Citric acid cross-linked pomegranate peel extract-loaded pH-responsive ß-cyclodextrin/carboxymethyl tapioca starch hydrogel film for diabetic wound healing.

Pomegranate peel extract (PPE) hydrogel films filled with citric acid (CA) and ß-cyclodextrin-carboxymethyl tapioca starch (CMS) were designed mainly to prevent wound infections and speed up the healing process. FTIR and NMR studies corroborated the carboxymethylation of neat tapioca starch (NS). CMS exhibited superior swelling behavior than NS. The amount of CA and ß-CD controlled the physicochemical parameters of developed PPE/CA/ß-CD/CMS films. Optimized film (OF) exhibited acceptable swellability, wound fluid absorptivity, water vapor transmission rate, water contact angle, and mechanical properties. Biodegradable, biocompatible, and antibacterial films exhibited pH dependence in the release of ellagic acid for up to 24 h. In mice model, PPE/CA/ß-CD/CMS hydrogel film treatment showed promising wound healing effects, including increased collagen deposition, reduced inflammation, activation of the Wingless-related integration site (wnt) pathway leading to cell division, proliferation, and migration to the wound site. The expression of the WNT3A gene did not show any significant differences among all the studied groups. Developed PPE-loaded CA/ß-CD/CMS film promoted wound healing by epithelialization, granulation tissue thickness, collagen deposition, and angiogenesis, hence could be recommended as a biodegradable and antibacterial hydrogel platform to improve the cell proliferation during the healing of diabetic wounds.

Outcome of early emergency intubation and early emergency dialysis in deliberate self-harm with formic acid in a tertiary care center in South India: A retrospective cohort study.

OBJECTIVE: The objective is to evaluate the outcome of early emergency intubation and early dialysis in formic acid (FA) poisoning and to determine the clinical features associated with its mortality. METHODS: It is a retrospective cohort study of 78 patients who presented to the emergency medicine department from July 2008 to June 2015 with alleged history and clinical features of FA poisoning. The outcome of early intubation and early dialysis was studied in terms of 7-day and 30-day mortality. The outcome was compared in severe and not severe groups separately. Severity was graded according to Med-Tu chart used for corrosive poisoning. RESULTS: In the severe group (n = 53), early dialysis was done in 15 patients. There was 53% (n = 8) 30-day mortality. In the group where early dialysis was not done there was a significant increase in mortality 92.1% (n = 35). This was statistically significant with a P = 0.003. In a similar fashion 7-day mortality was analyzed in the severe group where mortality was higher when early dialysis was not done. In not severe group early dialysis has minimally decreased the mortality. Early intubation in severe group did not demonstrate any mortality benefit. Patients who were intubated early and not intubated early had equally high mortality. In not severe group, intubation could not make any significant difference in mortality. CONCLUSION: In this retrospective study, we observed that early dialysis in the severe group has a better outcome in terms of 7-day and 30-day mortality.

Types and Mechanisms of Efflux Pump Systems and the Potential of Efflux Pump Inhibitors in the Restoration of Antimicrobial Susceptibility, with a Special Reference to Acinetobacter baumannii.

Bacteria express a plethora of efflux pumps that can transport structurally varied molecules, including antimicrobial agents and antibiotics, out of cells. Thus, efflux pump systems participate in lowering intracellular concentrations of antibiotics, which allows phenotypic multidrug-resistant (MDR) bacteria to survive effectively amid higher concentrations of antibiotics. Acinetobacter baumannii is one of the classic examples of pathogens that can carry multiple efflux pump systems, which allows these bacteria to be MDR-to-pan-drug resistant and is now considered a public health threat. Therefore, efflux pumps in A. baumannii have gained major attention worldwide, and there has been increased interest in studying their mechanism of action, substrates, and potential efflux pump inhibitors (EPIs). Efflux pump inhibitors are molecules that can inhibit efflux pumps, rendering pathogens susceptible to antimicrobial agents, and are thus considered potential therapeutic agents for use in conjunction with antibiotics. This review focuses on the types of various efflux pumps detected in A. baumannii, their molecular mechanisms of action, the substrates they transport, and the challenges in developing EPIs that can be clinically useful in reference to A. baumannii.

Effect of Different Molecular Weight Hyaluronic Acids on Skim Milk Functional Properties.

