Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes.

Adipose tissue can recruit catabolic adipocytes that utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of Ucp1. Furthermore, FC-adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.

Development of a functional beige fat cell line uncovers independent subclasses of cells expressing UCP1 and the futile creatine cycle.

Although uncoupling protein 1 (UCP1) is established as a major contributor to adipose thermogenesis, recent data have illustrated an important role for alternative pathways, particularly the futile creatine cycle (FCC). How these pathways co-exist in cells and tissues has not been explored. Beige cell adipogenesis occurs in vivo but has been difficult to model in vitro; here, we describe the development of a murine beige cell line that executes a robust respiratory response, including uncoupled respiration and the FCC. The key FCC enzyme, tissue-nonspecific alkaline phosphatase (TNAP), is localized almost exclusively to mitochondria in these cells. Surprisingly, single-cell cloning from this cell line shows that cells with the highest levels of UCP1 express little TNAP, and cells with the highest expression of TNAP express little UCP1. Immunofluorescence analysis of subcutaneous fat from cold-exposed mice confirms that the highest levels of these critical thermogenic components are expressed in distinct fat cell populations.

Enhancing optimal molecular interactions during food processing to design starch key structures for regulating quality and nutrition of starch-based foods: an overview from a synergistic regulatory perspective.

Charting out personalized and/or optimized diets offers new opportunities in the field of food science, although with inherent challenges. Starch-based foods are a major component of daily energy intake in humans. In addition to being rich in starch, starchy foods also contain a multitude of bioactive substances (e.g., polyphenols, lipids). Food processing including storage affects the consistency and interactions between starch and other food components, which can affect the quality and nutritional characteristics of starch-based foods. This review describes the effects of interactions between starch and other components on the structural evolution of starch during food processing. We ponder upon how the evolution of starch molecular structure affects the quality and nutritional characteristics of starch-based foods vis-a-vis the structure-property relationship. Furthermore, we formulate best practices in processing starchy food to retain the quality and nutritional value by rationally designing starch structural domains. Interestingly, we found that inhibiting the formation of a crystalline structures while promoting the formation of short-range ordered structures and nano-aggregates can synchronously slow down its digestion and retrogradation properties, thus improving the quality and nutritional characteristics of starch-based food. This review provides theoretical guidelines for new researchers and food innovators of starch-based foods.

Percutaneous coronary intervention outcomes based on American College of Cardiology/American Heart Association coronary lesion classification over 14 years - Melbourne interventional group (MIG) registry.

BACKGROUND: The American College of Cardiology / American Heart Association (ACC/AHA) introduced a coronary lesion classification in 1988 to stratify coronary lesions for probability of procedural success and complications after coronary angioplasty. Our aim is to assess the validity of the ACC/AHA lesion classification in predicting outcomes of percutaneous coronary intervention (PCI) in a contemporary cohort of patients. METHODS: Consecutive PCI procedures performed between 2005 and 2018, were divided into three periods. At each period, the ACC/AHA lesion classification (A, B1, B2, C) was analysed with respect to procedural characteristics, in-hospital and 30-day outcomes, as well as long-term mortality by linkage to the National Death Index (NDI). RESULTS: In total, 21,437 lesions were included with 7399 lesions (2005-2009), 6917 lesions (2010-2014) and 7121 lesions (2015-2018). There was a progressive increase in the number of complex lesions treated over time with ACC/AHA type C (15 %, 21 % and 26 %, p < 0.01). The rate of PCI procedural success decreased with increase in the complexity of lesions treated across all three periods (p < 0.01). Further, in-hospital and 30-day major adverse cardiovascular events (MACE), major adverse cardiac and cerebrovascular events (MACCE) increased across all three time periods (all p < 0.05). CONCLUSIONS: Our study validates the ACC/AHA lesion classification as a meaningful tool for prediction of PCI outcomes. Despite advances in PCI techniques and technology, complex lesion PCI defined by this classification continues to be associated with adverse outcomes.

Clinical and laboratory parameters as predictors of mortality in patients with chronic liver disease presenting to emergency department- a cross sectional study.

