improve recognition and management of menopause symptoms in routine clinical practice.

Background: Itraconazole is the preferred antifungal agent for mild to moderate histoplasmosis and step-down therapy following amphotericin B treatment. Although hydroxy-itraconazole, a major metabolite of itraconazole, displays antifungal activity comparable with that of the parent compound, its role in therapeutic drug monitoring targets for histoplasmosis remains uncertain. Methods: The objective was to compare clinical outcomes and adverse events using itraconazole parent-compound concentrations alone versus combined itraconazole and hydroxy-itraconazole concentrations in patients treated for histoplasmosis. This retrospective cohort study included adults with probable or proven histoplasmosis who received itraconazole and had at least 1 documented serum concentration. The primary outcome was clinical response across 3 groups: (1) parent (itraconazole parent-compound concentration >1.0 mcg/mL), (2) combined (parent-compound concentration <1.0 mcg/mL with combined itraconazole plus hydroxy-itraconazole >1.0 mcg/mL), and (3) subtherapeutic (failure to reach either threshold). Treatment response and adverse events were analyzed using the Fisher exact test. Results: Among 108 patients (parent, n = 40; combined, n = 40; subtherapeutic, n = 28), response rates differed across groups (parent (95%); combined (90%); subtherapeutic (67.9%); P = 0.006). There was no difference between the parent and combined groups. Adverse events did not differ, although drug discontinuation occurred more frequently in the subtherapeutic group (parent (5%); combined (20%); subtherapeutic (25%); P = 0.04). Conclusions: Patients who failed to achieve either an itraconazole concentration >1 mcg/mL or a combined itraconazole plus hydroxy-itraconazole concentration >1 mcg/mL had lower response rates. Similar outcomes among patients achieving the itraconazole target alone and those achieving the combined target suggest that hydroxy-itraconazole concentrations may contribute to therapeutic drug monitoring targets in histoplasmosis.

Background: Central line-associated bloodstream infections (CLABSIs) remain a challenge in pediatric intensive care units (PICUs); central line days have been directly correlated with risk of CLABSI. The Mayo Clinic PICU is a 23-bed multidisciplinary unit including dedicated bone marrow transplant beds with an average of 1048 admissions annually. In 2024, the unit’s CLABSI rate was 0.82 per 1,000 central line days or approximately 1–3 CLABSIs per year. Weekly multidisciplinary CLABSI Prevention Rounds were piloted from August 2024 to March 2025 with the aim of reducing central line device utilization rate as a method to reduce CLABSI risk. Methods: A multidisciplinary team of Clinical Nurse Specialists (CNS), Nurse Managers, and off-service PICU physicians conducted weekly CLABSI rounds on PICU beds (excluding 4 BMT beds), meeting with each bedside nurse as well as the on-service providers. The CLABSI team assessed central line necessity using a standard questionnaire and provided education to physicians and nurses regarding central line care and CLABSI prevention. Monthly data were compared for the same 8 calendar months pre versus post intervention for central line days, patient days, and device utilization rate (DUR; central line days/patient days), both unadjusted and adjusted for PRISM (Pediatric Risk of Mortality) 3 severity of illness score. Pre- and post-implementation staff surveys assessed confidence in line management and interdisciplinary communication using Likert scales. Results: Thirty-two CLABSI rounds with a total of 118 individual patients and 45 discrete interventions were noted over 8 months and compared to the 8 pre-intervention corresponding months. Pre versus post monthly DUR was 0.42 [0.32–0.57] vs 0.46 [0.30–0.55], p = 0.49 (PRISM 3–adjusted p = 0.97). Nursing confidence in ‘discussing central line need’ significantly improved post-implementation, 5 [4–5] vs 5 [5–5], p = 0.035. Nurses also positively perceived third-party involvement in need assessment, 4 [3–4] vs 4 [3–4], p = 0.06. All surveyed clinicians trended toward being less likely to think a central line was left in too long, 3 [3–4] vs 3 [2–4], p = 0.06. Conclusion: Structured weekly multidisciplinary CLABSI rounds are a feasible intervention that empowers bedside nurses and improves confidence in line maintenance and interdisciplinary communication. Median DUR was not significantly altered by the intervention, but nursing perception of central line management improved qualitatively in pre- versus post-implementation surveys. Continued expansion of multidisciplinary initiatives addressing central line necessity and management is needed to further evaluate overall effects on DUR and CLABSI incidence.

