Search

BackgroundSphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized inborn error of metabolism associated with steroid-resistant nephrotic syndrome as well as adrenal insufficiency and immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5'phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Some SPLIS patients have undergone kidney transplantation, and others have been treated with vitamin B6 supplementation. In addition, targeted therapies including gene therapy are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing. The main objective of the study was to identify factors influencing survival in SPLIS subjects.ResultsOverall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 48 SPLIS patients with nephropathy who had not received a kidney transplant, two clinical subgroups were distinguished. Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report. Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes.ConclusionOur results demonstrate that SPLIS is a phenotypically heterogeneous condition. We find that patients diagnosed with SPLIS nephropathy in the first year of life and patients presenting with prenatal findings represent two high-risk subgroups, whereas patients harboring the R222Q SGPL1 variant fare better than the rest. Time to progression from onset of proteinuria to end stage kidney disease varies from less than one month to five years, and kidney transplantation may be lifesaving.

BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young-to-middle-aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging-related conditions. Using plasma specimens from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA-IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA-sequencing data from a subset of participants, we observed a significant reduction in a senescence-focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.

Abstract This study investigated sex differences in clinical characteristics and in-hospital outcomes of heart failure (HF) hospitalizations using the National Inpatient Sample data, 2016–2019. HF hospitalizations ≥ 41 years of age were included and stratified by sex. Study outcomes were in-hospital mortality, prolonged length of stay, mechanical ventilation, mechanical circulatory support, vasopressor use, and disposition other than home. Propensity score matched regression analysis was done to compare outcomes between sex. A total of 4,704,684 primary HF hospitalizations were included in the analysis. Of these, 2,447,784 (52.0%) were males and 2,256,899 (48.0%) were females. Regression analysis showed that females had significantly lower odds for mortality (aOR, 0.92, 95% CI: 0.89–0.94), mechanical ventilation (aOR, 0.89, 95% CI: 0.86–0.92), mechanical circulatory support (aOR, 0.54, 95% CI: 0.51–0.58), and vasopressor use (aOR, 0.71, 95% CI: 0.66–0.74), compared to males. However, the odds for prolonged length of stay (aOR, 1.05, 95% CI: 1.04–1.06) and disposition other than home (aOR, 1.32, 95% CI: 1.31–1.34) were significantly higher among females, compared to males. There were significant differences in outcomes between males and females hospitalized for HF. Further research is required to delineate how sex affects several aspects of HF, including epidemiology, risk factors, pathogenesis, and response to medications.

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers among men in India. Stereotactic body radiation therapy (SBRT) has recently become a promising treatment modality for HCC before liver transplantation. Objectives: In this retrospective study, we aimed primarily to determine the clinical details of patients with HCC and response of SBRT in treating such patients with a secondary objective of assessing the impact of SBRT on patient survival. Materials and Methods: This retrospective analysis was conducted from January 2016 to January 2019 at the Department of Radiotherapy at Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. Six MV photons were used in conjunction with volumetric modulated arc treatment to deliver SBRT. Tumor response was evaluated as per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. For both overall survival (OS) and progression-free survival (PFS), Kaplan–Meier curves were created. Results: We included 21 patients with HCC who received SBRT treatment. The median age of our patients was 63 (45–74) years. The radiation dose ranged from 36–50 Gy in 3–5 fractions. Of the 21 patients, 5 (23.8%) had a complete response, whereas 9 (42.9%) showed a partial response. After 2 years, the local control rate was 66.7%. The overall survival was 28 months (interquartile range, IQR, 22–37), and the median progression-free survival was 20 months (IQR, 16–27). The overall survival rate at 2 years was 59%. There was no treatment-related mortality observed and no patient required an urgent transplant for acute decompensation. Conclusion: SBRT was well tolerated by our patients. With advancements in external beam radiotherapy (EBRT) techniques, it is possible to practice higher dose fractionation regimens due to more precise targeting and sparing of normal liver tissue. Considering the long waiting period for liver transplantation, liver SBRT can prove to be a successful bridging tool.

Abstract Background Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized inborn error of metabolism associated with steroid-resistant nephrotic syndrome as well as adrenal insufficiency and immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5’phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Some SPLIS patients have undergone kidney transplantation, and others have been treated with vitamin B6 supplementation. In addition, targeted therapies including gene therapy are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing. The main objective of the study was to identify factors influencing survival in SPLIS subjects. Results Overall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 48 SPLIS patients with nephropathy who had not received a kidney transplant, two clinical subgroups were distinguished. Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report. Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes. Conclusion Our results demonstrate that SPLIS is a phenotypically heterogeneous condition. We find that patients diagnosed with SPLIS nephropathy in the first year of life and patients presenting with prenatal findings represent two high-risk subgroups, whereas patients harboring the R222Q SGPL1 variant fare better than the rest. Time to progression from onset of proteinuria to end stage kidney disease varies from less than one month to five years, and kidney transplantation may be lifesaving.