BACKGROUND: The World Health Organization (WHO) reports that Asia and Africa have the highest Chronic Liver Disease (CLD) mortality rate. Cirrhosis, responsible for 22.2 fatalities per 100,000 people, is India's 10th most common cause of mortality. The increasing prevalence of chronic liver disease necessitates a study to identify predictive factors for patients who visit the emergency department. Identifying elements that enhance the predictive value of mortality in unstable patients with CLD complications is important in emergency departments. This study aims to determine Clinical and Laboratory Parameters as mortality predictors in adult chronic liver disease patients. METHODOLOGY: The study was conducted at the emergency department of a tertiary healthcare center in Northern India. Patients with chronic liver disease above 18 years of age who satisfied the inclusion criteria were clinically evaluated. Clinical and demographic details were collected, and data was analyzed. RESULTS: Two hundred thirty-six patients were enrolled. The mean age was 50.77 ± 14.26 years. 78.4% of the participants were men. Abdominal distension, affecting 59.7% of patients, was the most common presenting ailment, followed by melena and hematemesis, affecting 41.9% and 32.6%, respectively. The mean stay in the emergency department was 10.29 ± 8.10 h. Refractory septic shock, the leading cause of mortality, accounts for 69.2% of all deaths, alongside grade 4 hepatic encephalopathy and massive Upper Gastrointestinal (UGI) bleeding, as identified in our study. Factors such as altered mental sensorium, high respiratory rate, low SpO2, increased heart rate, low systolic blood pressure, low diastolic blood pressure, and low Glasgow Coma Scale (GCS) on Emergency Department (ED) arrival are significantly associated with mortality. CONCLUSIONS: Chronic liver disease, a prevalent condition in India, most commonly seen in middle aged men and lower socioeconomic groups. The parameters independently associated with mortality in our study were presence of altered mental sensorium, Glasgow coma scale, Child Pugh class and need for ICU admission. Understanding the presentation pattern, and mortality predictors can help ED physicians in managing acute events and follow-ups.

Safety and Efficacy of the Ayurvedic Formulation Guduchi Ghana Vati as a Preventive Remedy in COVID-19.

Background and objectives Guduchi (Tinospora cordifolia) is a well-known Ayurvedic herb used as a preventive and curative remedy for various infections and immunity-related conditions. This study aimed to evaluate Guduchi Ghana Vati as a preventive remedy for COVID-19 and non-COVID-19 infections in a healthy population. Materials and methods An open-labeled, multi-centric, randomized, comparative, interventional, prospective community-based clinical study was conducted on healthy individuals at the community level in five different districts of Rajasthan by the National Institute of Ayurveda (NIA), Jaipur, India. Participants were divided into two groups. One group received Guduchi Ghana Vati as an intervention for 45 days, and the control group did not receive any intervention. Incidences of COVID-19 infection, non-COVID-19 infections, their severity, and hospitalization requirements were assessed. Safety was evaluated through monitoring of adverse reactions. Results Among the 10,022 participants who completed the study, the incidence of COVID-19 infection was found to be lower in those taking Guduchi Ghana Vati compared to the control group; however, the difference was statistically non-significant. The severity of COVID-19 based on the WHO ordinal scale was found to be significantly lower in the Guduchi Ghana Vati group compared to the control group. The number of episodes and severity of non-COVID-19 illness were also significantly lower in participants taking Guduchi Ghana Vati compared to the control group. No major adverse drug reactions were observed. Conclusion Guduchi Ghana Vati has the potential to act as a safe and effective remedy for the prevention of infection and immunity-related conditions, including COVID-19.

Futile cycles: Emerging utility from apparent futility.

Futile cycles are biological phenomena where two opposing biochemical reactions run simultaneously, resulting in a net energy loss without appreciable productivity. Such a state was presumed to be a biological aberration and thus deemed an energy-wasting "futile" cycle. However, multiple pieces of evidence suggest that biological utilities emerge from futile cycles. A few established functions of futile cycles are to control metabolic sensitivity, modulate energy homeostasis, and drive adaptive thermogenesis. Yet, the physiological regulation, implication, and pathological relevance of most futile cycles remain poorly studied. In this review, we highlight the abundance and versatility of futile cycles and propose a classification scheme. We further discuss the energetic implications of various futile cycles and their impact on basal metabolic rate, their bona fide and tentative pathophysiological implications, and putative drug interactions.

