Category: Statistics

Clin Cancer Res. 2025 Jul 24. doi: 10.1158/1078-0432.CCR-25-0201. Online ahead of print.

ABSTRACT

PURPOSE: The optimal treatment of recurrent ovarian clear cell carcinoma (rOCCC) remains unknown. This is the first randomized trial to compare durvalumab with chemotherapy in rOCCC.

PATIENTS AND METHODS: MOCCA is a randomized, phase 2 trial conducted in Singapore, Korea and Australia. Eligible patients had rOCCC with recurrence after platinum-based chemotherapy, ECOG performance status ≤2 and no prior immune checkpoint blockade. Patients were randomly assigned (2:1) to durvalumab (1500mg every 4 weeks) or chemotherapy. Patients progressing on chemotherapy were allowed to crossover to durvalumab. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), objective response rates (ORR), and safety.

RESULTS: 48 eligible women were assigned to durvalumab (N= 31) or chemotherapy (N= 17). Median PFS was 7.6 (95% CI 7.0-16.0) and 14.0 (95% CI 7.0-32.9) weeks with durvalumab or chemotherapy, (HR 1.6, 95% CI 0.8-3.0; P= 0.92). Median OS was 37.9 (95% CI 21.7-143.0) and 40.6 (95% CI 25.0-not reached) weeks, respectively (HR 1.5, 95% CI 0.7-3.3; P= 0.85). The difference in ORR between groups was not statistically significant (durvalumab 9.7% vs PCC 18.8%; difference -9.1%, 95% CI -31.3%-12.9%; P= 0.83). Fewer all-grade (35.5% vs 68.8%) and high-grade (9.7% vs 31.3%) treatment-related adverse events were observed for durvalumab. PD-L1 CPS+ was observed in 28.9% (CPS≥1%) and 10.5% (CPS≥10%) of patients. PIK3CA mutations were associated with time to progression on durvalumab ³12 weeks (RR(-mutated vs -wildtype) 2.83, 95% CI 1.16 to 14.17).

CONCLUSIONS: Durvalumab was well-tolerated, but did not improve efficacy outcomes compared with chemotherapy in rOCCC.

PMID:40705396 | DOI:10.1158/1078-0432.CCR-25-0201

Shock. 2025 Jul 23. doi: 10.1097/SHK.0000000000002652. Online ahead of print.

ABSTRACT

BACKGROUND: Sepsis, a life-threatening syndrome triggered by a dysregulated host response to infection, continues to impose a substantial global health burden. Advances in genomics and transcriptomics now enable systematic exploration of sepsis pathogenesis at the genetic level. The integration of genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS) offers a powerful framework to identify causal genetic variants and delineate molecular mechanisms underlying sepsis susceptibility and clinical outcomes.

METHODS: A cross-tissue TWAS was implemented using UTMOST to integrate sepsis GWAS summary statistics with transcriptomic data from the Genotype-Tissue Expression version 8 (GTEx v8) project. Candidate genes were validated through complementary approaches: FUSION, FOCUS, and MAGMA. Tissue-specific and pathway enrichment analyses were applied to prioritize sepsis-associated genes and characterize their functional roles in disease-relevant biological processes. Bayesian colocalization and two-sample Mendelian randomization (MR) analyses were employed to infer putative causal relationships between prioritized genes and sepsis risk.

RESULTS: Four genes-ZCCHC4, PDGFB, C18orf54, and ATG4B-demonstrated significant associations with sepsis susceptibility in cross-tissue analyses. Two-sample MR provided evidence for causal effects of genetically regulated expression of these genes on sepsis risk. Bayesian colocalization identified shared causal variants between sepsis-associated loci and expression quantitative trait loci (eQTLs), implicating dysregulation of inflammatory and autophagy pathways in sepsis pathogenesis.

CONCLUSION: Our results highlight the efficacy of cross-tissue TWAS in mapping sepsis-associated loci and elucidating the genetic architecture underlying sepsis susceptibility. These prioritized loci constitute compelling targets for functional validation and represent actionable candidates for therapeutic intervention in sepsis.

PMID:40705358 | DOI:10.1097/SHK.0000000000002652

Shock. 2025 Jun 30. doi: 10.1097/SHK.0000000000002661. Online ahead of print.

ABSTRACT

BACKGROUND: Sepsis heterogeneity affects the identification of high-risk patients. Outcomes in low- and middle-income countries are worse than those in developed nations. This study aimed to assess the prognostic potential of the previously described molecular endotypes, Mars1, Mars2, Mars3, and Mars4, in a Brazilian cohort with sepsis.