Abstract Objectives To describe and compare anorectal manometry findings in constipated adolescents with and without dyssynergic defecation (DD). Methods We retrospectively reviewed adolescents ≤18 years who underwent anorectal manometry (ARM) and/or balloon expulsion testing (BET) between 2015 and 2022. Patients with prior pelvic floor therapy, inflammatory bowel disease, or colon surgery were excluded. DD was defined by abnormal ARM (paradoxical anal contraction or inadequate anal relaxation ≤20% during simulated evacuation) and/or abnormal BET (>60 s). Manometric parameters were compared between patients with and without DD and between those with abnormal versus normal BET. Diagnostic performance of rectoanal pressure gradient cutoffs were assessed. Results A total of 170 adolescents were included; 69 (40.6%) met criteria for DD. Median age was 17 years (interquartile range [IQR] 16–18), and 80.7% were female. Gastrointestinal symptoms did not differ between groups. Patients with DD demonstrated significantly more negative rectoanal pressure gradients compared with those without DD (median [IQR]: −49.0 mmHg [−73.9 to −31.4] vs. −25.2 mmHg [−40.2 to −9.8]; p < 0.001). Rectal sensory thresholds did not differ significantly between groups. A rectoanal pressure gradient cutoff of −45 mmHg demonstrated the best balance of sensitivity (58%) and specificity (86%) for identifying DD. Depression was more prevalent among adolescents with DD ( p = 0.007). Conclusions Rectoanal pressure gradient is a useful manometric parameter for identifying DD in constipated adolescents, particularly when BET is unavailable. Psychological factors such as depression may be more prevalent in this population.

ABSTRACT Clinical pharmacists are increasingly recognized as vital contributors to acute stroke care, yet their role remains inconsistently defined and underutilized across health care systems. This consensus statement explores the expanding presence of clinical pharmacists within interdisciplinary stroke teams, particularly in the management of both acute ischemic stroke ( AIS ) and hemorrhagic stroke. This consensus statement panel was composed of clinical pharmacists, emergency medicine physicians, and a vascular neurologist. The Grading of Recommendations, Assessment, Development, and Evaluation ( GRADE ) approach was used to assess the level of certainty and strength of recommendations. We focused on two questions regarding the clinical pharmacist's role in caring for adult patients presenting to the emergency department ( ED ) with AIS or hemorrhagic stroke. Despite the very low level of evidence, a consensus was reached for the following recommendations: (1) clinical pharmacist involvement in AIS care for adult patients presenting to the ED and (2) clinical pharmacist involvement in hemorrhagic stroke care for adult patients presenting to the ED . Based on the available literature, we believe optimizing the clinical pharmacist role is a critical factor in improving time‐sensitive treatment and equity in care delivery.

Background Chlorhexidine is commonly used in prevention bundles for ventilator-associated pneumonia. Results for use of chlorhexidine in critically ill patients requiring mechanical ventilation via an endotracheal tube are mixed, and data for patients using a tracheostomy are lacking. Objectives To assess the risk for ventilator-associated pneumonia according to chlorhexidine exposure in patients requiring a new tracheostomy for mechanical ventilation. Methods This single-center, retrospective cohort study compared the development of ventilator-associated pneumonia according to chlorhexidine exposure in adult intensive care unit patients requiring new tracheostomy at a large academic medical center. Adults who received a new tracheostomy and required ventilator support for at least 48 hours were included. Patients treated for pneumonia at the time of tracheostomy or who met additional exclusion criteria were excluded. Results Of 235 patients who met the inclusion criteria, 203 received chlorhexidine and 32 did not. The cohort was predominantly White, male, and admitted to a surgical intensive care unit. Incidence of ventilator-associated pneumonia did not differ significantly between patients exposed or not to chlorhexidine (by 30 days, 32.5% vs 35.7%, P = .87). Time to development of ventilator-associated pneumonia also did not differ significantly between patients exposed or not (9 vs 12 days, respectively, P = .34). Conclusions Chlorhexidine exposure was not associated with a difference in the incidence of or time to ventilator-associated pneumonia after new tracheostomy. Further study is needed on the role of chlorhexidine in preventing ventilator-associated pneumonia after a new tracheostomy.