Antibody Drug Conjugates in Urological Cancers: A Review of the Current Landscape.

PURPOSE OF REVIEW: Our review delves into the progress across urological malignancies and discusses ongoing challenges and future directions in antibody-drug conjugate (ADC) development, emphasising their transformative potential in cancer care. RECENT FINDINGS: ADCs have advanced from hematologic to solid tumours, notably in breast cancer, and are now pivotal in metastatic urological cancers as both monotherapies and in combination regimens, underscored by the FDA's approval of enfortumab vedotin and sacituzumab govitecan for metastatic urothelial cancer. Progress in metastatic prostate cancer, particularly with ADCs targeting PSMA and STEAP1, is noteworthy, although renal cell cancer presents ongoing challenges. There is a continual search for agents in the metastatic, relapsed testicular cancer landscape. ADCs have emerged as a pivotal innovation in oncology, blending targeted antibody therapy with potent cytotoxic drugs, significantly advancing treatment options for urological malignancies.

Futile lipid cycling: from biochemistry to physiology.

In the healthy state, the fat stored in our body isn't just inert. Rather, it is dynamically mobilized to maintain an adequate concentration of fatty acids (FAs) in our bloodstream. Our body tends to produce excess FAs to ensure that the FA availability is not limiting. The surplus FAs are actively re-esterified into glycerides, initiating a cycle of breakdown and resynthesis of glycerides. This cycle consumes energy without generating a new product and is commonly referred to as the 'futile lipid cycle' or the glyceride/FA cycle. Contrary to the notion that it's a wasteful process, it turns out this cycle is crucial for systemic metabolic homeostasis. It acts as a control point in intra-adipocyte and inter-organ cross-talk, a metabolic rheostat, an energy sensor and a lipid diversifying mechanism. In this Review, we discuss the metabolic regulation and physiological implications of the glyceride/FA cycle and its mechanistic underpinnings.

Rural-urban disparity in cancer burden and care: findings from an Indian cancer registry.

BACKGROUND: Cancer incidence and mortality vary across the globe, with nearly two-thirds of cancer-related deaths occurring in low- and middle-income countries. The rural-urban disparity in socio-demographic, behavioural, and lifestyle-related factors, as well as in access to cancer care, is one of the contributing factors. Population-based cancer registries serve as a measure for understanding the burden of cancer. We aimed to evaluate the rural-urban disparity in cancer burden and care of patients registered by an Indian population-based cancer registry. METHODS: This study collected data from Varanasi, Uttar Pradesh, India, between 2017 and 2019. Sex and site-specific age-standardised rates for incidence and mortality per 100,000 population were calculated. Rural-urban disparities in cancer incidence and mortality were estimated through rate differences and standardised rate ratios (with 95% confidence intervals). Univariable and multivariable regressions were applied to determine any significant differences in socio-demographic and cancer-related variables according to place of residence (rural/urban). Crude and adjusted odds ratios with 95% confidence intervals were calculated. RESULTS: 6721 cancer patients were registered during the study duration. Urban patients were older and had better literacy and socioeconomic levels, while rural patients had higher odds of having unskilled or semi-skilled professions. Diagnostic and clinical confirmation for cancer was significantly higher in urban patients, while verbal autopsy-based confirmation was higher in rural patients. Rural patients were more likely to receive palliative or alternative systems of medicine, and urban patients had higher chances of treatment completion. Significantly higher incidence and mortality were observed for oral cancer among urban men and for cervical cancer among rural women. Despite the higher incidence of breast cancer in urban women, significantly higher mortality was observed in rural women. CONCLUSIONS: Low- and middle-income countries are facing dual challenges for cancer control and prevention. Their urban populations experience unhealthy lifestyles, while their rural populations lack healthcare accessibility. The distinctness in cancer burden and pattern calls for a re-evaluation of cancer control strategies that are tailor-made with an understanding of urban-rural disparities. Context-specific interventional programmes targeting risk-factor modifications, cancer awareness, early detection, and accessibility to diagnosis and care are essential.