MATERIAL AND METHODS: This prospective, multicenter, observational study identified molecular expression-based endotypes in adults from four intensive care units in Brazil. Patients on their first 24-hour diagnosis of sepsis based on the Sepsis 3 criteria were included. Health care workers were included in the control group. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to quantify the transcripted levels of eight genes and determine the four endotypes. The primary endpoint was 28-day mortality with a secondary analysis of diagnostic accuracy. Statistical significance was set at P < 0.05.

RESULTS: One-hundred-sixty-eight participants and twenty-five controls were enrolled in this study. The overall mortality rate was 44%. The Mars1 group showed a higher 28-day mortality than the non-Mars1group. The log-rank test showed a worst survival probability in Mars1 subgroup (P = 0.013), and the hazard ratio was 1.78 (P = 0.017). Compared to control, area-under-the-curve (AUC) of ROC curves for diagnosing sepsis were: 0.69 for Mars1 (SD 0.62-0.77 / P = 0.0016), 0.89 for Mars2 (SD 0.85-0.94 / P < 0.0001), 0.82 for Mars3 (SD 0.75-0.88 / P < 0.0001) and 0.71 for Mars4 (SD 0.64-0.79 / P < 0.0006).

CONCLUSION: The Mars1 endotype detected by qRT-PCR was associated with worse sepsis survival in low-to middle-income countries. We also identified the Mars 2 endotype as a potential diagnostic marker for sepsis.

PMID:40705347 | DOI:10.1097/SHK.0000000000002661

JAMA Netw Open. 2025 Jul 1;8(7):e2522740. doi: 10.1001/jamanetworkopen.2025.22740.

ABSTRACT

IMPORTANCE: Intestinal multidrug-resistant organism (MDRO) colonization is highly prevalent in long-term acute care hospital (LTACH) patients and is associated with MDRO infection and transmission. However, there are no therapies approved by the US Food and Drug Administration to reduce intestinal MDRO colonization.

OBJECTIVE: To determine the safety and acceptability of fecal microbiota transplantation (FMT) in LTACH patients.

DESIGN, SETTING, AND PARTICIPANTS: This single-center, open-label nonrandomized clinical trial was conducted from April to December 2023 at an LTACH in the Southeastern US with median 50-patient census and 28-day length of stay. Patients with MDRO colonization were identified by perirectal prevalence sampling. Patients colonized with at least 1 target MDRO were approached for informed consent for FMT. FMT recipients were compared with untreated controls with MDRO colonization. Data were analyzed from August 2024 to May 2025.

INTERVENTION: Healthy donor fecal microbiota (50-100 g stool and 250 mL normal saline with 9% glycerol) instilled via gastrostomy tube or enema without antibiotic or bowel preparation conditioning.

MAIN OUTCOMES AND MEASURES: The primary outcome was frequency and severity of adverse events. Solicited adverse events were recorded for 7 days. Unsolicited adverse events were recorded for 6 months. Four weekly perirectal MDRO cultures were performed after FMT.

RESULTS: A total of 42 patients, including 10 (mean [SD] age, 63.8 (14.5) years; 7 [70%] female) who received FMT and 32 contemporaneous controls (mean [SD] age, 64.0 [13.7] years; 13 [41%] female) were assessed. In 2 prevalence surveys, 23 of 32 (72%) and 26 of 34 (77%) perirectal cultures grew at least 1 MDRO. Among the FMT group, 5 patients received FMT via gastrostomy alone, 4 via enema alone, and 1 with both routes more than 30 days apart. No serious adverse events were attributed to FMT, and post-FMT solicited adverse events were mild. At final visit, all perirectal cultures from FMT recipients grew at least 1 MDRO. Post hoc analyses found numerically fewer FMT recipients had positive blood culture results (0 individuals vs 6 individuals [19%]; P = .31), pathogen intestinal dominance (2 of 8 individuals [25%] vs 4 of 8 individuals [50%]; P = .61), and 7 fewer days of antibiotic therapy per 1000 patient days (median [IQR], 12.6 [0-25.2] days vs 19.7 [6.5-36.1] days; P = .38) compared with controls in the 6 months after prevalence survey, although these differences were not statistically significant. Accounting for higher baseline FMT recipient antibiotic use, difference-in-differences analysis estimated 26 (95% CI, -64 to 12) fewer days of antibiotic therapy per 1000 patient-days after FMT, although this difference was also not statistically significant.