Hyaluronic acid (HA), a naturally occurring polysaccharide with recognized health benefits, has gained approval for use in the food industry as a food additive, ingredient, and health supplement in numerous countries. HA can increase viscosity in solutions and is available commercially in various molecular weights (MW) depending on end applications. Nevertheless, no research has explored the impact of different MW HAs on functionality, rheological properties, and texture-building benefits in the dairy product matrix wherein they are incorporated. Therefore, the objective of this study was to evaluate how varying MWs of HA-specifically 8 kDa, 320 kDa, 980 kDa, and 2550 kDa at 0.25% (w/w) concentration-impact rheological characteristics, functional attributes, heat stability, protein stability, protein structure, and protein fractions within skim milk. The addition of HA led to an increase in the apparent viscosity of all samples. A higher G″ value over G' values for all HA samples was observed in frequency sweep, indicating the absence of interparticle interactions between HA particles. Protein stability and heat stability were significantly lower for 980 kDa and 2550 kDa HA as compared to the control and 8 kDa HA samples. As the MW increased, WHC, emulsion properties, and foaming stability notably increased. However, reversed results were found in the case of foaming activity. Moreover, no significant changes were observed in the percent area of individual protein fractions and the hydrodynamic diameter of protein particles. This study would help to understand the effect of HA when incorporated in dairy products for water binding or enhancement in viscosity-based applications.

Averting catastrophic tuberculosis costs in an Indian state: integration of Ayushman Bharat Arogya Karnataka with National Tuberculosis Elimination Program.

The WHO's "End TB" initiative aims to reduce catastrophic expenses, incidence, and mortality by 90%, 80%, and 0%, respectively by 2030 and Government of India has committed to reaching these goals by 2025. Despite tremendous progress, tuberculosis (TB) remains one of the main public health issues. To limit TB transmission and expedite reduction in incidence, further measures are needed. These milestones and objectives remain aspirational until we achieve "Universal access" to high-quality TB diagnosis and treatment. The goals of the study include outlining the process of 'Ayushman Bharat-Pradhan Mantri Jan Arogya Yojana-Arogya Karnataka' (AB-PMJAY-ArK) integration with the National TB Elimination Program (NTEP) in Karnataka, the types of TB patients who used AB-PMJAY-ArK services, and calculating the cost per TB patient at primary, secondary, and tertiary healthcare facilities, both public and private, stratified by type of service. Increased coverage, elimination of treatment delays, early and free treatment, and prevention of missing patients are benefits of integrating NTEP with Ayushman Bharat-PMJAY.

Do alternative tobacco products induce less adverse respiratory risk than cigarettes?

RATIONALE: Due to the relatively short existence of alternative tobacco products, gaps exist in our current understanding of their long-term respiratory health effects. We therefore undertook the first-ever side-by-side comparison of the impact of chronic inhalation of aerosols emitted from electronic cigarettes (EC) and heated tobacco products (HTP), and combustible cigarettes (CC) smoke. OBJECTIVES: To evaluate the potential differential effects of alternative tobacco products on lung inflammatory responses and efficacy of vaccination in comparison to CC. METHODS: Mice were exposed to emissions from EC, HTP, CC, or air for 8 weeks. BAL and lung tissue were analyzed for markers of inflammation, lung damage, and oxidative stress. Another group was exposed for 12 weeks and vaccinated and challenged with a bacterial respiratory infection. Antibody titers in BAL and sera and pulmonary bacterial clearance were assessed. MAIN RESULTS: EC- and HTP-aerosols significantly augmented lung immune cell infiltrates equivalent to that achieved following CC-exposure. HTP and CC significantly increased neutrophil numbers compared to EC. All products augmented numbers of B cells, T cells, and pro-inflammatory IL17A+ T cells in the lungs. Decreased lung antioxidant activity and lung epithelial and endothelial damage was induced by all products. EC and HTP differentially augmented inflammatory cytokines/chemokines in the BAL. Generation of immunity following vaccination was impaired by EC and HTP but to a lesser extent than CC, with a CC > HTP > EC hierarchy of suppression of pulmonary bacterial clearance. CONCLUSIONS: HTP and EC-aerosols induced a proinflammatory pulmonary microenvironment, lung damage, and suppressed efficacy of vaccination.

