We have developed a Diels Alder cycloaddition route toward 3-aroyl quinolines from enaminones and in situ generated aza-o-quinone methides. The reaction was found to be general with a range of ...substituted enaminones and aza-o-quinone methides, and we could validate the applicability of the methodology in gram scale. We also demonstrated a one-pot strategy toward 3-acyl quinolines starting from the corresponding aliphatic ketones. Finally, we utilized the 3-aroyl quinolines for synthesizing indeno1,2-bquinolinones via a Pd-catalyzed dual C–H activation approach.
Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear.
In this double-blind, placebo-controlled, ...randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort.
In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval CI, 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy.
In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.).
The survey given by the World Health Organization (WHO), says that most of the women who are pregnant die every day related to issues during pregnancy and childbirth such as still ...birth/pre-term/miscarriage etc., which are preventable at an earlier stage. The women need support and access to care by the skilled nurse at the appropriate time during the period of pregnancy. But due to the factors such as lack of awareness, delays, lack of information, poverty, few skilled health professionals, and less adequate health care services, pregnant women do not receive proper care during pregnancy. In poor and rural areas, the ratio of maternal mortality is high, as these areas are too remote to have an access to immediate medical attention. Timely monitoring of vital parameters during pregnancy can help in identification and diagnosis of such pregnancy related risks. The proposed remote pregnancy risk monitoring (RPRM) system is a non-invasive and real-time system which uses a combination of wireless sensors and the internet to measure the risk status of such pregnant women. The proposed remote pregnancy risk monitoring (RPRM) system provides healthcare services, which can be used by pregnant women in the comfort of the home,. It allows connecting these pregnant women to their healthcare providers thus allowing remote supervision and consultation in time of need. In addition, the proposed system also provides an effective data visualization mechanism for the health care provider to view and monitor the status of their patients remotely overcoming the barriers of distance.
Sound plays an important role in day to day life among all living organisms. It tells us about the environment, the characteristics of it, about people, place and move in a way where visuals cannot. ...In today’s world, various types of sound are included in the environment and there is a need to classify the useful sounds and noise in the environment. The various types of sounds produced in the urban areas are considered for classification. This classified sound can be especially useful to the Hearing impaired people who are in need to identify the types of sound and to react accordingly. Most of the hearing impaired is caused due to the inner ear or nerve damage. There are various reasons for the damage caused. It could be due to congenital defect, diseases, injury, expose to loud noise for a long period of time and age related wear and tear. Among the above stated reasons, only few cases can be resolved using the Hearing Aid. The rest have to live with the defect, as there hasn’t been any significant improvement in this field. Thus the proposed Sound Classification System for Hearing Impaired People (SCSHIP) focuses on aiding the hearing impaired people for their development in the society. The proposed Sound Classification System for Hearing Impaired People (SCSHIP) is designed that could work for all the sound impaired people regardless of the case they hold. To make sure that the Hearing Impaired people are not isolated with the rest of the world, the proposed Sound Classification System for Hearing Impaired People (SCSHIP) is designed with an integration of IoT and Machine Learning that captures the sound in Real-Time, processes it and then classifies it using a trained machine. The machine is trained using the Feature Extraction Techniques and the final result is given as a push notification to the user. Observations made from the results state that the proposed system can be used in a deaf school or in a place where there are a group of Hearing Impaired people so that they are also connected to the happenings of the environment.
Background:
Recognizing the need for good quality, scientific and reliable information for strengthening mental health policies and programmes, the National Mental Health Survey (NMHS) of India was ...implemented by National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, in the year 2015–2016.
Aim:
To estimate the prevalence, socio-demographic correlates and treatment gap of mental morbidity in a representative population of India.
Methods:
NMHS was conducted across 12 Indian states where trained field investigators completed 34,802 interviews using tablet-assisted personal interviews. Eligible study subjects (18+ years) in households were selected by a multi-stage, stratified, random cluster sampling technique. Mental morbidity was assessed using MINI 6. Three-tier data monitoring system was adopted for quality assurance. Weighted and specific prevalence estimates were derived (current and lifetime) for different mental disorders. Mental morbidity was defined as those disorders as per the International Statistical Classification of Diseases, Tenth Revision Diagnostic Criteria for Research (ICD-10 DCR). Multivariate logistic regression was conducted to examine risk for mental morbidity by different socio-demographic factors. Survey was approved by central and state-level institutional ethical committees.
Results:
The weighted lifetime prevalence of ‘any mental morbidity’ was estimated at 13.67% (95% confidence interval (CI) = 13.61, 13.73) and current prevalence was 10.56% (95% CI = 10.51, 10.61). Mental and behavioural problems due to psychoactive substance use (F10–F19; 22.44%), mood disorders (F30–F39; 5.61%) and neurotic and stress-related disorders (F40–F48; 3.70%) were the most commonly prevalent mental morbidity in India. The overall prevalence was estimated to be higher among males, middle-aged individuals, in urban-metros, among less educated and in households with lower income. Treatment gap for overall mental morbidity was 84.5%.
