The world is worsely hit by the COVID-19 pandemic resulting in increased morbidity and mortality. Increased mortality has been observed in older adults with multiple comorbidities. Six-minute walk ...distance (6MWD) at admission can help us to guide the requirement of oxygen during hospital stay that can be used to determine which patient can be managed at home.
This study was a prospective observational study conducted on COVID-19 patients admitted at AIIMS, New Delhi, from October to December 2020. Patients aged more than 60 years were included in the study and underwent 6-min walk tests. Polypharmacy and multimorbidity were also assessed along with dyspnea which was measured on BORG scale.
< 0.05 was considered statistically significant. Statistical software STATA (version 14.2) was used for all the analyses.
The mean age of the study population was 68.76 (7.4). Oxygen saturation prior to the 6-MWT was normal and has significantly higher than the post test (
≤ 0.001). 6MWD was significantly correlated with pre values of oxygen saturation. 6MWD was observed more in patients who did not require oxygen during hospital stay. Self-reported dyspnea, pulse rate, oxygen saturation, and systolic blood pressure were significantly associated with the patients who had an oxygen requirement during the hospital stay.
Self-reported dyspnea after 6MWT was found to be associated with oxygen requirement during hospital stay. Patients who have covered more distance in 6-min walk test have less oxygen requirement during hospital stay hence can be managed at home. This will reduce the health-care burden and will help to tackle the outburst during the ongoing pandemic.
Regimens for palliation in patients with head and neck cancer recommended by the US National Comprehensive Cancer Network (NCCN) have low applicability (less than 1–3%) in low-income and ...middle-income countries (LMICs) because of their cost. In a previous phase 2 study, patients with head and neck cancer who received metronomic chemotherapy had better outcomes when compared with those who received intravenous cisplatin, which is commonly used as the standard of care in LMICs. We aimed to do a phase 3 study to substantiate these findings.
We did an open-label, parallel-group, non-inferiority, randomised, phase 3 trial at the Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India. We enrolled adult patients (aged 18–70 years) who planned to receive palliative systemic treatment for relapsed, recurrent, or newly diagnosed squamous cell carcinoma of the head and neck, and who had an Eastern Cooperative Oncology Group performance status score of 0–1 and measurable disease, as defined by the Response Evaluation Criteria In Solid Tumors. We randomly assigned (1:1) participants to receive either oral metronomic chemotherapy, consisting of 15 mg/m2 methotrexate once per week plus 200 mg celecoxib twice per day until disease progression or until the development of intolerable side-effects, or 75 mg/m2 intravenous cisplatin once every 3 weeks for six cycles. Randomisation was done by use of a computer-generated randomisation sequence, with a block size of four, and patients were stratified by primary tumour site and previous cancer-directed treatment. The primary endpoint was median overall survival. Assuming that 6-month overall survival in the intravenous cisplatin group would be 40%, a non-inferiority margin of 13% was defined. Both intention-to-treat and per-protocol analyses were done. All patients who completed at least one cycle of the assigned treatment were included in the safety analysis. This trial is registered with the Clinical Trials Registry-India, CTRI/2015/11/006388, and is completed.
Between May 16, 2016, and Jan 17, 2020, 422 patients were randomly assigned: 213 to the oral metronomic chemotherapy group and 209 to the intravenous cisplatin group. All 422 patients were included in the intention-to-treat analysis, and 418 patients (211 in the oral metronomic chemotherapy group and 207 in the intravenous cisplatin group) were included in the per-protocol analysis. At a median follow-up of 15·73 months, median overall survival in the intention-to-treat analysis population was 7·5 months (IQR 4·6–12·6) in the oral metronomic chemotherapy group compared with 6·1 months (3·2–9·6) in the intravenous cisplatin group (unadjusted HR for death 0·773 95% CI 0·615–0·97, p=0·026). In the per-protocol analysis population, median overall survival was 7·5 months (4·7–12·8) in the oral metronomic chemotherapy group and 6·1 months (3·4–9·6) in the intravenous cisplatin group (unadjusted HR for death 0·775 95% CI 0·616–0·974, p=0·029). Grade 3 or higher adverse events were observed in 37 (19%) of 196 patients in the oral metronomic chemotherapy group versus 61 (30%) of 202 patients in the intravenous cisplatin group (p=0·01).
Oral metronomic chemotherapy is non-inferior to intravenous cisplatin with respect to overall survival in head and neck cancer in the palliative setting, and is associated with fewer adverse events. It therefore represents a new alternative standard of care if current NCCN-approved options for palliative therapy are not feasible.