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Microbial degradation of organochlorine pesticide: 2,4-Dichlorophenoxyacetic acid by axenic and mixed consortium.

The presence of 2,4-dichlorophenoxyacetic acid (2,4-D), an organochlorine herbicide, in the environment has raised public concern as it poses hazard to both humans and the ecosystem. Three potential strains having the capability to degrade 2,4-D were isolated from on site agricultural soil and identified as Arthrobacter sp. SVMIICT25, Sphingomonas sp. SVMIICT11 and Stenotrophomonas sp. SVMIICT13. Over 12 days of incubation, 81-90% of 100 mg/L of 2,4-D degradation was observed at 2% inoculum. A shorter lag phase with 80% of degradation efficiency was observed within 5 days when the inoculum size was increased to 10%. Six microbial consortia were prepared by combining the isolates along with in-house strains, Bacillus sp. and Pseudomonas sp. Consortia R3 (Arthrobacter sp. + Sphingomonas sp.), operated with 10% of inoculum, showed 85-90% degradation within 4 days and 98-100% in 9 days. Further, targeted exo-metabolite analysis confirmed the presence and catabolism of intermediate 2,4-dichlorophenol and 4-chlorophenol compounds.

Hydrothermal processing of agar waste to levulinic acid and fermentation of hydrolysate to bioethanol.

Increasing global energy consumption and depleting fossil-fuel reserves prompted the search for green alternatives. This study focuses on conversion of waste agar using different acids/alkalis (0.5% and 1%) as catalysts under varied temperature and time towards galactose (Gal), 5-hydroxymethylfurfural (HMF) and levulinic acid (LA) production in sequential reactions. The optimized process for agar depolymerisation was achieved using 1% acid (H2SO4/HCl) catalysed conditions with a maximum of 11 g/L Gal yield (121 °C; 15 min). Increase in temperature (150 °C) and time (180 min) with 1% HCl/H2SO4 catalyst resulted in improved LA production along with Gal and HMF. The hydrolysis process was optimised for the selective production of LA (10 g/L at 175 °C; 180 min). Further, galactose-rich hydrolysates were assessed for bioethanol production using Saccharomyces cerevisiae that resulted in 3 g/L ethanol. Thus, the study comprehensively demonstrates waste agar utilization to yield biochemicals/fuels in a circular bio-based economy approach.

Light-dependent biohydrogen production: Progress and perspectives.

The fourth industrial revolution anticipates energy to be sustainable, renewable and green. Hydrogen (H2) is one of the green forms of energy and is deemed a possible solution to climate change. Light-dependent H2 production is a promising method derived from nature's most copious resources: solar energy, water and biomass. Reduced environmental impacts, absorption of carbon dioxide, relative efficiency, and cost economics made it an eye-catching approach. However, low light conversion efficiency, limited ability to utilize complex carbohydrates, and the O2 sensitivity of enzymes result in low yield. Isolation of efficient H2 producers, development of microbial consortia having a synergistic impact, genetically improved strains, regulating bidirectional hydrogenase activity, physiological parameters, immobilization, novel photobioreactors, and additive strategies are summarized for their possibilities to augment the processes of bio-photolysis and photo-fermentation. The challenges and future perspectives have been addressed to explore a sustainable way forward in a bio-refinery approach.

Effect of Hyaluronic Acid and Kappa-Carrageenan on Milk Properties: Rheology, Protein Stability, Foaming, Water-Holding, and Emulsification Properties.

Hyaluronic acid (HA) is now widely known for its ability to bind water and impart texture. The combined effects of HA and kappa-carrageenan (KC) have not yet been investigated, though. In this study, we looked at the synergistic effects of HA and KC (concentrations of 0.1 and 0.25%, and ratios of 85:15, 70:30, and 50:50 for each concentration) on the rheological properties, heat stability, protein phase separation, water-holding capacity, emulsification properties, and foaming properties of skim milk. When HA and KC were combined in various ratios with a skim milk sample, this resulted in lesser protein phase separation and a higher water-holding capacity than when HA and KC were utilized separately. Similarly, for the sample with a 0.1% concentration, the combination of HA + KC blends demonstrated a synergistic impact with greater emulsifying activity and stability. The samples with a concentration of 0.25% did not exhibit this synergistic effect, and the emulsifying activity and stability were mostly due to the HA's higher emulsifying activity and stability at 0.25% concentration. Similarly, for rheological (apparent viscosity, consistency coefficient K, and flow behavior index n) and foaming properties, the synergistic effect of the HA + KC blend was not readily apparent; rather, these values were mostly due to an increase in the amount of KC in the HA + KC blend ratios. When HC-control and KC-control samples were compared to various HA + KC mix ratios, there was no discernible difference in the heat stability. With the added benefits of protein stability (reduced phase separation), increased water-holding capacity, improved emulsification capabilities, and foaming abilities, the combination of HA + KC would be highly helpful in many texture-modifying applications.