High Mortality With Non-O1/Non-O139 Vibrio cholera Bacteraemia in Patients With Cirrhosis.

Background: Data on non-O1/non-O139 Vibrio cholera (NOVC) infection in liver disease is limited. We studied the clinical features and outcome of patients with cirrhosis with non-NOVC bacteraemia and/or spontaneous bacterial peritonitis (SBP) when compared to non-extended spectrum beta lactamase (non-ESBL) Escherichia coli (E. coli). Methods: Hospital information system of patients with cirrhosis admitted with bacteraemia and/or SBP from 2010 to 2020 was searched to include patients with NOVC infection. Non-ESBL E. coli bacteraemia/bacterascites were chosen as a comparator group, matched for the date of admission within 5 days of index case. Propensity score matching (PSM) was done for patient's age and Child score to compare outcome at discharge between NOVC-infected and E. coli-infected cirrhotic patients. Results: There were 2545 patients admitted with bacteraemia and/or SBP during the study period; 29 had NOVC isolated (M:F = 23:6; age: 39, 18-54 years; median, range; model for end-stage liver disease [MELD] score: 25, 12-38; Child score: 11, 10-12.5) from either blood (26), ascites (3), or both (8). Of these, 26 isolates were pan-sensitive to antibiotic sensitivity tests. Fifty-three patients with non-ESBL E. coli were isolated (M: F = 43:10; age: 48; 18-69 years; MELD score: 25, 20-32; Child score:12,11-13) from blood (31), ascites (17), or both (5) within the selected time frame. Of these, 48 isolates were sensitive to the empirical antibiotics initiated.After PSM, in comparison with 29 non-ESBL E. coli patients (age: 41, 18-55 years; MELD score: 24, 19-31; Child score: 12, 11-13), NOVC patients had higher incidence of circulatory failure at admission (14 [49 %] vs 4 [13 %]; P: 0.01) and significantly higher in-hospital mortality (15 [52 %] vs 6 [20 %];P: 0.028]. Conclusions: Bacteraemia due to non-O1/non-O139 strains of V. cholera, is an uncommon cause of bacteraemia or bacterascites in patients with cirrhosis and is associated with high incidence of circulatory failure and significant mortality.

Standard Versus Modified Ipilimumab, in Combination With Nivolumab, in Advanced Renal Cell Carcinoma: A Randomized Phase II Trial (PRISM).

PURPOSE: Ipilimumab (IPI), in combination with nivolumab (NIVO), is an approved frontline treatment option for patients with intermediate- or poor-risk advanced renal cell carcinoma (aRCC). We conducted a randomized phase II trial to evaluate whether administering IPI once every 12 weeks (modified), instead of once every 3 weeks (standard), in combination with NIVO, is associated with a favorable toxicity profile. METHODS: Treatment-naïve patients with clear-cell aRCC were randomly assigned 2:1 to receive four doses of modified or standard IPI, 1 mg/kg, in combination with NIVO (3 mg/kg). The primary end point was the proportion of patients with a grade 3-5 treatment-related adverse event (trAE) among those who received at least one dose of therapy. The key secondary end point was 12-month progression-free survival (PFS) in the modified arm compared with historical sunitinib control. The study was not designed to formally compare arms for efficacy. RESULTS: Between March 2018 and January 2020, 192 patients (69.8% intermediate/poor-risk) were randomly assigned and received at least one dose of study drug. The incidence of grade 3-5 trAEs was significantly lower among participants receiving modified versus standard IPI (32.8% v 53.1%; odds ratio, 0.43 [90% CI, 0.25 to 0.72]; P = .0075). The 12-month PFS (90% CI) using modified IPI was 46.1% (38.6 to 53.2). At a median follow-up of 21 months, the overall response rate was 45.3% versus 35.9% and the median PFS was 10.8 months versus 9.8 months in the modified and standard IPI groups, respectively. CONCLUSION: Rates of grade 3-5 trAEs were significantly lower in patients receiving modified versus standard IPI. Although 12-month PFS did not meet the prespecified efficacy threshold compared with historical control, informal comparison of treatment groups did not suggest any reduction in efficacy with the modified schedule.

