Citations

Abstract Alternaria spp. are dematiaceous ascomycetes that can cause opportunistic infections in immunocompromised hosts. They are challenging to identify and treat. However, optimal antifungal therapy remains undefined. We retrospectively reviewed antifungal susceptibilities (AST) of all Alternaria spp. isolates from adults at a tertiary care center between 2011 and 2025. We evaluated culture sources, minimum inhibitory concentration (MIC) and minimal effective concentration (MEC) distributions, and MIC₅₀/MIC₉₀ and MEC50/MEC90 values. Clinical characteristics, treatment measures, and outcomes of patients with clinically significant Alternaria spp. infections were described. Forty-one patients had Alternaria spp. isolated, most commonly from skin (n = 13), bone/joint (n = 5), nail (n = 3), or cornea (n = 3). Posaconazole and itraconazole demonstrated low MICs (MIC₅₀/MIC₉₀: 0.06/0.5 and 0.25/0.5 µg/mL, respectively). Voriconazole and isavuconazole showed higher MIC₅₀/MIC₉₀ (1/2 and 2/4 µg/mL). Caspofungin (0.125/0.5 µg/mL) and amphotericin B (0.25/1 µg/mL) had low MICs and MECs.s. Alternaria spp. represented clinically significant infection in 27 cases (66%); 26% were solid organ transplant recipients and 15% had hematologic malignancies. Other risk factors included preceding trauma (22%) and autoimmune disease (15%). Posaconazole was the most frequently used empiric agent (6, 32%). Following AST results, 14 patients (52%) received oral antifungal therapy; posaconazole was used in all 14. In addition, 7 patients (26%) received combination therapy with IV amphotericin B. Adjunctive surgery occurred in 14 cases (52%). Five patients (19%) died before completing therapy; Alternaria infections occurred predominantly in immunocompromised hosts and were frequently managed with posaconazole and surgery. Interpretive criteria for Alternaria spp. are needed to guide empiric and definitive therapy.

Abstract Objective The goal of this study was to synthesize the evidence on how “status migrainosus” is defined in research studies in comparison to established International Classification of Headache Disorders (ICHD) criteria. Background Current ICHD‐3 criteria define status migrainosus as a headache attack occurring in a patient with a history of migraine with or without aura that is typical of previous attacks except for its duration (>72 h) and severity (debilitating). Despite the ICHD criteria, there are varying inclusion criteria noted in studies enrolling patients with status migrainosus. With this diagnostic uncertainty, there remains difficulty in studying this patient population. Methods This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. Ovid MEDLINE, Ovid EMBASE, All Evidence‐Based Medicine Reviews, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov , and the World Health Organization International Clinical Trials Registry Platform were searched with the end search date of August 29, 2025. We included studies that were original research focused on status migrainosus, published in English after January 1, 1988, and also included diagnostic criteria to define this condition. The abstracts and full texts were screened by independent reviewers, with a third independent reviewer remaining available to settle disputes. There were 45 studies that underwent full text review, with 19 of these studies included. Data extraction was conducted recording the criteria used to define status migrainosus, headache characteristics, and goals of each study. Results We identified four common domains among studies of status migrainosus, including use of ICHD criteria, headache duration, symptom severity, and treatment response. Reference to ICHD criteria was variable, with only 68% (13/19) of studies specifying an edition of ICHD criteria applied in recruiting or studying patients with status migrainosus. The majority of studies (16/19; 84%) used a headache duration greater than 72 h to define status migrainosus. The use of symptom severity with “debilitating” or “severe” was present in 63% (12/19) of studies and depended on the edition of ICHD criteria that was referenced. Treatment response was rarely used as a condition in defining status migrainosus, with only 15% (3/19) of studies utilizing this stipulation in diagnostic criteria. Conclusion The results of this systematic review show inconsistent application of ICHD criteria in research studies focusing on status migrainosus. These inconsistencies lead to ambiguity in how status migrainosus is defined in the research setting and limit the ability to replicate or compare studies. Guidelines outlining best practices for research of status migrainosus are necessary. For prospective studies, consistent utilization of ICHD criteria is necessary, with potential need to revise these criteria to better reflect the clinical realities of this entity. For retrospective studies, implementation of a standardized International Classification of Diseases code for status migrainosus would be of benefit to improve diagnostic clarity because the current codes are lengthy, cumbersome, and unclear.