Not all vaping is the same: differential pulmonary effects of vaping cannabidiol versus nicotine.

RATIONALE: Vaping has become a popular method of inhaling various psychoactive substances. While evaluating respiratory effects of vaping have primarily focused on nicotine-containing products, cannabidiol (CBD)-vaping is increasingly becoming popular. It currently remains unknown whether the health effects of vaping nicotine and cannabinoids are similar. OBJECTIVES: This study compares side by side the pulmonary effects of acute inhalation of vaporised CBD versus nicotine. METHODS: In vivo inhalation study in mice and in vitro cytotoxicity experiments with human cells were performed to assess the pulmonary damage-inducing effects of CBD or nicotine aerosols emitted from vaping devices. MEASUREMENTS AND MAIN RESULTS: Pulmonary inflammation in mice was scored by histology, flow cytometry, and quantifying levels of proinflammatory cytokines and chemokines. Lung damage was assessed by histology, measurement of myeloperoxidase activity and neutrophil elastase levels in the bronchoalveolar lavage fluid and lung tissue. Lung epithelial/endothelial integrity was assessed by quantifying BAL protein levels, albumin leak and pulmonary FITC-dextran leak. Oxidative stress was determined by measuring the antioxidant potential in the BAL and lungs. The cytotoxic effects of CBD and nicotine aerosols on human neutrophils and human small airway epithelial cells were evaluated using in vitro air-liquid interface system. Inhalation of CBD aerosol resulted in greater inflammatory changes, more severe lung damage and higher oxidative stress compared with nicotine. CBD aerosol also showed higher toxicity to human cells compared with nicotine. CONCLUSIONS: Vaping of CBD induces a potent inflammatory response and leads to more pathological changes associated with lung injury than vaping of nicotine.

Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma.

PURPOSE: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Exploration of Cassia fistula L. seed mucilage into floating drug delivery system.

The aim of the present study was to explore Cassia fistula L. seed mucilage as a natural polymer in controlled release floating drug delivery system. First, seed mucilage was extracted and evaluated for phytochemical screening, solubility studies, swelling index, viscosity and surface tension. Then, Atenolol floating systems were prepared with and without the C. fistula L. seed mucilage by direct compression method. Phytochemical screening resulted from the presence of secondary metabolite carbohydrates, glycosides, flavonoids and phenolic compounds in good amounts. Results of hardness, friability, drug content and swelling index were satisfactory. The floating behaviour can increase the gastric residence time and eventually improve the bioavailability of the drug as evidence from in vitro buoyancy and dissolution studies. Interestingly, developed floating system showed remarkable increase in dissolution. Conclusively, the results suggest that developed Atenolol floating system with C. fistula L. seed mucilage demonstrate interesting attributes to be explored for potential pharmaceutical application.

Routine Application of Lung Ultrasonography in Respiratory Care: Knowledge, Perceptions, and Barriers to Instigate.