CONCLUSIONS AND RELEVANCE: In this nonrandomized pilot clinical trial, FMT was acceptable for LTACH patients without related serious adverse events. Although not powered to test these outcomes, this study found potential reductions in bacteremia, intestinal pathogen domination, and antibiotic use associated with FMT, suggesting FMT should be evaluated in larger, randomized trials.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05780801.

PMID:40705333 | DOI:10.1001/jamanetworkopen.2025.22740

JAMA Netw Open. 2025 Jul 1;8(7):e2523044. doi: 10.1001/jamanetworkopen.2025.23044.

ABSTRACT

IMPORTANCE: The US Preventive Services Task Force (USPSTF) recommends annual computed tomographic (CT) screening for individuals aged 50 to 80 years at high risk of lung cancer. Other countries are issuing similar recommendations, with some opting for biennial screening to reduce the burden of screening. However, it is unknown whether benefits of annual screening can be preserved when adapting the interval to age, sex, and smoking history.

OBJECTIVE: To evaluate the health outcomes and costs of adaptive lung cancer screening intervals relative to annual screening.

DESIGN, SETTING, AND PARTICIPANTS: This economic evaluation used comparative modeling methods with 3 models: 2 Cancer Intervention and Surveillance Modeling Network models and the OncoSim model from the Canadian Partnership Against Cancer. Screening of the US 1965 birth cohort with adaptive intervals was evaluated according to age, sex, and smoking exposure. Simulated outcomes are recorded from 2005 to 2065 for subpopulations of 200 000 individuals with smoking history of 10 to less than 20, 20 to less than 30, and 30 or greater pack-years (PY) for each sex. This evaluation was conducted between September 19, 2023, to December 1, 2024.

EXPOSURE: Low-dose regular CT screening among those eligible per USPSTF 2021 recommendations.

MAIN OUTCOMES AND MEASURES: Strategy effectiveness was evaluated as lung cancer deaths prevented and life-years gained relative to annual screening. Screening burden is measured by the number of CT screens. To determine cost-effectiveness, quality-adjusted life-years (QALYs) gained and Surveillance, Epidemiology, and End Results- and Medicare-derived costs of treatment were calculated, as well as CT and follow-up examination costs. A willingness-to-pay (WTP) threshold of $100 000/QALY for cost-effectiveness was assumed.

RESULTS: Biennial screening at 50 to 60 years of age, followed by annual screening, reduced CT requirements while preserving most benefits. This strategy preserved 95.9% (intermodel range, 93.5%-97.5%) of lung cancer deaths prevented, compared with annual screening, with 20.6% (intermodel range, 19.3%-21.9%) fewer screens. Annual screening from 50 to 80 years of age was not cost-effective at a WTP threshold of $100 000/QALY. Cost-effective strategies varied by risk group, but all cost-effective strategies started with biennial screening and moved to annual screening at 60 years of age or a PY threshold of 30 to 40 was reached.

CONCLUSIONS AND RELEVANCE: In this economic evaluation of lung cancer screening, biennial screening for participants younger than 60 years and those with less than 30 PY of smoking exposure maintained screening benefits relative to annual screening. Resource-constricted screening programs may consider adaptive intervals.

PMID:40705331 | DOI:10.1001/jamanetworkopen.2025.23044

Med Mycol. 2025 Jul 24:myaf060. doi: 10.1093/mmy/myaf060. Online ahead of print.

ABSTRACT

INTRODUCTION: Sporotrichosis is a worldwide endemic mycosis caused by thermodimorphic fungi of the genus Sporothrix. Of the around 70 Sporothrix species, four are classified within the clinical or pathogenic clade (S. schenckii, S. brasiliensis, S. globosa and S. luriei), which are usually isolated from animal and human infections. The disease shows various clinical presentations (fixed and disseminated cutaneous, lymphocutaneous, systemic or extracutaneous forms), with itraconazole being the antifungal of choice in most cases. The cat is the key player in the zoonotic scenario of sporotrichosis, but despite the high number of felines with sporotrichosis, there are few studies that explore the clinical aspects of the disease in dogs and cats. The objective of this review was to establish associations between clinical aspects and treatment outcomes in feline and canine sporotrichosis.