This paper explores teachers' conceptions of climate change knowledge, contributing to the growing body of work on the geographies of climate change. The paper focuses on the data generated through in-depth semi-structured interviews with a sample of 48 teachers in India to address the research question: What discourses about climate change knowledge are being constructed by teachers in India? We argue that teachers' lesson planning and searches for information are at the forefront of the changing ways in which individuals engage with, find out and construct meaning about climate change. These teachers' beliefs about climate change are very strongly held, even in the face of a perceived lack of expertise or understanding: climate change is described as the 'need of the hour', which this work understands as not only involving material impacts and processes but also important epistemological, collaborative needs through which education might contribute to public reasoning about climate change. Through this analysis we present a 'certainty problematic' as a heuristic device that foregrounds tensions between the inherent uncertainty of knowledge and (against climate denialism) certainty about anthropogenic climate change.

Background: Adductor canal block (ACB) is an emerging technique for postoperative analgesia following knee surgery. ACB technique is relatively easy and is performed under ultrasound guidance. Aims: This study aimed to compare the efficacy of fentanyl and magnesium sulfate as adjuvants with 0.5% ropivacaine in ACB for patients undergoing knee surgeries. Adverse events if any were also noted. Materials and Methods: The study was conducted on 100 patients aged 40–80 years posted for knee surgeries. They were divided into two groups of 50 each: Group ropivacaine with fentanyl (RF) and Group ropivacaine with magnesium (RM). Group RF received 30 mL of 0.5% ropivacaine with 50 μg of fentanyl. Group RM received 30 mL of 0.5% ropivacaine with 125 mg of magnesium sulfate. Both the groups were compared on the basis of time for the first rescue analgesia given after the block. The results were analyzed using the SPSS software. Results: The mean time of the first rescue analgesia was 8.40 ± 0.85 h in Group RF and 10.63 ± 1.10 h in Group RM, which was higher and statistically significant (P = 0.002). Rescue analgesia was given more frequently in Group RF (5.77±3.84) compared to group RM (3.20±1.27) and this was statistically significant (P = 0.000). There were no significant adverse events noted in both the groups. Conclusion: Both the adjuvants, when added to ropivacaine, prolong the duration of blockade and reduce the requirement of rescue analgesia without causing significant adverse effects, but magnesium sulfate has an extra edge over fentanyl in terms of longer duration of postoperative analgesia.

Dengue infection can take on many different forms, ranging from no symptoms to a mild fever, all the way to a severe condition known as dengue shock syndrome. Although the typical symptoms of dengue are well known, the virus can also cause rare neurological complications. Dengue encephalitis is a severe form of neuroinvasive dengue that can be fatal as the virus directly affects the central nervous system. This case series provides a comprehensive overview of dengue, its clinical spectrum, and the potential for severe neurological complications such as dengue encephalitis. It highlights the importance of considering dengue as a possible diagnosis in patients with encephalitis, particularly during a dengue epidemic.

Abstract Background Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. Discussion In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Abstract Background This study delves into newborn care and infant-feeding practices in rural Odisha, specifically focusing on the rural KBK + region of Odisha (Kalahandi-Bolangir-Koraput region), inhabited predominantly by Schedule Tribes and Schedule Castes individuals. There has been an improvement in the health indicators in these areas in recent times. In the background of improved health indicators in these areas, this research explores the current and changing newborn care practices and attempts to gain insight into people’s perceptions of the factors that brought about the changes. Methods This qualitative study was conducted between February and July 2023 at Christian Hospital, Bissamcuttack in Odisha. The methodology involved focused group discussions with mothers and grandmothers. Results Analysis revealed healthy practices like exclusive breastfeeding till six months of age, appropriate timing of the first bath, and prompt healthcare-seeking behavior for minor illnesses among the mothers. The use of cow ghee or breast milk in a baby’s eyes, the application of ash on the umbilical cord, and the use of herbal medicines for minor illnesses were practiced more by the grandmothers in the past and were not as popular among the mothers. It is noteworthy that the cultural practices to ward off the ‘evil eye’ were practiced by both mothers and grandmothers alike. Despite the influence of traditional cultural practices on the beliefs and norms of the community, the study identified a shift in health-seeking behavior, with increased reliance on healthcare providers and safe healthcare practices. The study identifies the pivotal role of Accredited Social Health Activists (ASHAs) as a bridge between the rural communities and the healthcare system. Conclusions This research provides valuable insights for healthcare providers aiming to enhance community-centric safe newborn care practices in rural settings. The emphasis is on the importance of understanding the current and changing local practices. This would help the healthcare providers to encourage healthy practices while eliminating the harmful practices related to newborn care through community workers like ASHA and Anganwadi workers.

