In a phase 2, randomized trial comparing placebo with each of five doses of a selective tyrosine kinase 2 inhibitor, the four highest doses resulted in greater clearing of psoriasis than did placebo. ...There was one case of melanoma in a patient receiving the active drug.
Wheat blast, caused by the fungus Magnaporthe oryzae pathotype Triticum (MoT), constitutes one of the major obstacles to the expansion of wheat production in Bangladesh. In the absence of resistant ...variety, fungicide control is the first-hand effort. Determining an effective and economic fungicide spray schedule in controlling blast disease of wheat was aimed. Ten fungicides were tested during two consecutive cropping seasons of 2018-2019 to 2019-2020. The wheat plants of blast susceptible cultivar BARI Gom 26 were inoculated with spores (107 spores ml-1) of MoT at pre-heading stage of wheat (52 days age). Fungicides were applied both before inoculation and after the appearance of blast symptoms in cocktail for three times starting from booting of wheat at 7 days interval. Plants received the combination of Filia (Tricyclazole 40% + Propiconazole 12.5%) and Seltima (Pyraclostrobin 10%) had significantly lower blast incidence and severity (1.23% and 3.33%) against untreated plants. Cocktail of Nativo and Trooper (Tricyclazole 75 wp) proved 2nd best curative measure. Application of Nativo (Tebuconazole 50% + Trifloxystrobin 25%) alone ranked third in its efficacy. The fungicide spray schedule covered booting, pre-heading and heading stages of wheat. The results indicate a mixture of Tebuconazole + Tricyclazole + Pyraclostrobin is more effective (97% blast reduction) and economic (BCR 1.45) than a single compound application in reducing incidence and severity of wheat blast.
In this trial, which was stratified by time since menopause (<6 or ≥10 years), 17β-estradiol treatment was associated with less progression of atherosclerosis than was placebo when therapy was ...initiated early after menopause but not when initiated late after menopause.
After dozens of observational studies consistently showed inverse associations between postmenopausal hormone therapy and the risk of coronary heart disease and death from any cause, it was difficult to understand the null or adverse effects of the therapy on coronary heart disease that were reported from randomized, controlled trials. One explanation is that in observational studies, women were younger (approximately 50 years of age) and closer to menopause (typically within 2 years) when they initiated hormone therapy than were the women included in randomized trials (mean age in the 60s, typically >10 years past menopause). This so-called timing hypothesis posits . . .
Summary Background Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and ...sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. Methods In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov , number NCT00326898. Findings Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 44% of 438 patients on sunitinib, 199 45% of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6–8·2) for sunitinib (hazard ratio HR 1·02, 97·5% CI 0·85–1·23, p=0·8038), 6·1 years (IQR 1·7–not estimable NE) for sorafenib (HR 0·97, 97·5% CI 0·80–1·17, p=0·7184), and 6·6 years (IQR 1·5–NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 17% patients on sunitinib and 102 16% patients on sorafenib), hand-foot syndrome (94 15% patients on sunitinib and 208 33% patients on sorafenib), rash (15 2% patients on sunitinib and 95 15% patients on sorafenib), and fatigue (110 17% patients on sunitinib and 44 7% patients on sorafenib). There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. Interpretation Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. Funding US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.
This research aims to develop a Flutter-based mobile application that provides users with information regarding class schedules and assignments. The application includes a reminder feature that sends ...notifications about lectures and assignments through WhatsApp and in-app notifications. The development methodology employed is the waterfall model, while testing utilizes black-box testing and Firebase Test Lab. The test results demonstrate the successful development of the application. Additionally, this application facilitates efficient and easy access to class schedules and assignments. It is expected to enhance users' academic performance and be applicable across various educational institutions. Overall, the development of this application offers users the advantage of effectively and efficiently managing study time and completing tasks, thereby contributing to the improvement of educational quality within institutions.
Night shift work has been classified by the International Agency for Research on Cancer as a probable carcinogen in humans. Several studies have assessed night shift work in relation to breast cancer ...risk, with inconsistent results.
In the prospective Sister Study cohort, current and past occupational history was collected for 48,451 participants. We used Cox proportional hazards models to estimate adjusted HRs and 95% confidence intervals (CI) for the association between baseline work schedule characteristics and incident breast cancer.
During follow-up (mean = 9.1 years), 3,191 incident cases were diagnosed. We observed little to no increase in risk associated with work schedule characteristics (ever working rotating shifts: HR = 1.04, 95% CI, 0.91-1.20; ever working rotating night shifts: HR = 1.08, 95% CI, 0.92-1.27; ever working at night: HR = 1.01, 95% CI, 0.94-1.10; and ever working irregular hours: HR = 0.98, 95% CI, 0.91-1.06). Although short-term night work (>0 to 5 years vs. never: HR = 1.12; 95% CI, 1.00-1.26) and rotating shift work at night (>0 to 5 years vs. never: HR = 1.30; 95% CI, 1.05-1.61) were associated with increased breast cancer risk, working nights for more than 5 years was not associated with risk.
Overall, we observed little evidence that rotating shift work or work at night was associated with a higher risk of breast cancer, except possibly among those who participated in such work for short durations of time.
