Nevin Manimala

J Immunother Cancer. 2024 May 15;12(5):e008927. doi: 10.1136/jitc-2024-008927.

ABSTRACT

BACKGROUND: Only a subset of patients with gastric cancer experience long-term benefits from immune checkpoint inhibitors (ICIs). Currently, there is a deficiency in precise predictive biomarkers for ICI efficacy. The aim of this study was to develop and validate a pathomics-driven ensemble model for predicting the response to ICIs in gastric cancer, using H&E-stained whole slide images (WSI).

METHODS: This multicenter study retrospectively collected and analyzed H&E-stained WSIs and clinical data from 584 patients with gastric cancer. An ensemble model, integrating four classifiers: least absolute shrinkage and selection operator, k-nearest neighbors, decision trees, and random forests, was developed and validated using pathomics features, with the objective of predicting the therapeutic efficacy of immune checkpoint inhibition. Model performance was evaluated using metrics including the area under the curve (AUC), sensitivity, and specificity. Additionally, SHAP (SHapley Additive exPlanations) analysis was used to explain the model’s predicted values as the sum of the attribution values for each input feature. Pathogenomics analysis was employed to explain the molecular mechanisms underlying the model’s predictions.

RESULTS: Our pathomics-driven ensemble model effectively stratified the response to ICIs in training cohort (AUC 0.985 (95% CI 0.971 to 0.999)), which was further validated in internal validation cohort (AUC 0.921 (95% CI 0.839 to 0.999)), as well as in external validation cohort 1 (AUC 0.914 (95% CI 0.837 to 0.990)), and external validation cohort 2 (0.927 (95% CI 0.802 to 0.999)). The univariate Cox regression analysis revealed that the prediction signature of pathomics-driven ensemble model was a prognostic factor for progression-free survival in patients with gastric cancer who underwent immunotherapy (p<0.001, HR 0.35 (95% CI 0.24 to 0.50)), and remained an independent predictor after multivariable Cox regression adjusted for clinicopathological variables, (including sex, age, carcinoembryonic antigen, carbohydrate antigen 19-9, therapy regime, line of therapy, differentiation, location and programmed death ligand 1 (PD-L1) expression in all patients (p<0.001, HR 0.34 (95% CI 0.24 to 0.50)). Pathogenomics analysis suggested that the ensemble model is driven by molecular-level immune, cancer, metabolism-related pathways, and was correlated with the immune-related characteristics, including immune score, Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data score, and tumor purity.

CONCLUSIONS: Our pathomics-driven ensemble model exhibited high accuracy and robustness in predicting the response to ICIs using WSIs. Therefore, it could serve as a novel and valuable tool to facilitate precision immunotherapy.

PMID:38749538 | DOI:10.1136/jitc-2024-008927

Stroke Vasc Neurol. 2024 May 15:svn-2023-003004. doi: 10.1136/svn-2023-003004. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aims to investigate the prevalence of familial cerebral cavernous malformations (FCCMs) in first-degree relatives (FDRs) using familial screening, to describe the distribution of initial symptoms, lesion count on cranial MRI and pathogenic gene in patients.

METHODS: Patients with multiple CCMs who enrolled from the Treatments and Outcomes of Untreated Cerebral Cavernous Malformations in China database were considered as probands and FDRs were recruited. Cranial MRI was performed to screen the CCMs lesions, and whole-exome sequencing was performed to identify CCM mutations. MRI and genetic screening were combined to diagnose FCCM in FDRs, and the results were presented as prevalence and 95% CIs. The Kaplan-Meier (KM) method was used to calculate the cumulative incidence of FCCM.

RESULTS: 33 (76.74%) of the 43 families (110 FDRs) were identified as FCCM (85 FDRs). Receiver operating characteristic analysis revealed three lesions on T2-weighted imaging (T2WI) were the strong indicator for distinguishing probands with FCCM (sensitivity, 87.10%; specificity, 87.50%). Of the 85 FDRs, 31 were diagnosed with FCCM, resulting in a prevalence of 36.5% (26.2%-46.7%). In families with FCCMs, the mutation rates for CCM1, CCM2 and CCM3 were 45.45%, 21.21% and 9.09%, respectively. Furthermore, 53.13% of patients were asymptomatic, 17.19% were intracranial haemorrhage and 9.38% were epilepsy. The mean age of symptom onset analysed by KM was 46.67 (40.56-52.78) years.

CONCLUSION: Based on MRI and genetic analysis, the prevalence of CCMs in the FDRs of families with FCCMs in China was 36.5%. Genetic counselling and MRI screening are recommended for FDRs in patients with more than three CCM lesions on T2WI.

PMID:38749536 | DOI:10.1136/svn-2023-003004

BMJ Open Respir Res. 2024 May 15;11(1):e001962. doi: 10.1136/bmjresp-2023-001962.