Tata Memorial Center Research Administration Council.
For the Hindi, Marathi, Gujarati, Kannada, Malayalam, Telugu, Oriya, Bengali, and Punjabi translations of the abstract see Supplementary Materials section.
Chikungunya fever is reported in India after 32 years. Immunoglobulin M antibodies and virus isolation confirmed the cause. Phylogenic analysis based on partial sequences of NS4 and E1 genes showed ...that all earlier isolates (1963-1973) were Asian genotype, whereas the current and Yawat (2000) isolates were African genotype.
Summary Background Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. ...We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India. Methods We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6–7 weeks were randomly assigned (2:1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6–7 weeks, 10 weeks, and 14 weeks. Infants' families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (≥11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry–India (CTRI/2010/091/000102) and ClinicalTrials.gov ( NCT01305109 ). Findings 4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53·6% (95% CI 35·0–66·9; p=0·0013) and 56·4% (36·6–70·1; p<0·0001) in the first year of life. The number of infants needed to be immunised to prevent one severe rotavirus gastroenteritis episode was 55 (95% CI 37–97). The incidence of severe rotavirus gastroenteritis per 100 person-years was 1·5 in the vaccine group and 3·2 in the placebo group, with an incidence rate ratio of 0·46 (95% CI 0·33–0·65). Prevalence of immediate, solicited, and serious adverse events was similar in both groups. One case of urticaria in the vaccine group and one each of acute gastroenteritis and suspected sepsis in the placebo group were regarded as related to the study product. We recorded six cases of intussusception in the vaccine group and two in the placebo group, all of which happened after the third dose. 25 (<1%) infants in the vaccine group and 17 (<1%) in the placebo group died; no death was regarded as related to the study product. Interpretation Monovalent human-bovine (116E) rotavirus vaccine is effective and well tolerated in Indian infants. Funding Department of Biotechnology and the Biotechnology Industry Research Assistance Council, Government of India; Bill & Melinda Gates Foundation to PATH, USA; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; and Bharat Biotech International, Hyderabad, India.
Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor-encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing ...these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. These killing effects of H3B-8800 are due to its direct interaction with the SF3b complex, as evidenced by loss of H3B-8800 activity in drug-resistant cells bearing mutations in genes encoding SF3b components. Although H3B-8800 modulates WT and mutant spliceosome activity, the preferential killing of spliceosome-mutant cells is due to retention of short, GC-rich introns, which are enriched for genes encoding spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.
Therapeutic interventions to treat multidrug-resistant (MDR) Pseudomonas aeruginosa infections are severely limited and often require the use of colistin as drug of last resort. The major challenges ...impeding the development of novel antipseudomonal agents are the lack of cell penetration and extensive efflux. We have discovered a tobramycin–moxifloxacin hybrid core structure which enhances outer membrane permeability and reduces efflux by dissipating the proton motive force of the cytoplasmic membrane in P. aeruginosa. The optimized hybrid protects Galleria mellonella larvae from the lethal effects of MDR P. aeruginosa. Attempts to select for resistance over a period of 25 days resulted in a 2-fold increase in the minimal inhibitory concentration (MIC) for the hybrid, while moxifloxacin or tobramycin resulted in a 16- and 512-fold increase in MIC. Although the hybrid possesses potent activity against MDR, P. aeruginosa isolates the activity that can be synergized when used in combination with other classes of antibiotics.
•Water and energy are highly entwined.•Direct energy use is relatively well accounted and studied than indirect or embodied energy use.•Energy use of water end use is comparatively overlooked.•The ...main assessment technique is Life Cycle Assessment (LCA).•Lack of a holistic and systemic framework to capture the water–energy dynamics in urban water system.
Water supply and wastewater services incur a large amount of energy and GHG emissions. It is therefore imperative to understand the link between water and energy as their availability and demand are closely interrelated. This paper presents a literature review and assessment of knowledge gaps related to water–energy–greenhouse gas (GHG) nexus studies in an urban context from an ‘energy for water’ perspective. The review comprehensively surveyed various studies undertaken in various regions of the world and focusing on individual or multiple subsystems of an urban water system. The paper also analyses the energy intensity of decentralized water systems and various water end-uses together with the major tools and models used. A major gap identified from this review is the lack of a holistic and systematic framework to capture the dynamics of multiple water–energy–GHG linkages in an integrated urban water system where centralized and decentralized water systems are combined to meet increased water demand. Other knowledge gaps identified are the absence of studies, peer reviewed papers, data and information on water–energy interactions while adopting a ‘fit for purpose water strategy’ for water supply. Finally, based on this review, we propose a water–energy nexus framework to investigate ‘fit-for-purpose’ water strategy.