Abstract While alterations in nucleus size, shape, and color are ubiquitous in cancer, comprehensive quantification of nuclear morphology across a whole-slide histologic image remains a challenge. Here, we describe the development of a pan-tissue, deep learning-based digital pathology pipeline for exhaustive nucleus detection, segmentation, and classification and the utility of this pipeline for nuclear morphologic biomarker discovery. Manually-collected nucleus annotations were used to train an object detection and segmentation model for identifying nuclei, which was deployed to segment nuclei in H&E-stained slides from the BRCA, LUAD, and PRAD TCGA cohorts. Interpretable features describing the shape, size, color, and texture of each nucleus were extracted from segmented nuclei and compared to measurements of genomic instability, gene expression, and prognosis. The nuclear segmentation and classification model trained herein performed comparably to previously reported models. Features extracted from the model revealed differences sufficient to distinguish between BRCA, LUAD, and PRAD. Furthermore, cancer cell nuclear area was associated with increased aneuploidy score and homologous recombination deficiency. In BRCA, increased fibroblast nuclear area was indicative of poor progression-free and overall survival and was associated with gene expression signatures related to extracellular matrix remodeling and anti-tumor immunity. Thus, we developed a powerful pan-tissue approach for nucleus segmentation and featurization, enabling the construction of predictive models and the identification of features linking nuclear morphology with clinically-relevant prognostic biomarkers across multiple cancer types.

Abstract Background Persistent acute SARS-CoV- 2 infection is characterised by the persistence of symptoms of a COVID-19 illness and a persistently positive SARS-CoV-2 RT PCR result. It is often seen in immunocompromised individuals. Currently, there are no approved treatment regimens or guidelines for management. Methods Our patient is a middle-aged male who had received chemotherapy prior to the onset of his SARS- CoV-2 infection and subsequently was diagnosed with a persistent and acute SARS- CoV-2 infection after presenting to us with a pyrexia of unknown origin. He was treated on an off-label basis following informed consent with casirivimab-imdevimab monoclonal antibody therapy, comprising two IgG1 neutralising human monoclonal antibodies at a dose of 600 mg each. Results Our patient had significant clinical improvement on treatment with the monoclonal antibody therapy and it was well tolerated without any adverse effects. He is currently doing well during follow up. Conclusions Casirivimab-imdevimab monoclonal antibody therapy could be beneficial for people with persistent acute SARS-CoV-2 infection. Therapy is warranted on a case-to-case basis. This highlights the need to identify immunocompromised individuals who are at risk of developing persistent acute SARS-CoV-2 infection to enable their prompt treatment.

PURPOSEThe information on the practice of radiotherapy, including intensity-modulated radiotherapy (IMRT) use for rectal cancer in India, is lacking. This national survey was planned to understand the current status of knowledge, attitudes, and practice among radiation oncologists, specifically concerning the practice of IMRT for rectal cancers.MATERIALS AND METHODSA national survey was sent to radiation oncologists through e-mail or a WhatsApp message, where feasible, with a request letter containing the link to the survey questionnaire. The survey questionnaire was adapted from the UK IMRT survey with permission from the authors. It explored rectal cancer management, IMRT use, reasons for nonadoption, total neoadjuvant therapy (TNT), dose fractionation schedules and radiotherapy processes like radiotherapy simulation, target volume/organ at risk definition, and treatment planning, evaluation, and verification. Descriptive statistics is used to present the results.RESULTSOver 300 radiation oncologists were approached, and 182 (60.6%) of the 153 institutes responded. Around 88% (160 of 182) indicated using IMRT or volumetric modulated arc therapy (VMAT) to treat rectal cancer, of whom 32% used exclusively IMRT/VMAT in all their patients. The reasons for not adopting IMRT were affordability/lack of insurance, resource constraints, and lack of guidelines. Long-course chemoradiation (capecitabine-based) followed by surgery was the most common neoadjuvant approach, with short course and TNT in less than a third of patients. Daily verification feasibility was reported by 60%. Seventy-three percent emphasized the need for a national IMRT guidance document.CONCLUSIONThis national survey from India indicates a scope of routine implementation of IMRT in rectal cancer, highlighting the urgent need for a national IMRT guidance document, which could significantly enhance the quality of care for patients with rectal cancer in India.