Neutrophil Gelatinase-associated Lipocalin Predicts Short-term Outcomes in Decompensated Cirrhosis With Acute Kidney Injury.

Background and aims: Acute kidney injury (AKI) increases mortality in cirrhosis. Early identification of the cause of AKI helps in planning appropriate management. We aimed to find whether neutrophil gelatinase-associated lipocalin (NGAL) can be used to differentiate between different types of AKI in cirrhosis and predict short-term outcomes in patients with decompensated cirrhosis and AKI. Method: This was a time-bound study in which consecutive hospitalized patients with cirrhosis and AKI were prospectively recruited and managed as per standard care. Acute on chronic liver failure (ACLF) was diagnosed as per the EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) criteria. Urine NGAL was measured by enzyme-linked immunosorbent assay (ELISA) by Epitope Diagnostics Inc. kit (San Diego, USA.) in all patients on admission, and patients were followed up until hospital discharge or death. Results: A total of 110 consecutive patients (median [range] age: 44 [28-81] years;87.3%were male; ACLF: 71.8%; acute decompensation 28.2%; Model for end-stage liver disease (MELD) 27 [13-46]; Child-Turcotte-Pugh (CTP) 11 [7-15]) with cirrhosis and AKI were recruited. Alcohol was the most common etiology of cirrhosis(64.5%)). Pre-renal azotemia (PRA) was the most common cause of AKI (n = 56). Urine NGAL was significantly elevated in acute tubular necrosis (ATN) (1747 [6-6141] ng/ml than in hepatorenal syndrome (HRS) (379 [33.5-2320] ng/ml; P < 0.0001) and PRA (167 ng/ml [3.34-660]; P < 0.0001). Sixty-four percent patients with ATN, 27.6% patients with HRS, and none with PRA required dialysis. A total of 79.31% patients with HRS and 76% with ATN died. Urine NGAL was significantly higher in patients who required hemodialysis than in those who did not (1733 [243-6141] ng/ml vs 235 [3.34-2320] ng/ml; P < 0.0001). Both urine NGAL (n = 110) and plasma NGAL (n = 90) were significantly higher in patients who died (urine NGAL: -475 [6-6141] ng/ml vs 247 [3.34-2320] ng/ml; P = 0.002;plasma NGAL-950 [94-4859] ng/ml vs 608 [18-3300)]g/ml; P < 0.001). On multivariate analysis, urine NGAL and INR could predict mortality. Conclusion: NGAL can differentiate between different types of AKI in cirrhosis and predict the need for hemodialysis and mortality in decompensated cirrhosis with AKI.

Fertility outcomes following surgery and multiagent chemotherapy in malignant ovarian germ cell tumor survivors: a survey study.

OBJECTIVE: To assess fertility outcomes in long-term survivors of malignant ovarian germ cell tumors treated with fertility-sparing surgery with or without additional chemotherapy. METHODS: Women diagnosed and treated for malignant ovarian germ cell tumors at Charing Cross Hospital or Mount Vernon Cancer Centre between 1977 and 2015 were included. Questionnaires assessing fertility issues were sent to patients treated with fertility-sparing surgery. Fertility outcomes were evaluated according to the treatment received. The effect of the mean total dose of cyclophosphamide and cisplatin was assessed. RESULTS: A total of 146 patients were sent the questionnaire; 77 (56.5%) patients were included in the analysis. A total of 49 (64%) patients received platinum-based chemotherapy after surgery, 39 (79.6%) of these with cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, and etoposide, while 10 (20.4%) with bleomycin, etoposide, and cisplatin. After any treatment, 39/46 patients (85%) became pregnant: the conception rate was not different between those receiving surgery only and those receiving also chemotherapy (85.7% vs 84.4%, p=1.0). Live birth rate was 80.4% (37/46), with no statistically significant difference between the treatment groups (p=0.42). Median age of women achieving conception was 29 years (IQR 26-33). The probability of live birth at 5 years was 48% and 40% for patients in the surgery only and chemotherapy group, respectively (p=0.55). Infertility and miscarriage rates did not differ significantly between the two treatment groups (p=0.30 and p=0.32). The mean doses of cisplatin and cyclophosphamide received by patients failing and achieving conception were not different (p=0.10, p=0.47). CONCLUSIONS: Our results suggest that fertility may not be hampered in patients with malignant ovarian germ cell tumor treated with fertility-sparing surgery or receiving additional chemotherapy.