METHODS: through a systematic review using the PRISMA method, scientific articles from WOS and Scopus databases were collected. The presence of information about the treatment and clinical outcome of feline and canine sporotrichosis were used as inclusion criterion. We included articles in English, Portuguese or Spanish, published from 1978 to August 5, 2024. The data collected included patient species, sex, country, lifestyle, predisposing factors, diagnosis, sporotrichosis clinical form, disease evolution time, therapy type, treatment, treatment duration, clinical outcomes, and side effects. To analyze the data, we used RStudio and the Python programming language in the COLAB environment. Using violin plots we analyzed the distribution of the time of disease evolution and the duration of treatment according to 1) patient species, 2) sporotrichosis clinical form, 3) diagnosis and 4) clinical outcome. Additionally, we analyzed the independence between qualitative variables and the strength of the association between 9 different groups of variables.

RESULTS: of the total of 508 articles initially found, 54 met the inclusion criteria, of which 152 cases of animal sporotrichosis were reported (131 cat cases and 21 dog cases). Most of the reported cases came from Brazil, with S. brasiliensis being the species found in the highest proportion. 19.73% of the cases were male cats, linked to outdoor behavior. Monotherapies were the most used type of therapy, and itraconazole was the most used antifungal, with high favorable responses and low adverse effects. Analysis of relationship of the treatment duration with the clinical outcomes showed significant association of longer treatment period and favorable clinical outcome, when compared with death or diseases relapse. Furthermore, we found statistically significant associations when the clinical outcomes were correlated with clinical type of sporotrichosis, antifungal therapy type and antifungal drug side effects.

CONCLUSIONS: This work confirm previous finds that S. brasiliensis has a key role in the feline sporotrichosis epidemic ongoing in Brazil and highlights the importance of a thorough initial diagnosis to animal cases guaranteeing personalized first-line treatment for each patient, increasing cure rates, as well as decreasing S. brasiliensis transmission.

PMID:40705328 | DOI:10.1093/mmy/myaf060

Neurol India. 2025 Jul 1;73(4):740-745. doi: 10.4103/neurol-india.Neurol-India-D-24-00251. Epub 2025 Jul 24.

ABSTRACT

BACKGROUND: Ictal cognitive assessments carried out in Epilepsy Monitoring Units (EMUs) have been standardized on the Western population which is unable to capture the socioeducational differences present in the Indian population.

OBJECTIVE: This study focuses on modifying and rearranging components of the International League Against Epilepsy’s Ictal Testing Battery (ILAE-ITB) in a local setting at an Indian epilepsy center.

METHODS: The Customizable Ictal Testing Battery (C-ITB) was modified using ILAE-ITB by enabling variable order of item administration, prioritizing items testing the suspect seizure onset region. The consenting participants were assessed using both batteries. The diagnostic performance and localization ability of C-ITB were also measured.

RESULTS: 116 patients with drug-resistant epilepsy were recruited. Association between both batteries was statistically significant using the Chi-square/Fisher’s exact test (P value < 0.001). The Cohen’s kappa was 85.6 and the sensitivity and specificity indices were 100% and 80% respectively. C-ITB demonstrated an inherent validity of 94.8%. There was a significant association between the localization demonstrated by C-ITB and vEEG, MRI. The localization capabilities of C-ITB and ILAE-ITB were comparable.

SIGNIFICANCE: C-ITB is a comprehensive measure of ictal functioning adapted according to the requirements of Indian patients with epilepsy and might facilitate further research into the domain of ictal response deficits.

PMID:40705291 | DOI:10.4103/neurol-india.Neurol-India-D-24-00251

Neurol India. 2025 Jul 1;73(4):721-726. doi: 10.4103/neurol-india.Neurol-India-D-23-00646. Epub 2025 Jul 24.

ABSTRACT

BACKGROUND: The repercussions of inadequate treatment in children with migraine can be disastrous. For this reason, our study aimed to evaluate the pizotifen’s efficacy and tolerance in the control of migraine attacks in children.

METHODS: This research was a cross-sectional, quantitative and retrospective study. The medical records of 65 patients children or adolescents diagnosed with migraine according to the criteria of third edition of the International Classification of Headaches, and treated with pizotifen, were analyzed, considering the follow-up of one year after starting treatment. The correlation between the selected variables was performed using Fisher’s exact test.

