TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes.

BACKGROUND: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up. RESULTS: Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status. CONCLUSIONS: With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups.

Osteoporosis management in adults with schizophrenia following index hip fracture event: a 10-year population-based retrospective cohort study, Ontario, Canada.

Little is known about the incidence of osteoporosis testing and treatment in individuals with schizophrenia, who may be more likely to fracture. Using competing risk models, we found that schizophrenia was associated with lower incidence of testing or treatment. Implications are for understanding barriers and solutions for this disadvantaged group. PURPOSE: Evidence suggests that individuals with schizophrenia may be more likely to experience hip fractures than the general population; however, little is known about osteoporosis management in this disadvantaged subpopulation. Our study objective was to compare bone mineral density (BMD) testing and pharmacologic treatment in hip fracture patients with versus without schizophrenia. METHODS: This was a retrospective population-based cohort study leveraging health administrative databases, and individuals aged 66-105 years with hip fracture between fiscal years 2009 and 2018 in Ontario, Canada. Schizophrenia was ascertained using a validated algorithm. The outcome was a composite measure of (1) pharmacologic prescription for osteoporosis; or (2) a BMD test. Inferential analyses were conducted using Fine-Gray subdistribution hazard regression, with mortality as the competing event. RESULTS: A total of 52,722 individuals aged 66 to 105 years who sustained an index hip fracture in Ontario during the study period were identified, of whom 1890 (3.6%) had schizophrenia. Hip fracture patients with vs without schizophrenia were more likely to be long-term care residents (44.3% vs. 18.1%; standardized difference, 0.59), frail (62.5% vs. 36.5%; standardized difference, 0.54) and without a primary care provider (9.2% vs. 4.8%; standardized difference, 0.18). In Fine-Gray models, schizophrenia was associated with a lower incidence of testing or treatment (0.795 (0.721, 0.877)). CONCLUSIONS: In this population-based retrospective cohort study, a schizophrenia diagnosis among hip fracture patients was associated with a lower incidence of testing or treatment, after accounting for mortality, and several enabling and predisposing factors. Further research is required to investigate barriers to osteoporosis management in this disadvantaged population.

Proton Shell Gaps in N=28 Nuclei from the First Complete Spectroscopy Study with FRIB Decay Station Initiator.

The first complete measurement of the ß-decay strength distribution of _{17}^{45}Cl_{28} was performed at the Facility for Rare Isotope Beams (FRIB) with the FRIB Decay Station Initiator during the second FRIB experiment. The measurement involved the detection of neutrons and γ rays in two focal planes of the FRIB Decay Station Initiator in a single experiment for the first time. This enabled an analytical consistency in extracting the ß-decay strength distribution over the large range of excitation energies, including neutron unbound states. We observe a rapid increase in the ß-decay strength distribution above the neutron separation energy in _{18}^{45}Ar_{27}. This was interpreted to be caused by the transitioning of neutrons into protons excited across the Z=20 shell gap. The SDPF-MU interaction with reduced shell gap best reproduced the data. The measurement demonstrates a new approach that is sensitive to the proton shell gap in neutron rich nuclei according to SDPF-MU calculations.

Fetal cardiovascular changes during open and fetoscopic in-utero spina bifida closure.