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma.

Background: A randomized, phase II, placebo-controlled, and blinded clinical trial (NCT01062425) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, versus placebo in combination with radiation and temozolomide in newly diagnosed glioblastoma. Methods: Patients with newly diagnosed glioblastoma were randomly assigned 2:1 to receive (1) cediranib (20 mg) in combination with radiation and temozolomide; (2) placebo in combination with radiation and temozolomide. The primary endpoint was 6-month progression-free survival (PFS) based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted MRI brain scans and was tested using a 1-sided Z test for 2 proportions. Adverse events (AEs) were evaluated per CTCAE version 4. Results: One hundred and fifty-eight patients were randomized, out of which 9 were ineligible and 12 were not evaluable for the primary endpoint, leaving 137 eligible and evaluable. 6-month PFS was 46.6% in the cediranib arm versus 24.5% in the placebo arm (P = .005). There was no significant difference in overall survival between the 2 arms. There was more grade ≥ 3 AEs in the cediranib arm than in the placebo arm (P = .02). Conclusions: This study met its primary endpoint of prolongation of 6-month PFS with cediranib in combination with radiation and temozolomide versus placebo in combination with radiation and temozolomide. There was no difference in overall survival between the 2 arms.

DGAT inhibition at the post-absorptive phase reduces plasma FA by increasing FA oxidation.

In this Correspondence, A. Sharma & C. Wolfrum report that DGAT1/2 pharmacological inhibition at post-absorptive phase in mice leads to increased fatty acid oxidation and reduced plasma fatty acid levels, which could open new therapeutic avenues to avoid GI complications observed in clinical trials.

Circularly polarized printed dual port MIMO antenna with polarization diversity optimized by machine learning approach for 5G NR n77/n78 frequency band applications.

In this communication, a planar dual port multiple input multiple output antenna of size 1.2λ0 × 0.6λ0 × 0.008λ0 with LHCP/RHCP features is reported for the fifth-generation new radio n77/n78 sub-6 GHz wireless applications band. The single unit of the proposed design consists of a modified L-shape rectangular radiator with Z-shape slot loaded DGS. The defected ground structure is optimized through machine learning algorithms to achieve the maximum ARBW (output) by Right Shifting (RS) and left shifting (LS) the DGS and obtaining input features. The performance metric for ANN with ADAM optimizer was found to be optimal with MSE and R2 of 0.99 and 0.82, respectively. ANNs can leverage gradient information to guide the optimization process. This enables faster convergence towards optimal solutions compared to popular GAs and PSO, which are often gradient-free optimization methods. The MIMO configuration is achieved by creating a mirror image of the single unit about the x-axis. The salient features of the proposed design are (a) Impedance bandwidth (IBW) of 3.0-4.2 GHz covering the n77/n78 band, (b) 3-dB axial ratio bandwidth (ARBW) of the 2.6-3.9 GHz (c) Port-1 is generating RHCP while Port-2 is generating LHCP, results in polarization diversity. Different diversity performance parameters (ECC < 0.005, DG ~ 9.99 dB, and MEG < 3 dB) are in the optimum range confirming the proposed configuration as a suitable design for a MIMO radiator.

Role of verbal autopsy in cancer registration: A mixed-methods study from the population-based cancer registry of Northern India.