Background: Pulse pressure variation (PPV) is widely used to guide fluid responsiveness in mechanically ventilated patients, but its accuracy in the prone position remains uncertain. Prone positioning alters respiratory mechanics and venous return, potentially diminishing the respiratory variation in stroke volume that PPV is designed to detect. We conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of PPV for predicting fluid responsiveness during prone spine surgery. Methods: We searched MEDLINE, Embase, Scopus, and Cochrane through July 2025 for prospective studies evaluating PPV in adults undergoing prone spine surgery. Two reviewers independently screened studies, extracted data, assessed risk of bias using QUADAS-2, and pooled diagnostic performance using a bivariate random-effects model. The protocol was registered with PROSPERO (CRD420251106134). Results: Of 599 records, 34 underwent full-text review, and 10 studies (433 patients) were included. PPV thresholds ranged from 7% to 15%. Most studies were at low risk of bias except for the index test because thresholds were determined post hoc. For predicting fluid responsiveness, PPV had a pooled sensitivity of 68% (95% CI: 61%-75%) and specificity of 76% (95% CI: 65%-84%), with a summary area under the receiver operating characteristic curve of 0.72 (95% CI: 0.64-0.80). Conclusions: PPV showed only moderate diagnostic performance for predicting fluid responsiveness during prone spine surgery. Its performance may have been influenced by threshold variability, heterogeneous reference standards, fluid-challenge protocols, ventilation strategies, and positioning systems. PPV should therefore be interpreted alongside complementary dynamic assessments rather than in isolation, particularly during lung-protective ventilation.

Prolonged durations of hypotension during septic shock promote organ injury and mortality. Empirical evidence suggests that earlier vasopressin initiation may improve outcomes in septic shock. The objective of this study was to determine the effect of a ready-to-use vasopressin formulation availability in intensive care unit automated dispensing cabinets on outcomes in septic shock. This was a pre-post quasi experimental study of adults admitted for septic shock who received vasopressin as a second line vasopressor after norepinephrine. Inverse probability of treatment weighting with propensity scores was used to balance baseline covariates between those who received the ready-to-use vasopressin product and the traditional pharmacy-compounded vasopressin product. Outcomes included time from vasopressin order to administration, time to target mean arterial pressure, length of stay, and mortality. A total of 1104 patients with septic shock were included. After propensity score adjustment, the ready-to-use group was associated with faster time to vasopressin administration (17 vs 41 min, P < 0.001), faster time to target mean arterial pressure (hazard ratio 1.29, 95% CI 1.14 to 1.47, P < 0.001), and a shorter length of intensive care unit stay (hazard ratio 1.23, 95% CI 1.06 to 1.43, P = 0.006) as the compounded group. Mortality was not significantly different. In patients with septic shock, availability of a ready-to-use vasopressin product in the intensive care unit automated medication dispensing cabinet was associated with faster time to administration, improved time to target mean arterial pressure, and reduced duration of intensive care.

Abstract Purpose Bevacizumab is an effective treatment for radiation necrosis; dose dependent radiographic and edema response data are lacking. Methods Multicenter, retrospective cohort study of adult patients with primary central nervous system tumors or brain metastases who received bevacizumab for radiation necrosis between June 2021 and July 2024. Patients were grouped by bevacizumab dose (7.5 mg/kg vs 10 mg/kg administered every three weeks). Primary outcome was edema response, assessed by a blinded neuro-oncologist. Secondary outcomes included contrast enhancing disease response, clinical response, adverse events, treatment discontinuation, and re-dosing for recurrent radiation necrosis. Analyses were performed with and without adjustment for tumor type. Results 104 patients were included (7.5 mg/kg, n = 53; 10 mg/kg, n = 51). Edema response differed between dosing groups in unadjusted analyses (p = 0.032), favoring the 7.5 mg/kg cohort; however, this association was attenuated after adjustment for tumor type. Contrast enhancing disease response did not differ between groups in either unadjusted or adjusted analyses (p = 0.43). Clinical response was higher in the 7.5 mg/kg group (65.2% vs 37.8%, p = 0.013). Tumor type differed significantly between cohorts (p < 0.001), with more primary CNS tumors in the 10 mg/kg group. Rates of adverse events, treatment discontinuation, and re-dosing were similar. Conclusions While lower-dose bevacizumab was associated with greater edema reduction in unadjusted analyses, this effect was attenuated after accounting for tumor type. Importantly, 7.5 mg/kg dosing appeared sufficient for achieving edema control and contrast enhancing disease response. These findings support an individualized approach to bevacizumab dosing in radiation necrosis and highlight the need for prospective, tumor-stratified studies.