Background: Lung Ultrasound (LUS) had proved to be beneficial in detecting respiratory disorders at the bedside. Understanding the important role of Respiratory Therapists (RTs) in the critical care, we aimed to assess their knowledge, perceived relevance of LUS to clinical practice, current skill gaps, and barriers to practice. Methods: A cross-sectional, nationwide survey conducted among the RTs working in the Kingdom of Saudi Arabia. The validated questionnaire included 4 sections; the demographics, knowledge and perceptions, applicability and self-reported proficiency, and barriers to the use of LUS by RTs. Results: A total of 256 RTs across different regions of Saudi Arabia participated in this survey. 71.9% of them were males, and 46.1% of the participants were having <5 years of working experience. Only (18.1%) of the participants used LUS in their clinical practice, and (43%) of them had never received any training. 66% of the participants perceived LUS as an effective tool in the RT practice and immensely valuable in their daily practice (70%). A large proportion of RTs perceived LUS to be ineffective in calculating the lung score (50.4%), assessing the diaphragm (40.2%), and detecting pulmonary edema (38.3%). Calculating lung score has a lower mean score of 2.55 on both skills, and identifying its applicability to clinical practice with a mean score of 2.71 than other indications. Lack of training and curriculum (154/256; 60.2%) remains the top barrier that prevented RTs from using LUS in their clinical practice. Conclusion: While many RTs in Saudi Arabia perceived LUS as an effective tool in the RT practice, considerable competence gap exist, indicating the need for LUS training. There is a need for incorporating LUS into the curriculum of RT schools and promoting competency-based training for the current RT workforce to help improve patient care.

Anesthetic Challenges and Perioperative Factors Affecting Delayed Graft Function in Robotic-Assisted Kidney Transplant: A Review of a Single-Center Experience of 100 Cases.

Background and objective The advent of robot-assisted kidney transplant (RAKT) has ushered in a new set of challenges. In this single-center retrospective observational study, we aimed to highlight the anesthetic challenges and analyze perioperative parameters to identify the risk factors for delayed graft function (DGF) in RAKT. Methods A descriptive analysis of perioperative factors of the first 100 cases of RAKT at our center was performed. Data were retrieved from the hospital's electronic medical records (EMR) of donors and adult patients who underwent RAKT between July 2015 and December 2020. The data analyzed included demographics, preoperative optimization, intraoperative and postoperative management, and complications. DGF was defined as a requirement of dialysis within one week of transplant. The Fisher's exact test, independent sample t-test, and the Mann-Whitney test were used to analyze data. Results Among a total of 193 renal transplants performed during the study period, 100 patients underwent RAKT, which included 27 females and 73 males. Of these, 91 were live while the remaining involved deceased-donor transplants. Pneumoperitoneum and steep Trendelenburg position required various "anesthetic maneuvers" to maintain hemodynamics and respiratory parameters. Optimal fluid management, with frusemide and mannitol, ensured good urine output (UOP) (93%). Post-reperfusion, the release of pneumoperitoneum, maintenance of adequate perfusion pressures, immunosuppression, and regional hypothermia helped in ensuring adequate graft function (93%). The incidence of DGF in our series was 7% and the mortality rate was 3%. Recipient age (p=0.045), dyslipidemia (p=0.021), and diabetes mellitus (p=0.023) were identified as significant risk factors for DGF. Conclusion Advanced recipient age, diabetes, and dyslipidemia were factors significantly associated with DGF in RAKT in our series of 100 cases. However, the duration of the steep Trendelenburg position, docking of robot/pneumoperitoneum (console time), fluid management, warm and cold ischemia times, rewarming time, and type of graft did not influence DGF. Awareness of the systemic involvement in RAKT, proper preoperative optimization, and knowledge of potential problems are essential for the efficient anesthetic management of RAKT.

Pazopanib-laden lipid based nanovesicular delivery with augmented oral bioavailability and therapeutic efficacy against non-small cell lung cancer.

The present investigation deals with the pazopanib-loaded solid lipid nanoparticles (Pazo-SLNs) and their in-vitro and in-vivo assessments. Quality by design approach employing the Plackett-Burman and central composite design was used to identify the formulation variables, including drug/lipid ratio, organic/aqueous phase ratio, and surfactant concentration with a significant impact on the process and to fabricate a safe and efficacious novel oral dosage form of pazopanib. Particle size, drug loading, entrapment efficiency, and zeta potential of optimal Pazo-SLNs formulation were 210.03 ± 7.68 nm, 13.35 ± 0.95 %, 79.05 ± 2.55 % and -18.29 ± 1.89 mV (n = 3) respectively. FTIR study affirmed the absence of incompatibilities between the drug and the excipients. DSC and XRD measurements substantiated the amorphous form of pazopanib entrapped within the SLNs. Pazo-SLNs demonstrated high cellular uptake, showed substantial cytotoxicity to A-549 lung cancer cells due to apoptotic mode and inhibited tyrosine kinase in-vitro. Pazo-SLNs were found to be stable for three months. SLNs greatly ameliorated the pharmacokinetic behavior and bioavailability (9.5 folds) of pazopanib with a sustained-release pattern (92.67 ± 4.68 % within 24 h). A biodistribution study corroborated the lung targeting potential of Pazo-SLNs. Thus, SLNs could potentially boost the oral route efficacy of pazopanib against cancer cells.