Objectives: Elevated intracranial pressure (ICP) remains a challenge and immediate danger in patients with acute brain injury. Current literature supports the use of a single hyperosmolar agent to reduce ICP. However, the efficacy and safety of overlapping hyperosmolar agents have not been evaluated. The objectives of this study are to analyze the ICP lowering effects and evaluate the safety profile of overlapping hyperosmolar therapy. Materials and Methods: This single-center, retrospective study included adults (≥18 y) admitted to the Neurosciences Intensive Care Unit between May 2018 and September 2024 with acute brain injury leading to intracranial hypertension refractory to a single hyperosmolar agent and an ICP monitor. They received overlapping doses of mannitol and hypertonic sodium approximately every 3 hours. We evaluated the impact of overlapping hyperosmolar therapy on ICP. Safety outcomes included acute kidney injury incidence, electrolyte disturbances, and volume status changes. Results: Forty-six patients were included in this study with a median (IQR) age of 46.5 (35.9, 62.4) years. Median (IQR) dose of mannitol was 40.1 (34.6, 50.0) g, while median (IQR) dose of hypertonic sodium was 120 (90, 125) mEq. About 86% of patients experienced a decrease in ICP after initiation of overlapping hyperosmolar therapy. Six acute kidney injuries occurred, and 7 patients experienced pulmonary edema. Median (IQR) peak sodium, chloride, and osmolar gap values were 149 (144, 155) mEq/L, 115 (111, 119) mEq/L, and 5.7 (0.7, 9.0) mOsm/kg. Conclusions: Overlapping hyperosmolar therapy may provide a transient ICP reduction without excessive adverse effects in patients with refractory ICP to a single hyperosmolar agent.

Introduction To assess and compare the accuracy, readability, and overall performance of large language models (LLMs) in answering questions about functional hypothalamic amenorrhea (FHA) for patients and healthcare professionals. Methods A total of 11 patient-level and 15 clinician-level FHA-related questions were entered separately into four LLMs: ChatGPT 3.5 (free version), ChatGPT 4.0 (updated, paid subscription), Gemini, and OpenEvidence. OpenEvidence was used only for clinician-based questions. Responses were evaluated by three expert reviewers blinded to the LLM used who rated them as accurate and complete, accurate but incomplete, or inaccurate. A fourth reviewer resolved discordant scores. Readability for patient-level questions was assessed using the Flesch Reading Ease Score (FRES) and word count. Lower FRES scores indicate more difficult reading. Accuracy and completeness were compared using odds ratios (95% CI) with ChatGPT 3.5 as the reference model, and differences in readability were analyzed using Friedman’s test. Results LLM performance varied across question types. For patient-level questions, ChatGPT 4.0 achieved the highest accuracy (9 of 11; 82%), followed by ChatGPT 3.5 and Gemini (each 8 of 11; 73%), with no statistically significant differences. Among clinician-level questions, OpenEvidence demonstrated perfect accuracy (15 of 15; 100%), compared with 93% for and 80% for ChatGPT 4.0 and Gemini. Completeness followed similar patterns, with OpenEvidence providing the most complete clinician responses (93%) and ChatGPT 4.0 the most complete patient-level responses (89%). Readability differed significantly among models ( p = 0.012), with Gemini producing the most readable patient-level content (median FRES 43.5 [IQR 36.8–53.4]) compared with ChatGPT 3.5 (30.6 [16.8–48.4]) and ChatGPT 4.0 (28.8 [22.1–37.6]). Word counts did not differ significantly ( p = 0.39). Discussion LLMs demonstrated good overall performance in answering FHA-related questions but often provided incorrect or incomplete information. Fine tuning field-specific data, engineered prompts, and obtaining human-in-the-loop feedback may help improve the accuracy of these models.

Objectives: We evaluated agreement between human papillomavirus (HPV) tests performed on self-collected vaginal and clinician-collected cervical specimens to advance HPV self-collection as a cervical cancer screening option in our health care system. Methods: This diagnostic accuracy study was conducted at an academic medical center. Participants were 25–65 years old with upcoming colposcopy appointments. One cohort (n = 79) self-collected a vaginal specimen in the clinic immediately before a clinician-collected cervical specimen. The second cohort (n = 115) self-collected a vaginal specimen at home, mailed it in, and had a clinician-collected cervical specimen in the clinic. Paired specimens were evaluated for total (TPA), positive (PPA), and negative (NPA) percentage agreement. Extreme temperature stability studies were also conducted. Results: Compared with clinician-collected cervical specimens, in-clinic self-collected vaginal specimens showed a TPA, PPA, and NPA of 98%, 100%, and 97% for HPV16; 99%, 100%, and 99% for HPV18; 86%, 94%, and 79% for high-risk other (HRO) HPV. The TPA, PPA, and NPA for at-home self-collected vaginal specimens compared with clinician-collected cervical specimens were 94%, 79%, and 96% for HPV16; 95%, 43%, and 98% for HPV18; 89%, 80%, and 93% for HRO. Vaginal specimens showed prolonged stability and were unaffected by extreme temperatures. Conclusions: In general, in-clinic and at-home self-collected vaginal HPV specimens for HPV screening demonstrate high agreement with clinician-collected cervical specimens, with the exception of low PPA in the at-home self-collected vaginal HPV18 subgroup. Our findings support the use of HPV self-collection as a practical option to expand access to cervical cancer screening.