ABSTRACT

INTRODUCTION: Early enteral nutrition (EN) in critically ill adult patients is thought to improve mortality and morbidity; expert guidelines recommend early initiation of EN in critically ill adults. However, the ideal schedule and dose of EN remain understudied.

STUDY OBJECTIVE: Our objective was to evaluate the relationship between achieving 70% of recommended EN within 2 days of intubation (‘early goal EN’) and clinical outcomes in mechanically ventilated medically critically ill adults. We hypothesised that early goal EN would be associated with reduced in-hospital death.

METHODS: We conducted a retrospective cohort study of mechanically ventilated adult patients admitted to our medical intensive care unit during 2013-2019. We assessed the proportion of recommended total EN provided to the patient each day following intubation until extubation, death or 7 days whichever was shortest. Patients who received 70% or more of their recommended total daily EN within 2 days of intubation (ie, ‘baseline period’) were considered to have achieved ‘early goal EN’; these patients were compared with patients who did not (‘low EN’). The primary outcome was in-hospital death; secondary outcomes were successful extubation and discharge alive.

RESULTS: 938 patients met eligibility criteria and survived the baseline period. During the 7-day postintubation period, 64% of all patients reached 70% of recommended daily calories; 33% of patients achieved early goal EN. In unadjusted and adjusted models, early goal EN versus low EN was associated with a lower incidence of in-hospital death (subdistribution HR (SHR) unadjusted=0.63, p=0.0003, SHR adjusted=0.73, p=0.02). Early goal EN was also associated with a higher incidence of successful extubation (SHR unadjusted=1.41, p<0.00001, SHR adjusted=1.27, p=0.002) and discharge alive (SHR unadjusted=1.54, p<0.00001, SHR adjusted=1.24, p=0.02).

CONCLUSIONS: Early goal EN was associated with significant improvement in clinical metrics of decreased in-hospital death, increased extubation and increased hospital discharge alive.

PMID:38749534 | DOI:10.1136/bmjresp-2023-001962

BMJ Open Respir Res. 2024 May 15;11(1):e001918. doi: 10.1136/bmjresp-2023-001918.

ABSTRACT

BACKGROUND: The prevalence, Medicaid use and mortality risk associated with low forced expiratory volume in 1 s (FEV₁) among young adults aged 20-35 years are not well understood, despite its potential implications for the development of chronic pulmonary disease and overall prognosis.

METHODS: A retrospective cohort study was conducted among young adults aged 20-35 years old, using data from the National Health and Nutrition Examination Survey, National Death Index and Centers for Medicare & Medicaid Services. Participants were categorised into a low FEV₁ group (pre-bronchodilator FEV₁%pred <80%) and a normal FEV₁ group (FEV₁%pred ≥80%). Weighted logistic regression analysis was employed to identify the risk factors associated with low FEV₁, while Cox proportional hazard models were used to calculate the hazard ratio (HR) for Medicaid use and the all-cause mortality between the two groups.

RESULTS: A total of 5346 participants aged 20-35 were included in the study, with 329 in the low FEV₁ group and 5017 in the normal group. The weighted prevalence of low FEV₁ among young adults was 7.1% (95% CI 6.0 to 8.2). Low body mass index (OR=3.06, 95% CI 1.79 to 5.24), doctor-diagnosed asthma (OR=2.25, 1.28 to 3.93), and wheezing or whistling (OR=1.57, 1.06 to 2.33) were identified as independent risk factors for low FEV₁. Over a 15-year follow-up, individuals in the low FEV₁ group exhibited a higher likelihood of Medicaid use compared with those in the normal group (HR=1.73, 1.07 to 2.79). However, there was no statistically significant increase in the risk of all-cause mortality over a 30-year follow-up period (HR=1.48, 1.00 to 2.19).

CONCLUSIONS: A considerable portion of young adults demonstrated low FEV₁ levels, a characteristic that was associated with a higher risk of Medicaid use over a long-term follow-up, yet not linked to an augmented risk of all-cause mortality.

PMID:38749533 | DOI:10.1136/bmjresp-2023-001918

BMJ Glob Health. 2024 May 14;9(5):e014367. doi: 10.1136/bmjgh-2023-014367.

ABSTRACT

INTRODUCTION: There are no published data on the long-term impact of invasive group B Streptococcus disease (iGBS) on economic costs or health-related quality of life (HRQoL) in low-income and middle-income countries. We assessed the impact of iGBS on healthcare utilisation, costs and HRQoL in Argentina, India, Kenya, Mozambique and South Africa.