Villin is a tissue-specific, actin-binding protein involved in the assembly and maintenance of microvilli in polarized epithelial cells. Conversely, villin is also linked with the loss of epithelial ...polarity and gain of the mesenchymal phenotype in migrating, invasive cells. In this study, we describe for the first time how villin can switch between these disparate functions to change tissue architecture by moonlighting in the nucleus. Our study reveals that the moonlighting function of villin in the nucleus may play an important role in tissue homeostasis and disease. Villin accumulates in the nucleus during wound repair, and altering the cellular microenvironment by inducing hypoxia increases the nuclear accumulation of villin. Nuclear villin is also associated with mouse models of tumorigenesis, and a systematic analysis of a large cohort of colorectal cancer specimens confirmed the nuclear distribution of villin in a subset of tumors. Our study demonstrates that nuclear villin regulates epithelial-mesenchymal transition (EMT). Altering the nuclear localization of villin affects the expression and activity of Slug, a key transcriptional regulator of EMT. In addition, we find that villin directly interacts with a transcriptional corepressor and ligand of the Slug promoter, ZBRK1. The outcome of this study underscores the role of nuclear villin and its binding partner ZBRK1 in the regulation of EMT and as potential new therapeutic targets to inhibit tumorigenesis.
Abstract Exenatide once-weekly is an extended release formulation of exenatide, a glucagon-like peptide (GLP)-1 receptor agonist, which can improve glycemic control, body weight, blood pressure, and ...lipid levels in patients with type 2 diabetes mellitus (T2DM). The EXenatide Study of Cardiovascular Event Lowering (EXSCEL) will compare the impact of adding exenatide once-weekly to usual care with usual care alone on major cardiovascular outcomes. EXSCEL is an academically-led, phase III/IV, double-blind, pragmatic placebo-controlled, global trial conducted in 35 countries aiming to enrol 14,000 patients with T2DM and a broad range of cardiovascular risk over approximately 5 years. Participants will be randomized (1:1) to receive exenatide once-weekly 2 mg or matching placebo by subcutaneous injections. The trial will continue until 1360 confirmed primary composite cardiovascular endpoints, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, have occurred. The primary efficacy hypothesis is that exenatide once-weekly is superior to usual care with respect to the primary composite cardiovascular endpoint. EXSCEL is powered to detect a 15% relative risk reduction in the exenatide once weekly group, with 85% power and a 2-sided 5% alpha. The primary safety hypothesis is that exenatide once-weekly is noninferior to usual care with respect to the primary cardiovascular composite endpoint. Noninferiority will be concluded if the upper limit of the confidence interval is <1.30. EXSCEL will assess whether exenatide once-weekly can reduce cardiovascular events in patients with T2DM with a broad range of cardiovascular risk. It will also provide long-term safety information on exenatide once-weekly in people with T2DM. ClinicalTrials.gov Identifier: NCT01144338
Adherens junctions (AJs) are a defining feature of all epithelial cells. They regulate epithelial tissue architecture and integrity, and their dysregulation is a key step in tumor metastasis. AJ ...remodeling is crucial for cancer progression, and it plays a key role in tumor cell survival, growth, and dissemination. Few studies have examined AJ remodeling in cancer cells consequently, it remains poorly understood and unleveraged in the treatment of metastatic carcinomas. Fascin1 is an actin‐bundling protein that is absent from the normal epithelium but its expression in colon cancer is linked to metastasis and increased mortality. Here, we provide the molecular mechanism of AJ remodeling in colon cancer cells and identify for the first time, fascin1's function in AJ remodeling. We show that in colon cancer cells fascin1 remodels junctional actin and actomyosin contractility which makes AJs less stable but more dynamic. By remodeling AJs fascin1 drives mechanoactivation of WNT/β‐catenin signaling and generates “collective plasticity” which influences the behavior of cells during cell migration. The impact of mechanical inputs on WNT/β‐catenin activation in cancer cells remains poorly understood. Our findings highlight the role of AJ remodeling and mechanosensitive WNT/β‐catenin signaling in the growth and dissemination of colorectal carcinomas.
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