OBJECTIVE: Fetoscopic closure of spina bifida using heated and humidified carbon dioxide gas (hhCO2) has been associated with lower maternal morbidity compared with open closure. Fetal cardiovascular changes during these surgical interventions are poorly defined. Our objective was to compare fetal bradycardia (defined as fetal heart rate (FHR) < 110 bpm for 10 min) and changes in umbilical artery (UA) Doppler parameters during open vs fetoscopic closure. METHODS: This was a prospective cohort study of 22 open and 46 fetoscopic consecutive in-utero closures conducted between 2019 and 2023. Both cohorts had similar preoperative counseling and clinical management. FHR and UA Doppler velocimetry were obtained systematically during preoperative assessment, every 5 min during the intraoperative period, and during the postoperative assessment. FHR, UA pulsatility index (PI) and UA end-diastolic flow (EDF) were segmented into hourly periods during surgery, and the lowest values were averaged for analysis. Umbilical vein maximum velocity was measured in the fetoscopic cohort. At each timepoint at which FHR was recorded, maternal heart rate and systolic and diastolic blood pressure were measured. RESULTS: Fetal bradycardia occurred in 4/22 (18.2%) cases of open closure and 21/46 (45.7%) cases of fetoscopic closure (P = 0.03). FHR decreased gradually in both cohorts after administration of general anesthesia and decreased further during surgery. FHR was significantly lower during hour 2 of surgery in the fetoscopic-repair cohort compared with the open-repair cohort. The change in FHR from baseline in the final stage of fetal surgery was significantly more pronounced in the fetoscopic-repair cohort compared with the open-repair cohort (mean, -32.4 (95% CI, -35.7 to -29.1) bpm vs -23.5 (95% CI, -28.1 to -18.8) bpm; P = 0.002). Abnormal UA-EDF (defined as absent or reversed EDF) occurred in 3/22 (13.6%) cases in the open-repair cohort and 23/46 (50.0%) cases in the fetoscopic-repair cohort (P = 0.004). There were no differences in UA-EDF or UA-PI between closure techniques at the individual stages of assessment. CONCLUSIONS: We observed a decrease in FHR and abnormalities in UA Doppler parameters during both open and fetoscopic spina bifida closure. Fetal bradycardia was more prominent during fetoscopic closure following hhCO2 insufflation, but FHR recovered after cessation of hhCO2. Changes in FHR and UA Doppler parameters during in-utero spina bifida closure were transient, no cases required emergency delivery and no fetoscopic closure was converted to open closure. These observations should inform algorithms for the perioperative management of fetal bradycardia associated with in-utero spina bifida closure. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Translation and Validation of Hindi Version of Adolescent Peer Relation Instrument for Bullying Victimization.

OBJECTIVES: To translate and validate Hindi version of Adolescent Peer Relation Instrument (APRI) and to evaluate burden of bullying victimization among school-going adolescents. METHODS: A school-based cross-sectional study was performed from July 2021 to June 2022 on 9th-12thclass students. Adolescent peer relation instrument was used to evaluate bullying victimization. Reliability and validity of tool, prevalence and strength of association was analyzed by appropriate statistical methods. RESULTS: Bullying and victimization were present in 70.8% and 62.9% adolescents, respectively. Total bullying was significantly less in students <16 years of age (OR 0.995, 95% CI 0.483, 2.049) and those with less than three friends (OR 0.816, 95% CI 0.482, 1.383). Total bullying and total victimization was significantly more in boys (OR 1.993, 95% CI 1.281, 3.099 for bullying and OR 1.584, 95% CI 1.047, 2.397 for victimization). Cronbach's alpha for bullying and victimization was 0.89 and 0.897, respectively. Convergent validity between items of different subscales of bullying and victimization was observed (r value > 0.7) except for social bullying and social victimization. There was weak correlation between subscales of bullying and victimization suggestive of discriminant validity (r value < 0.4). CONCLUSIONS: The Hindi version of APRI has a good reliability and construct validity. About three-fourths and two-thirds of adolescents were involved in bullying and victimization, respectively, with a few identified risk factors. Special counselling sessions at schools must be implemented for children involved in bullying.

Physical Activity of School-Going Adolescents During the COVID-19 Pandemic: A Natural Experiment Study.

OBJECTIVE: To assess the impact of the COVID-19 pandemic associated governmental restrictions on physical activity and sedentary behavior of school-going adolescents in India and its effect on nutrition and health status. METHODS: This was a before-after natural experiment study that recorded paired data of 449 (206 boys) school-going adolescents. COVID-19 related governmental measures (March 24, 2020 till February 2021) were taken as the natural experiment. The change in proportion of adolescents who met the recommended amount of physical activity guidelines and change in sedentary and dietary behaviors and body mass index (BMI) were compared. RESULTS: The proportion of adolescents performing adequate physical activity decreased from 33.9% to 30.7% (OR 1.2,95% CI 0.9,1.6) during the pandemic. Fruit intake increased by 8.1% during the pandemic while junk food intake decreased by 17% during the pandemic. Mean (SD) BMI z-scores increased from -0.7 )1.4) to -0.5 )1.3) (P < 0.001). CONCLUSION: While there was a small decrease in the proportion of physically active adolescents during the pandemic, a shift towards healthier dietary habits was seen.