This study indicates that if night shift work is associated with breast cancer, the increase in risk is small.
A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare ...Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimer's disease with a behavioural-predominant presentation (behavioural Alzheimer's disease) and a neuropathological diagnosis of high-likelihood Alzheimer's disease (n = 17) and/or biomarker evidence of Alzheimer's disease pathology (n = 44). In addition, we included 29 patients with autopsy/biomarker-defined Alzheimer's disease with a dysexecutive-predominant syndrome (dysexecutive Alzheimer's disease). We performed structured chart reviews to ascertain clinical features. First symptoms were more often cognitive (behavioural Alzheimer's disease: 53%; dysexecutive Alzheimer's disease: 83%) than behavioural (behavioural Alzheimer's disease: 25%; dysexecutive Alzheimer's disease: 3%). Apathy was the most common behavioural feature, while hyperorality and perseverative/compulsive behaviours were less prevalent. Fifty-two per cent of patients with behavioural Alzheimer's disease met diagnostic criteria for possible behavioural-variant frontotemporal dementia. Overlap between behavioural and dysexecutive Alzheimer's disease was modest (9/75 patients). Sixty per cent of patients with behavioural Alzheimer's disease and 40% of those with the dysexecutive syndrome carried at least one APOE ε4 allele. We also compared neuropsychological test performance and brain atrophy (applying voxel-based morphometry) with matched autopsy/biomarker-defined typical (amnestic-predominant) Alzheimer's disease (typical Alzheimer's disease, n = 58), autopsy-confirmed/Alzheimer's disease biomarker-negative behavioural variant frontotemporal dementia (n = 59), and controls (n = 61). Patients with behavioural Alzheimer's disease showed worse memory scores than behavioural variant frontotemporal dementia and did not differ from typical Alzheimer's disease, while executive function composite scores were lower compared to behavioural variant frontotemporal dementia and typical Alzheimer's disease. Voxel-wise contrasts between behavioural and dysexecutive Alzheimer's disease patients and controls revealed marked atrophy in bilateral temporoparietal regions and only limited atrophy in the frontal cortex. In direct comparison with behavioural and those with dysexecutive Alzheimer's disease, patients with behavioural variant frontotemporal dementia showed more frontal atrophy and less posterior involvement, whereas patients with typical Alzheimer's disease were slightly more affected posteriorly and showed less frontal atrophy (P < 0.001 uncorrected). Among 24 autopsied behavioural Alzheimer's disease/dysexecutive Alzheimer's disease patients, only two had primary co-morbid FTD-spectrum pathology (progressive supranuclear palsy). In conclusion, behavioural Alzheimer's disease presentations are characterized by a milder and more restricted behavioural profile than in behavioural variant frontotemporal dementia, co-occurrence of memory dysfunction and high APOE ε4 prevalence. Dysexecutive Alzheimer's disease presented as a primarily cognitive phenotype with minimal behavioural abnormalities and intermediate APOE ε4 prevalence. Both behavioural Alzheimer's disease and dysexecutive Alzheimer's disease presentations are distinguished by temporoparietal-predominant atrophy. Based on the relative sparing of frontal grey matter, we propose to redefine these clinical syndromes as 'the behavioural/dysexecutive variant of Alzheimer's disease' rather than frontal variant Alzheimer's disease. Further work is needed to determine whether behavioural and dysexecutive-predominant presentations of Alzheimer's disease represent distinct phenotypes or a single continuum.
Summary Background Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis. Methods We did a randomised ...controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15–20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15–20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov ( NCT01785186 ). Findings Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22–2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3–5 adverse events, with similar proportions in each arm. Interpretation A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost. Funding The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC).
ABSTRACT
Background:
Because of the changing epidemiology of Helicobacter pylori infection and low efficacy of currently recommended therapies, an update of the European Society for Paediatric ...Gastroenterology Hepatology and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations for the diagnosis and management of H pylori infection in children and adolescents is required.
Methods:
A systematic review of the literature (time period: 2009–2014) was performed. Representatives of both societies evaluated the quality of evidence using GRADE (Grading of Recommendation Assessment, Development, and Evaluation) to formulate recommendations, which were voted upon and finalized using a Delphi process and face‐to‐face meeting.
Results:
The consensus group recommended that invasive diagnostic testing for H pylori be performed only when treatment will be offered if tests are positive. To reach the aim of a 90% eradication rate with initial therapy, antibiotics should be tailored according to susceptibility testing. Therapy should be administered for 14 days, emphasizing strict adherence. Clarithromycin‐containing regimens should be restricted to children infected with susceptible strains. When antibiotic susceptibility profiles are not known, high‐dose triple therapy with proton pump inhibitor, amoxicillin, and metronidazole for 14 days or bismuth‐based quadruple therapy is recommended. Success of therapy should be monitored after 4 to 8 weeks by reliable noninvasive tests.
Conclusions:
The primary goal of clinical investigation is to identify the cause of upper gastrointestinal symptoms rather than H pylori infection. Therefore, we recommend against a test and treat strategy. Decreasing eradication rates with previously recommended treatments call for changes to first‐line therapies and broader availability of culture or molecular‐based testing to tailor treatment to the individual child.
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