Screening for Severe Illness at Diagnosis Has the Potential to Prevent Early TB Deaths: Programmatic Experience From Karnataka, India.

Due to the coronavirus disease (COVID-19) pandemic and its associated response, TB deaths increased for the first time in a decade. In any potentially fatal illness, an assessment of severity is essential. This is not systematically done for adults with TB, mostly due to a lack of policy and/or limited availability of diagnostic and clinical capacity. We developed a screening tool using simple and easily measurable indicators that can be used by paramedical TB program staff to quickly identify people with severe illness. During October-November 2020 in Karnataka, India, the paramedical program staff from 16 districts screened people with TB (aged ≥15 years) notified by public facilities for "high risk of severe illness," which was defined as the presence of any of the following indicators: (1) body mass index (BMI) ≤14.0 kg/m2; (2) BMI ≤16.0 kg/m2 with bilateral leg swelling; (3) respiratory rate >24/minute; (4) oxygen saturation <94%; (5) inability to stand without support. In this cohort study, we determined the incidence of program-recorded early deaths (within 2 months) and its association with high risk of severe illness. Of 3,010 people with TB, 1,529 (50.8%) were screened at diagnosis/notification, of whom 537 (35.1%) had a high risk of severe illness. There were 195 (6.5%, 95% CI=5.7, 7.4) early deaths: 59 (30.2%) within a week and 100 (51.3%) within 2 weeks of treatment initiation. The incidence of early deaths was significantly higher among those with high risk of severe illness (8.9%) at diagnosis compared to those without (3.8%) [adjusted relative risk: 2.36 (95% confidence interval=1.57, 3.55)]. To conclude, early deaths were especially high during the first 2 weeks and strongly associated with a high risk of severe illness at diagnosis/notification. Screening for severe illness should be explored as a potential strategy to end TB deaths.

Immunoscore Is Prognostic in Low-Risk and High-Risk Stage III Colon Carcinomas Treated With Adjuvant Infusional Fluorouracil, Leucovorin, and Oxaliplatin in a Phase III Trial.

PURPOSE: The recommended duration of adjuvant fluoropyrimidine and oxaliplatin chemotherapy for patients with stage III colon cancer is based on tumor classification into clinically low-risk (T1-3 N1) and high-risk (T4 or N2) groups. We determined whether Immunoscore can enhance prognostication within these risk groups. MATERIALS AND METHODS: Patients with stage III colon carcinomas (N = 600) were randomly selected from the infusional fluorouracil, leucovorin, and oxaliplatin arm of adjuvant trial NCCTG N0147 (Alliance for Clinical Trials in Oncology). Tumors were evaluated for Immunoscore that quantifies CD3+ and CD8+ T-cell densities in the tumor center and invasive margin by digital image analysis. Disease-free survival (DFS) by Immunoscore was analyzed using a multivariable Cox regression model in each risk group with adjustment for covariates including KRAS, BRAFV600E, and mismatch repair status. RESULTS: Of 559 cancers with Immunoscore data, 299 (53.5%) were classified as clinically low-risk (T1-3 N1) and 260 (46.5%) as clinically high-risk (T4 and/or N2). Among patients with low-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors had significantly worse 5-year DFS rates (77.5% v 91.8%; hazard ratio, 1.70; 95% CI, 1.03 to 2.79; P = .037). Among patients with high-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors also had significantly worse DFS (55.3% v 70.3%; hazard ratio, 1.65; 95% CI, 1.11 to 2.47; P = .013). Tumors that were low-risk/Immunoscore-Low had similar outcomes as did tumors that were high-risk/Immunoscore-High (P = .174). Prognostication was significantly improved in multivariable models where Immunoscore was added to clinical risk parameters and limited biomarkers (likelihood ratio test P = .0003). CONCLUSION: Immunoscore can refine patient prognosis beyond clinical risk group classification, suggesting its potential utility for adjuvant decision making.