Conclusion:
NMHS is the largest reported survey of mental morbidity in India. Survey estimated that nearly 150 million individuals suffer from one or the other mental morbidity in India. This information is to be used for planning, delivery and evaluating mental health programming in the country.
The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans. In this study, empagliflozin substantially decreased lithium ...reabsorption in the proximal tubule (PT) (a marker of proximal tubular sodium reabsorption), a magnitude out of proportion to that expected with only inhibition of sodium-glucose cotransporter-2. This finding was not driven by an "osmotic diuretic" effect; however, several parameters changed in a manner consistent with inhibition of the sodium-hydrogen exchanger 3. The large changes in proximal tubular handling were acutely buffered by increased reabsorption in both the loop of Henle and the distal nephron, resulting in the observed modest acute natriuresis with these agents. After 14 days of empagliflozin, natriuresis waned due to increased reabsorption in the PT and/or loop of Henle. These findings confirm in humans that SGLT2i have complex and important effects on renal tubular solute handling.
The effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits.
This study used a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the PT, loop of Henle (loop), and distal nephron was assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the loop using bumetanide.
Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5%±10.6%, P = 0.001), with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in approximately 40 g of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the loop ( P < 0.001) and distal nephron ( P < 0.001). Inhibition of sodium-glucose cotransporter-2 did not attenuate over 14 days of empagliflozin ( P = 0.14). However, there were significant reductions in FELi ( P = 0.009), fractional excretion of sodium ( P = 0.004), and absolute fractional distal sodium reabsorption ( P = 0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the loop and/or PT.
Empagliflozin caused substantial redistribution of intrarenal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile.
ClinicalTrials.gov ( NCT03027960 ).
OBJECTIVE:--To estimate the absolute and relative risk of cardiovascular disease (CVD) in patients with type 1 diabetes in the U.K. RESEARCH DESIGN AND METHODS--Subjects with type 1 diabetes (n = ...7,479) and five age- and sex-matched subjects without diabetes (n = 38,116) and free of CVD at baseline were selected from the General Practice Research Database (GPRD), a large primary care database representative of the U.K. population. Incident major CVD events, comprising myocardial infarction, acute coronary heart disease death, coronary revascularizations, or stroke, were captured for the period 1992-1999. RESULTS:--The hazard ratio (HR) for major CVD was 3.6 (95% CI 2.9-4.5) in type 1 diabetic men compared with those without diabetes and 7.7 (5.5-10.7) in women. Increased HRs were found for acute coronary events (3.0 and 7.6 in type 1 diabetic men and women, respectively, versus nondiabetic subjects), coronary revascularizations (5.0 in men, 16.8 in women), and for stroke (3.7 in men, 4.8 in women). Type 1 diabetic men aged 45-55 years had an absolute CVD risk similar to that of men in the general population 10-15 years older, with an even greater difference in women. CONCLUSIONS:--Despite advances in care, these data show that absolute and relative risks of CVD remain extremely high in patients with type 1 diabetes. Women with type 1 diabetes continue to experience greater relative risks of CVD than men compared with those without diabetes.
Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical ...unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer.
The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer.
This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab.
This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab.
Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy.
The primary endpoint is PFS in the intention-to-treat population.
Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events.
Expected complete accrual in 2024 with presentation of primary endpoint results in 2025.
NCT05281471.
Inflammation plays a major role in coronary artery disease (CAD). We investigated the polymorphisms in the interleukin 6 (IL6) gene and their effect on the expression of acute-phase proteins in ...premature CAD in Asian Indian families. One hundred and ninety affected sibling pairs (ASPs) were genotyped for three tag single nucleotide polymorphisms (SNPs) in the IL6 gene for linkage analysis. We observed suggestive logarithm of odds (LOD) score for one SNP (rs2066992) in a subset of 62 ASPs with the age at onset less than 45 years (LOD score=1.114, p=0.011 in linkage analysis; pi=0.55, p=0.008 in identity by descent; LOD score=1.06, p=0.014 in quantitative trait locus for plasma levels of high sensitivity C-reactive protein, hsCRP). This was followed by sequencing of the promoter region and haplotype analysis in 46 probands and 40 controls. Five out of the eight previously reported promoter SNPs were found to be polymorphic (rs1800797, rs1800796, rs7802307, rs7802308, rs1800795). Two novel sequence variants were also found. One promoter haplotype (GGAAG) was detected with an odds ratio (OR) of 3.676 (p=0.0017, 95% confidence interval CI: 1.68-8.045) and population attributable risk of 21.1% (95%CI: 9.2%-31.5%). The plasma levels of both hsCRP and fibrinogen exhibited significant association with these promoter SNP genotypes (p<0.001). In conclusion, IL6 gene polymorphisms appear to be important genetic factors in premature CAD, and in the regulation of key atherogenic markers in Asian Indian families.
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