There is growing evidence of the connection between variations in kinship intensity and cross-cultural differences in psychological traits. Contributing to this literature on kinship intensity, we put forward a mental model to explain the enduring connection between ancestral niche and psychological traits. Our model posits that two primary orientations or dispositions—strong-ties and weak-ties rationalities—have co-evolved with our ancestral niches to perpetuate—by internalizing and reproducing—the social structure (such as preferences for certain attitudes, values, and beliefs) of the ancestral niche. The findings from 1,291 participants across four societies—China, India, Taiwan, and the United States—support our hypothesis that strong-ties (weak-ties) rationalities, when activated, will endorse strong-tie (weak-ties) values and beliefs. This proposed model contributes to the toolbox of cultural and cross-cultural psychology in a twofold sense: First, in addition to the index of kinship intensity, it offers a measure of kin-based rationality as another predictor of psychological traits; second, it renders intelligible the niche and rationality disconnect prevalent in the globalizing era.

Purpose: Optical surface monitoring systems (OSMSs) have gained substantial attention in modern radiation therapy, specifically in the context of surface guided radiation therapy, which offers real-time patient surface monitoring, ensuring accurate and effective radiation therapy treatments. The aim of this article is to evaluate the OSMS camera sensitivity toward different skin tones, categorized according to the Fitzpatrick scale, a universal classification of human skin tones, using a phantom. Methods and Materials: This study used Catalyst and Sentinel OSMSs (C-RAD). The Alderson RANDO female pelvis phantom, located at the isocenter in computed tomography simulation and treatment rooms, served as an experimental subject. Eighteen skin tone–matching cotton cloths, selected on the basis of Von Luschan chromatic and Fitzpatrick scales, were wrapped around the phantom for sensitivity evaluation. Camera sensitivity was optimized by adjusting threshold/gain (100%-600%) and integration time during individual scans in both rooms. Temporal response analysis spanned 2 months, with 16 measurements for each OSMS taken in varying light conditions. Results: The OSMSs successfully detected the surface of cloth-covered phantoms with varying mean (SD) integration times: 550 (34) to 950 (43) μs for the Sentinel system and 2300 (71) to 12,000 (400) μs for the Catalyst system. The sensitivity parameters differed for each skin tone, with lighter skin requiring shorter integration times and gain/threshold values. Darker skin tones necessitated higher parameters for optimal surface images. The reliability of the systems declined with excessive parameters, leading to noise and compromised accuracy in patient positioning. Conclusions: Optimized sensitivity parameters tailored to individual skin tones are crucial for effective real-time patient surface monitoring in radiation therapy, as variations in skin color can affect the accuracy of measurements. The precision of skin color measurements in OSMSs relies on carefully adjusting camera sensitivity parameters. However, careful consideration is essential, as larger values are required for darker skin tones, compromising reliability. This suggests the need for exploring alternative image guidance methods for patients with darker skin tones.

The performance of commercial solar power plants degrades due to an increase in module temperatures for which standard PV-T air or water-cooling techniques are mostly used. In this study, a thermoelectric cooling system is studied for improving photovoltaic cell power efficiency and hence solar power generation. The cooling optimization requires solar cell temperature prediction of field operating PV modules, for which analysis of six models, is presented. The experimentation results show that TEC cooling maintains PV cell at 25 °C whereas PV cell without TEC operates at 55–63 °C, a higher temperature range, showing the effectiveness of the thermoelectric cooling system in precisely controlling PV cell temperature to operate at or near STC conditions in the field creating a temperature difference of 30–38 °C. The NOCT and Faiman model results are found close to the experimental values in comparison to other models. The potential for cooling and a corresponding increase in solar plant energy production is assessed using PV Syst modeling and simulation for three practical PV installation scenarios for 31 different climatic zone locations worldwide showing 6–27 % power loss due to elevated temperatures, which is not studied in previous studies adding novelty to the analysis. The results show that PV-TECS is an effective system to control the temperature of field operating PV modules, which can be used in future photovoltaic power plants. Field results and analysis of PV temperature models is crucial for the optimization and future development of PV-thermoelectric systems deployed under actual outdoor conditions as well as the expected cooling gains in different climatic locations. These aspects are collectively studied in the current work adding to the novelty of the study.