RESULTS: This study presents an average age of 10.4 years. The female gender predominated, especially in the pubescent age group, which corresponded to 69%. Migraine was disabling in 57% of cases. There was an improvement in 84.6% of the children with the use of pizotifen, and 18.5% of the patients made irregular use of the medication and 100% of these evolved with recurrent attacks. Side effects occurred in 16.9%, the most common being increased appetite and weight gain. Gender, puberty, frequency of attacks and migraine equivalents did not have a statistically significant influence on migraine control with the use of the drug.

CONCLUSIONS: Pizotifen proved to be effective in reducing the frequency and intensity of migraine attacks and had an acceptable tolerance profile, which makes it a good therapeutic option. Randomized clinical trials with a larger number of participants are needed to confirm our findings.

PMID:40705288 | DOI:10.4103/neurol-india.Neurol-India-D-23-00646

Neurol India. 2025 Jul 1;73(4):716-720. doi: 10.4103/neurol-india.Neurol-India-D-24-00524. Epub 2025 Jul 24.

ABSTRACT

BACKGROUND: The craniovertebral junction (CVJ) is associated with congenital anomalies such as atlanto-axial dislocation (AAD) and basilar invagination (BI). The role of bony anatomy in these pathologies is well studied. The posterior atlanto-occipital membrane complex (PAOMc) (equivalent of ligamentum flavum) is often seen to be forming a tight band-like constricting structure in the CVJ anomalies and has been less studied.

OBJECTIVES: This study aimed to compare the histological characteristics of PAOMc in CVJ anomaly patients with those in patients undergoing surgery for posterior fossa tumors (controls).

METHODS: This observational study included 41 patients, divided into two groups: 22 with congenital CVJ anomalies undergoing C1-C2/occipitocervical fixation and 19 undergoing surgeries for posterior fossa tumors. PAOMc samples from both groups were analyzed using hematoxylin and eosin, Mason Trichrome, Alcian Blue, and Van Gieson stains. Immunohistochemistry for CD34 and CD68 markers was performed. Histological parameters were graded and compared using appropriate statistical test.

RESULTS: Both the groups were comparable with respect to age and gender. Histological and immunohistochemistry comparison revealed no significant differences in all the evaluated parameters between the PAOMc of patients with congenital CVJ anomalies and those of the control group (p- value > 0.05).

CONCLUSION: The present study is the first study to study the role of PAOMc in congenital CVJ anomalies. The findings indicate that PAOMc may not play a significant role in the pathology of these anomalies, contrasting with the ligamentum flavum in other spinal regions.

PMID:40705287 | DOI:10.4103/neurol-india.Neurol-India-D-24-00524

Neurol India. 2025 Jul 1;73(4):678-691. doi: 10.4103/neurol-india.Neurol-India-D-24-00443. Epub 2025 Jul 24.

ABSTRACT

Tuberculous meningitis (TBM) is a critical form of tuberculosis with high morbidity and mortality. Paradoxical reactions (PR) are frequently observed in neurotuberculosis, with diverse manifestations. A selective immune dys/upregulation leads to cytokine surge. The exact immune pathogenesis is not known. This review explores the established literature-based knowledge in PR in HIV-ve TBM to visualize the gray zone in neurotuberculosis and possible immune therapeutic adventures. We undertook this systematic review as per the preferred reporting items for systematic reviews and meta-analyses guidelines and searched PubMed, Scopus, Embase, and Google Scholar database till July 25, 2024, to identify eligible studies focusing on PR in TBM/neurotuberculosis. Quality assessment followed the protocol of Murad MH et al. Data were synthesized narratively and statistically analyzed using Microsoft Excel. The search yielded 112 records describing 617 patients. PR is an immune dys/upregulated state in tuberculosis observed with a median age of 34 years (7-74 years), incidence of 12.7-64.7%, and 9.09-27.8% mortality. The spectrum involved clinical PR (tuberculomas, hydrocephalus, infarcts, arachnoiditis), imaging PR, cerebrospinal fluid PR, or in combinations. Treatment in the form of medical [corticosteroid, thalidomide, intrathecal hyaluronidase, biological (anti-tumor necrosis factor-alpha/TNF-α agents)], surgery (ventriculoperitoneal shunting) has shown good clinical response. Immunological and genetic studies in PR/neurotuberculosis are sparse. Immunological agents like corticosteroid, thalidomide, biologicals like anti-TNF-α have proven benefit in treating PR/neurotuberculosis. Research into the neuroimmunological and genetic aspects of PR is lacking and needs further exploration via predictive models and randomized therapy-based trials.

PMID:40705281 | DOI:10.4103/neurol-india.Neurol-India-D-24-00443