Perception of cure in prostate cancer: human-led and artificial intelligence-assisted landscape review and linguistic analysis of literature, social media and policy documents.

BACKGROUND: Understanding stakeholders' perception of cure in prostate cancer (PC) is essential to preparing for effective communication about emerging treatments with curative intent. This study used artificial intelligence (AI) for landscape review and linguistic analysis of definition, context and value of cure among stakeholders in PC. MATERIALS AND METHODS: Subject-matter experts (SMEs) selected cure-related key words using Elicit, a semantic literature search engine, and extracted hits containing the key words from Medline, Sermo and Overton, representing academic researchers, health care providers (HCPs) and policymakers, respectively. NetBase Quid, a social media analytics and natural language processing tool, was used to carry out key word searches in social media (representing the general public). NetBase Quid analysed linguistics of key word-specific hit sets for key word count, geolocation and sentiments. SMEs qualitatively summarised key word-specific insights. Contextual terms frequently occurring with key words were identified and quantified. RESULTS: SMEs identified seven key words applicable to PC (number of acquired hits) across four platforms: Cure (12429), Survivor (6063), Remission (1904), Survivorship (1179), Curative intent (432), No evidence of disease (381) and Complete remission (83). Most commonly used key words were Cure by the general public and HCPs (11815 and 224 hits), Survivorship by academic researchers and Survivor by policymakers (378 hits each). All stakeholders discussed Cure and cure-related key words primarily in early-stage PC and associated them with positive sentiments. All stakeholders defined cure differently but communicated about it in relation to disease measurements (e.g. prostate-specific antigen) or surgery. Stakeholders preferred different terms when discussing cure in PC: Cure (academic researchers), Cure rates (HCPs), Potential cure and Survivor/Survivorship (policymakers) and Cure and Survivor (general public). CONCLUSION: This human-led, AI-assisted large-scale qualitative language-based research revealed that cure was commonly discussed by academic researchers, HCPs, policymakers and the general public, especially in early-stage PC. Stakeholders defined and contextualised cure in their communications differently and associated it with positive value.

Nicotine promotes epithelial to mesenchymal transition and gemcitabine resistance via hENT1/RRM1 signalling in pancreatic cancer and chemosensitizing effects of Embelin-a naturally occurring benzoquinone.

Pancreatic cancer is lethal due to poor prognosis with 5-year survival rate lesser than 5 %. Gemcitabine is currently used to treat pancreatic cancer and development of chemoresistance is a major obstacle to overcome pancreatic cancer. Nicotine is a known inducer of drug resistance in pancreatic tumor micro-environment. Present study evaluates chemoresistance triggered by nicotine while treating with gemcitabine and chemosensitization using Embelin. Embelin is a naturally occurring benzoquinone from Embelia ribes possessing therapeutic potency. To develop nicotine-induced chemo-resistance, pancreatic cancer cells PANC-1 and MIA PaCa-2 were continuously treated with nicotine followed by exposure to gemcitabine. Gemcitabine sensitivity assay and immunoblotting was performed to assess the chemo-resistance. Antiproliferative assays such as migration assay, clonogenic assay, Mitochondrial Membrane Potential (MMP) assay, dual staining assay, comet assay, Reactive Oxygen Species (ROS) assay, cell cycle analysis and immunoblotting assays were performed to witness the protein expression involved in chemoresistance and chemosensitization. Epithelial to mesenchymal transition was observed in nicotine induced chemoresistant cells. Gemcitabine sensitivity assay revealed that relative resistance was increased to 6.26 (p < 0.0001) and 6.45 (p < 0.0001) folds in resistant PANC-1 and MIA PaCa-2 compared to parental cells. Protein expression studies confirmed resistance markers like hENT1 and dCK were downregulated with subsequent increase in RRM1 expression in resistant cells. Embelin considerably decreased the cell viability with an IC50 value of 4.03 ± 0.08 µM in resistant PANC-1 and 2.11 ± 0.04 µM in resistant MIA PaCa-2. Cell cycle analysis showed Embelin treatment caused cell cycle arrest at S phase in resistant PANC-1 cells; in resistant MIA PaCa-2 cells there was an escalation in the Sub G1. Embelin upregulated Bax, γH2AX, p53, ERK1/2 and hENT1 expression with concomitant down regulation of Bcl-2 and RRM1. Bioactive molecule embelin, its combination with gemcitabine could provide new vistas to overcome chemo resistance in pancreatic cancer.