METHODS: Inpatient and outpatient visits, out-of-pocket (OOP) healthcare payments in the 12 months before study enrolment, and health-state utility of children and caregivers (using the EuroQol 5-Dimensions-3-Level) were collected from iGBS survivors and an unexposed cohort matched on site, age at recruitment and sex. We used logistic or Poisson regression for analysing healthcare utilisation and zero-inflated gamma regression models for family and health system costs. For HRQoL, we used a zero-inflated beta model of disutility pooled data.

RESULTS: 161 iGBS-exposed and 439 unexposed children and young adults (age 1-20) were included in the analysis. Compared with unexposed participants, iGBS was associated with increased odds of any healthcare utilisation in India (adjusted OR 11.2, 95% CI 2.9 to 43.1) and Mozambique (6.8, 95% CI 2.2 to 21.1) and more frequent healthcare visits (adjusted incidence rate ratio (IRR) for India 1.7 (95% CI 1.4 to 2.2) and for Mozambique 6.0 (95% CI 3.2 to 11.2)). iGBS was also associated with more frequent days in inpatient care in India (adjusted IRR 4.0 (95% CI 2.3 to 6.8) and Kenya 6.4 (95% CI 2.9 to 14.3)). OOP payments were higher in the iGBS cohort in India (adjusted mean: Int$682.22 (95% CI Int$364.28 to Int$1000.16) vs Int$133.95 (95% CI Int$72.83 to Int$195.06)) and Argentina (Int$244.86 (95% CI Int$47.38 to Int$442.33) vs Int$52.38 (95% CI Int$-1.39 to Int$106.1)). For all remaining sites, differences were in the same direction but not statistically significant for almost all outcomes. Health-state disutility was higher in iGBS survivors (0.08, 0.04-0.13 vs 0.06, 0.02-0.10).

CONCLUSION: The iGBS health and economic burden may persist for years after acute disease. Larger studies are needed for more robust estimates to inform the cost-effectiveness of iGBS prevention.

PMID:38749511 | DOI:10.1136/bmjgh-2023-014367

Endoscopy. 2024 May 15. doi: 10.1055/a-2328-2844. Online ahead of print.

ABSTRACT

BACKGROUND AND STUDY AIM: Computer-aided detection (CADe) has been developed to improve detection during colonoscopy. After initial reports of high efficacy, there has been an increasing recognition of variability in the effectiveness of CADe systems. The aim of this study was to evaluate a CADe system (PENTAX Medical, Tokyo, Japan) in a varied colonoscopy population.

PATIENTS AND METHODS: A multicenter, randomized trial was conducted at 7 hospitals (both university and non-university) in Europe and Canada. Participants referred for diagnostic, non-iFOBT screening, or surveillance colonoscopy were randomized (1:1) to undergo CADe-assisted or conventional colonoscopy (CC) by experienced endoscopists. Participants with insufficient bowel preparation were excluded from the analysis. Primary outcome was adenoma detection rate (ADR). Secondary outcomes included adenomas per colonoscopy (APC) and sessile serrated lesions per colonoscopy (SSLPC).

RESULTS: In total, 581 participants were enrolled, of which 497 were included in the final analysis: 250 in the CADe-arm and 247 in the CC-arm. Surveillance was the indication in 202/497 (40.6%) colonoscopies, diagnostic in 199/497 (40.0%), and non-iFOBT screening in 96/497 (19.3%). Overall, ADR (38.4% vs. 37.7%; p=0.43) and APC (0.66 vs. 0.66; p=0.97) were similar between CADe and CC. SSLPC was increased (0.30 vs. 0.19; p=0.049) in the CADe-arm vs. CC.

CONCLUSIONS: In this study conducted by experienced endoscopists, CADe did not result in a statistically significant increase in ADR. However, the ADR of our control group substantially surpassed our sample size assumptions, increasing the risk of an underpowered trial. (Trialsearch.who.int:NL9135).

PMID:38749482 | DOI:10.1055/a-2328-2844

Dtsch Med Wochenschr. 2024 May;149(11):638-645. doi: 10.1055/a-2160-5397. Epub 2024 May 15.

ABSTRACT

The diagnosis and treatment of malignant lymphoma is rapidly advancing, offering hope but also highlighting inherent limitations. Technological breakthroughs in sequencing technologies enable more precise subtyping and risk stratification. For example, in diffuse large B-cell lymphoma (DLBCL), exome sequencing revealed molecular subtypes. Understanding these subtypes sheds light on lymphomagenesis and prognosis, and may provide targets for tailored therapies. Additionally, tumor-derived cell-free DNA (ctDNA) detected in blood plasma allows for genotyping, risk stratification, and measurement of minimal residual disease (MRD). Current studies often examine drug effectiveness through “all-comer” approaches or in transcriptionally defined subtypes. Molecular agnostic studies increasingly focus on clinically defined high-risk patients (e.g., using the IPI) to better demonstrate the statistical significance of therapy effects. Improved patient selection can enhance the cost-effectiveness of modern, often expensive, therapies.