OBJECTIVES: To describe utilisation of verbal autopsy as one of the data collection approaches in cancer registration in an Indian setting. We aimed to estimate the proportion and epidemiological characteristics of malignancies identified by the Varanasi population-based cancer registry (PBCR) using verbal autopsy between 2017 and 2019 and to develop a thematic network for implementing verbal autopsy. METHODS: This was a cross-sectional mixed-methods study. Quantitative methods were applied to analyse information from PBCR proforma of the verbal autopsy-confirmed cancers; qualitative methods were applied to evaluate verbal autopsy conducted by field staff from key informants. In-depth interviews of field staff for the challenges and potential solutions during verbal autopsy were assessed. RESULTS: Of 6466 registered cancers, 1103 (17.1%) were verbal autopsy-confirmed cancers, which had no other source of information. The majority of verbal autopsy cases were from vulnerable populations who were aged >50 years (721, 65.4%), female (607, 55.1%), from rural backgrounds (853, 77.3%), illiterate or just able to read and write (636, 57.7%), and from lower and middle-income groups (823, 74.6%). Verbal autopsy helped provide information about symptoms and site of disease, diagnostic and treatment details, and disease status. Major challenges during verbal autopsy described by field staff were incomplete cancer treatment, destruction of medical records and non-cooperation by the community and lack of support from the local workforce as cancer is not notifiable. CONCLUSION: Verbal autopsy helped identify cancers that would have been missed during active case finding from available resources. The majority of verbal autopsy-confirmed patients belonged to vulnerable populations. Non-cooperation from community and local health systems was major challenge during verbal autopsy. Developing robust cancer awareness, patient navigation, and social support programmes will strengthen verbal autopsy. Integration of standardised and reproducible methods of verbal autopsy in cancer registry and digitalization of health information, especially in limited-resource settings with weak vital registration, will facilitate completeness in cancer registration.

Reticuloendothelial activation and phenotypic alteration of peripheral monocytes with enhanced liver recruitment drive liver injury secondary to yellow phosphorus.

BACKGROUND AND AIM: Monocytes and macrophages play a crucial role in the pathogenesis of acute liver failure (ALF). We aimed to study reticuloendothelial activation and its correlation with disease severity in commonly encountered yellow phosphorus (rodenticide)-induced hepatotoxicity patients. We also studied peripheral monocyte phenotype in a subset of patients. METHODS: Reticuloendothelial activation markers were analyzed and correlated with disease severity score in a prospectively collected database of yellow phosphorus-related hepatoxicity patients between 2018 and 2021. In a prospective cohort of these patients and age-matched healthy controls, peripheral blood monocyte phenotyping was performed. RESULTS: Reticuloendothelial activation markers were analyzed in 67 patients [Age: 23(12-64) years; median (range), men: 25, acute liver injury (ALI): 38, ALF: 29, model for end-stage liver disease (MELD) score: 28 (7-40)] of yellow phosphorus-induced hepatotoxicity. Serum ferritin (927; 10.3-34 807 ng/mL), sCD163 (4.59; 0.11-12.7 µg/mL), sCD25 (3050; 5.6-17 300 pg/mL) and plasma von Willebrand factor (423.5, 103-1106 IU/dL) were increased and showed significant correlation with liver disease severity assessed by MELD score (ρ = 0.29, ρ = 0.6, ρ = 0.56 and ρ = 0.46 respectively). Phenotyping and serum immune markers were performed in seven patients (M: 4; age: 27, 15-37 years; median, range; MELD score: 36, 21-40) and compared with eight healthy controls. Increase in classical monocytes and decrease in patrolling and intermediate monocyte subsets were observed in ALF cohort. HLA-DRlow CD163hi (immune exhaustion), CD64hi (immune complex-mediated response), and CCR2hi (liver homing) monocyte phenotype was noted. CONCLUSION: Altered peripheral monocyte phenotype with enhanced liver homing and macrophage activation, suggests important role of innate immune activation, and provides a potential therapeutic target, in yellow phosphorus-induced hepatotoxicity.