Recommended Resting-State fMRI Acquisition and Preprocessing Steps for Preoperative Mapping of Language and Motor and Visual Areas in Adult and Pediatric Patients with Brain Tumors and Epilepsy.

Resting-state (rs) fMRI has been shown to be useful for preoperative mapping of functional areas in patients with brain tumors and epilepsy. However, its lack of standardization limits its widespread use and hinders multicenter collaboration. The American Society of Functional Neuroradiology, American Society of Pediatric Neuroradiology, and the American Society of Neuroradiology Functional and Diffusion MR Imaging Study Group recommend specific rs-fMRI acquisition approaches and preprocessing steps that will further support rs-fMRI for future clinical use. A task force with expertise in fMRI from multiple institutions provided recommendations on the rs-fMRI steps needed for mapping of language, motor, and visual areas in adult and pediatric patients with brain tumor and epilepsy. These were based on an extensive literature review and expert consensus.Following rs-fMRI acquisition parameters are recommended: minimum 6-minute acquisition time; scan with eyes open with fixation; obtain rs-fMRI before both task-based fMRI and contrast administration; temporal resolution of ≤2 seconds; scanner field strength of 3T or higher. The following rs-fMRI preprocessing steps and parameters are recommended: motion correction (seed-based correlation analysis [SBC], independent component analysis [ICA]); despiking (SBC); volume censoring (SBC, ICA); nuisance regression of CSF and white matter signals (SBC); head motion regression (SBC, ICA); bandpass filtering (SBC, ICA); and spatial smoothing with a kernel size that is twice the effective voxel size (SBC, ICA).The consensus recommendations put forth for rs-fMRI acquisition and preprocessing steps will aid in standardization of practice and guide rs-fMRI program development across institutions. Standardized rs-fMRI protocols and processing pipelines are essential for multicenter trials and to implement rs-fMRI as part of standard clinical practice.

Pharmacognostical studies of important arid zone plants / Estudos farmacognósticos de plantas importantes de zonas áridas

Arid zone of Rajasthan, India, has its own importance, great diversity and specific characteristic with respect to endemic and large number of plants of economic importance and medicinal use. Out of these, three arid zone plants Gisekia pharnaceoides L., Gisekiaceae, Sericostoma pauciflorum Stocks ex Wight, Boraginaceae, and Trianthema decandra L., Aizoaceae, which are traditionally used for different ailments (hepatitis, asthma, jaundice, skin-infections etc.) have been selected for the study. In the present paper, detailed pharmacognostical evaluation of these plant species using microscopy, standard physicochemical determinations and authentic phytochemical parameters has been carried out. Later, these morphological characteristics could be used for rapid identification of the drugs, particularly in case of powdered materials, and may possibly help to differentiate the drug from its other species.

A zona árida de Rajasthan, Índia, é importante pela grande diversidade e especificidade de plantas endêmicas de importância econômica e medicinal. Destas, três plantas de zonas áridas, Gisekia pharnaceoides L., Gisekiaceae, Sericostoma pauciflorum Stocks ex Wight, Boraginaceae, e Trianthema decandra L., Aizoaceae, que são tradicionalmente utilizados para diversas doenças (hepatite, asma, icterícia, infecções da pele etc.), foram selecionados para o estudo. Neste trabalho trabalho, a avaliação farmacognóstica detalhada destas espécies, através de estudo morfoanatômico, determinações físico-químicas e parâmetros fitoquímicos, foram realizados. As características morfológicas podem ser utilizados para rápida identificação das drogas, particularmente no caso de materiais em pó, e possivelmente ajudar a diferenciar a droga de outras espécies.