Abstract Senescent cell accumulation and fibrosis play a fundamental role in kidney ageing. Our aim was to determine whether the angiotensin IV/insulin-regulated aminopeptidase (IRAP) axis of the renin-angiotensin system contributes to renal function decline, fibrosis, and senescent cell accumulation in aged mice. We studied the role of IRAP in kidney ageing using IRAP knockout (KO) mice, as well as in wild-type (WT) mice treated with an IRAP inhibitor. Complementary proximal tubule and collecting duct cell models were used to determine the mechanisms by which IRAP inhibition exerts protective effects. Glomerular filtration rate (GFR) declined by 25% in WT mice between 3 and 23 months of age, concomitant with marked increases in albumin excretion, glomerulosclerosis, tubulointerstitial fibrosis, and accumulation of senescent cells in the proximal tubules of the kidney. IRAP KO mice were protected against age-related decline in GFR, renal fibrosis, and senescence burden compared with age-matched WT mice. IRAP inhibition for 4 weeks (HFI-419, 500 ng/kg/min) in 28-month-old WT mice similarly prevented age-related decline in GFR and attenuated expression of cellular senescence markers. Using an in vitro model of cultured proximal tubule cells, IRAP inhibition mitigated the pro-senescent effects of oxidative stress. This was associated with shifts in the metabolic phenotype of proximal tubular cells, indicating the senoprotective effects of IRAP inhibition may be mediated in part via mitochondrial function. These studies provide evidence that IRAP deficiency is protective against chronic renal cellular senescence, fibrosis, and functional decline. Therefore, IRAP inhibition has therapeutic potential to attenuate pathological cardiorenal ageing through senoprotective mechanisms.

Abstract Therapeutic resistance in ovarian cancer is frequently driven by persistent replication stress, yet the molecular mechanisms that convert replication stress into a therapeutically exploitable vulnerability remain incompletely understood. Here, we identify drug-induced nuclear cathepsin L (nCTSL) as a previously unrecognized regulator of replication stress and DNA repair. Clofarabine (CLF) combined with the ATR inhibitor AZD6738, or the CHK1 inhibitor prexasertib promoted nuclear accumulation of CTSL, where it remodeled the replication machinery through degradation of CCNE1, MCM3, MCM6, and geminin, accompanied by loss of RAD51 and 53BP1 and increased γH2AX and phospho-RPA2. DNA fiber analysis demonstrated marked inhibition of replication fork progression following CLF-based combinations, whereas CTSL depletion accelerated fork progression and abolished therapy-induced replication stress. Reconstitution with the nuclear M1F CTSL isoform restored replication restraint, confirming a direct role for nuclear CTSL in regulating replication dynamics. GFP-based DNA repair reporter assays further revealed that CLF-based combinations suppress DNA repair competence in a CTSL-dependent manner, indicating that nuclear CTSL couples replication stress amplification with functional inhibition of repair pathways. Functionally, CLF-based combinations selectively targeted transformed fallopian tube secretory epithelial cells while sparing non-transformed counterparts, demonstrated broad activity in patient-derived ovarian cancer ascites spheroids, and significantly inhibited tumor growth and prolonged survival in vivo . Collectively, our findings identify nuclear CTSL as a mechanistic driver of replication stress that remodels the replication machinery, impairs DNA repair, and creates a therapeutically exploitable vulnerability in ovarian cancer. We propose that nuclear CTSL promotes a transition from replication competence to replication catastrophe, thereby establishing a conceptual framework for biomarker-guided therapeutic strategies targeting CTSL-dependent replication stress.

Background & Aims: Multi-target stool DNA (mt-sDNA) is an established stool-based colorectal cancer screening test, yet long-term performance is not well-described. We evaluated follow-up colonoscopy rates & quality, neoplasia yield, and repeat-testing adherence over 10 years with an integrated screening program. Methods: We assembled a retrospective cohort of mt-sDNA tests (September 2014–July 2025) within a multi-site health system. A validated large-language-model pipeline extracted colonoscopy, pathology, and quality endpoints from free-text reports. Detection outcomes (adenoma detection rate, advanced neoplasia, modified advanced adenoma, sessile serrated lesion (SSL), and negative exams) were calculated among high-quality exams; adenocarcinoma, bowel preparation adequacy, and cecal intubation rate (CIR) used all screening exams. We assessed colonoscopy completion ≤1 year after positive mt-sDNA, follow-up colonoscopy findings, findings by time-to-colonoscopy, and adherence to repeat mt-sDNA after negative result. Results: Among 148,624 tests in 110,410 individuals, positivity was 13.6%. Of 19,506 positives, 65.1% completed colonoscopy within 12 months (median 82 days). Colonoscopy after a positive mt-sDNA had high yield: advanced adenoma diagnosis was 30.7%; adenocarcinoma was 1.3%. Of patients who had colonoscopy within 3 years of a negative mt-sDNA test, 45.2% had adenoma/serrated lesion, 9.3% had advanced adenoma and 0.5% had colon cancer. Adenoma detection rate after positive mt-sDNA (>50%) exceeded specialty society quality benchmarks and increased over time; Longer intervals (>6 months) to colonoscopy after a positive test were associated with higher advanced adenoma (trend P=0.001).After an initial negative mt-sDNA, only 35.3% were screened again by mt-sDNA testing within 3 years. Conclusions: Over a decade,mt-sDNA screening achieved high colonoscopy qualitybut revealed critical gaps in the care cascade. One-third of positive tests lacked timely follow-up and nearly two-thirds of negative tests were not repeated on schedule, suggesting opportunities for system-level interventions.