PMID:38749440 | DOI:10.1055/a-2160-5397

JMIR Form Res. 2024 May 15;8:e56198. doi: 10.2196/56198.

ABSTRACT

BACKGROUND: Lesbian, gay, bisexual, transgender, and queer (LGBTQ+) people are at higher risk of mental health problems due to widespread hetero- and cisnormativity, including negative public attitudes toward the LGBTQ+ community. In addition to combating social exclusion at the societal level, strengthening the coping abilities of young LGBTQ+ people is an important goal.

OBJECTIVE: In this transdiagnostic feasibility study, we tested a 6-week internet intervention program designed to increase the ability of nonclinical LGBTQ+ participants to cope with adverse events in their daily lives. The program was based on acceptance and commitment therapy principles.

METHODS: The program consists of 6 web-based modules and low-intensity assistance for homework provided by a single care provider asynchronously. The design was a single-group assignment of 15 self-identified LGB community members who agreed to participate in an open trial with a single group (pre- and postintervention design).

RESULTS: Before starting the program, participants found the intervention credible and expressed high satisfaction at the end of the intervention. Treatment adherence, operationalized by the percentage of completed homework assignments (32/36, 88%) was also high. When we compared participants’ pre- and postintervention scores, we found a significant decrease in clinical symptoms of depression (Cohen d=0.44, 90% CI 0.09-0.80), social phobia (d=0.39, 90% CI 0.07-0.72), and posttraumatic stress disorder (d=0.30, 90% CI 0.04-0.55). There was also a significant improvement in the level of self-acceptance and behavioral effectiveness (d=0.64, 90% CI 0.28-0.99) and a significant decrease in the tendency to avoid negative internal experiences (d=0.38, 90% CI 0.09-0.66). The level of general anxiety disorder (P=.11; d=0.29, 90% CI -0.10 to 0.68) and alcohol consumption (P=.35; d=-0.06, 90% CI -0.31 to 0.19) were the only 2 outcomes for which the results were not statistically significant.

CONCLUSIONS: The proposed web-based acceptance and commitment therapy program, designed to help LGBTQ+ participants better manage emotional difficulties and become more resilient, represents a promising therapeutic tool. The program could be further tested with more participants to ensure its efficacy and effectiveness.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05514964; https://clinicaltrials.gov/study/NCT05514964.

PMID:38749024 | DOI:10.2196/56198

Appl Neuropsychol Child. 2024 May 15:1-9. doi: 10.1080/21622965.2024.2353089. Online ahead of print.

ABSTRACT

The present study was conducted with the aim of investigating the effect of exergames in improving the motor memory and inhibitory control of children with executive functions disorder. Children, selected by simple random method were divided into two groups: experimental (n = 16) and control (n = 16). Circle drawing task, and The Serial Reaction Time Task were used to collect and analyze data. The current study is a randomized control trial (RCT) type of research with a two-group pretest, post-test, and follow up -test design in terms of the purpose of applied research and the method of data collection. T-test results for the differences in post- test mean scores between the two groups in motor memory and inhibitory control showed that the treatment group outperformed the control group. There were statistical differences between pre and post measures in favor of post test, and between pre and follow up measures in favor of follow up test, but no statistical differences between post and follow up test. This study demonstrates that it is possible to enhance motor memory and inhibitory control of children with executive functions disorder using exergames intervention.

PMID:38749023 | DOI:10.1080/21622965.2024.2353089

AIDS Care. 2024 May 15:1-14. doi: 10.1080/09540121.2024.2354225. Online ahead of print.

ABSTRACT

The objectives were to assess the self-efficacy and consistent condom use by people living with HIV (PLHIV). A cross-sectional, comparative study was carried out in outpatient clinics in Ceará State, Brazil, with a sample of 190 PLHIV, 95 serodiscordant and 95 seroconcordant. Interviews were conducted using the Socio-Demographic, Clinical, Epidemiological and Vulnerability Form and the Condom Use Self-Efficacy Scale. Descriptive analysis, associations between variables, odds ratio and 95% confidence interval were determined. P < 0.05 was considered statistically significant. Of the sample, 43.1% consistently used condoms (50.5% serodiscordant and 35.7% seroconcordant). Serodiscordant PLHIV without guidance on HIV prevention (P = 0.027) and without access to testing (P = 0.002) had lower self-efficacy and 11.5 times more chances for inconsistent condom use (P = 0.006), while those satisfied with follow-up in health were less likely to use condoms inconsistently (P = 0.011). We conclude that there is low consistent use of condoms among PLHIV, which increases the risk of HIV transmission and the acquisition of other sexually transmitted infections. Consistent condom use was greater among serodiscordant individuals, although there was no difference in self-efficacy in condom use between the groups.

PMID:38749020 | DOI:10.1080/09540121.2024.2354225