Abstract
More than 1.6 million Americans have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more than 10 times that number carry antibodies to it. High-risk ...patients with progressing symptomatic disease currently have only hospitalization treatment, with its high mortality, available to them. An outpatient treatment that prevents hospitalization is desperately needed. Two candidate medications have been widely discussed: remdesivir and hydroxychloroquine (HCQ) + azithromycin (AZ). Remdesivir has shown mild effectiveness in hospitalized inpatients, but no trials in outpatients have been registered. HCQ + AZ has been widely misrepresented in both clinical reports and public media, and results of outpatient trials are not expected until September. Early outpatient illness is very different from later florid disease requiring hospitalization, and the treatments differ. Evidence about use of HCQ alone, or of HCQ + AZ in inpatients, is irrelevant with regard to the efficacy of HCQ + AZ in early high-risk outpatient disease. Five studies, including 2 controlled clinical trials, have demonstrated significant major outpatient treatment efficacy. HCQ + AZ has been used as the standard of care in more than 300,000 older adults with multiple comorbid conditions; the estimated proportion of such patients diagnosed with cardiac arrhythmia attributable to the medications is 47 per 100,000 users, among whom estimated mortality is less than 20% (9/100,000 users), as compared with the 10,000 Americans now dying each week. These medications need to be made widely available and promoted immediately for physicians to prescribe.
To investigate the biologic relevance and clinical implication of genes involved in multiple gene expression signatures for breast cancer prognosis, we identified 16 published gene expression ...signatures, and selected two genes, MAD2L1 and BUB1. These genes appeared in 5 signatures and were involved in cell-cycle regulation. We analyzed the expression of these genes in relation to tumor features and disease outcomes. In vitro experiments were also performed in two breast cancer cell lines, MDA-MB-231 and MDA-MB-468, to assess cell proliferation, migration and invasion after knocking down the expression of these genes. High expression of these genes was found to be associated with aggressive tumors and poor disease-free survival of 203 breast cancer patients in our study, and the association with survival was confirmed in an online database consisting of 914 patients. In vitro experiments demonstrated that lowering the expression of these genes by siRNAs reduced tumor cell growth and inhibited cell migration and invasion. Our investigation suggests that MAD2L1 and BUB1 may play important roles in breast cancer progression, and measuring the expression of these genes may assist the prediction of breast cancer prognosis.
COVID‐19 put to the test the understanding of the meaning of “science” by the medical profession, the media, and the public. Unfortunately, the vast majority of individuals were misled by those who ...spoke on behalf of science but who confused plausible stories with scientific explanation. Scientific understanding comes from theories, which generate hypotheses, which are, in turn, confirmed or disconfirmed by empirical evidence that is evaluated using statistical methods. In our daily lives, we may judge the validity of a hypothesis based on its plausibility, and for most trivial cases that is sufficient. But it is a mistake to imagine that science can proceed on that basis. Yet, scientists themselves are often confused about the foundations of the scientific method. “Evidence‐based medicine” is now being used to discredit all medical evidence other than randomized controlled trials (RCTs), the supposed “gold standard” of medical research. This insistence on a single method that is deemed “best practice” has the ironic effect of replacing science with plausibility in medicine. RCTs fail to live up to their vaunted status because of frequent insufficiencies in randomization related to confounding errors and their magnitudes. When randomized trials were compared with observational studies in a meta‐analysis of thousands of studies, the differences in conclusions were negligible. The entire framework of COVID‐19 policy has been based on plausible hypotheses, not backed by genuine scientific evidence. Critics are correct in claiming that COVID‐19 policies have been based on politics, not science.
Worldwide, the prevalence of dementia is increasing and diet as a modifiable factor could play a role. Meat consumption has been cross-sectionally associated with dementia risk, but specific amounts ...and types related to risk of incident dementia remain poorly understood.
We aimed to investigate associations between meat consumption and risk of incident dementia in the UK Biobank cohort.
Meat consumption was estimated using a short dietary questionnaire at recruitment and repeated 24-h dietary assessments. Incident all-cause dementia comprising Alzheimer disease (AD) and vascular dementia (VD) was identified by electronic linkages to hospital and mortality records. HRs for each meat type in relation to each dementia outcome were estimated in Cox proportional hazard models. Interactions between meat consumption and the apolipoprotein E (APOE) ε4 allele were additionally explored.
Among 493,888 participants included, 2896 incident cases of all-cause dementia, 1006 cases of AD, and 490 cases of VD were identified, with mean ± SD follow-up of 8 ± 1.1 y. Each additional 25 g/day intake of processed meat was associated with increased risks of incident all-cause dementia (HR: 1.44; 95% CI: 1.24, 1.67; P-trend < 0.001) and AD (HR: 1.52; 95% CI: 1.18, 1.96; P-trend = 0.001). In contrast, a 50-g/d increment in unprocessed red meat intake was associated with reduced risks of all-cause dementia (HR: 0.81; 95% CI: 0.69, 0.95; P-trend = 0.011) and AD (HR: 0.70; 95% CI: 0.53, 0.92; P-trend = 0.009). The linear trend was not significant for unprocessed poultry and total meat. Regarding incident VD, there were no statistically significant linear trends identified, although for processed meat, higher consumption categories were associated with increased risks. The APOE ε4 allele increased dementia risk by 3 to 6 times but did not modify the associations with diet significantly.
These findings highlight processed-meat consumption as a potential risk factor for incident dementia, independent of the APOE ε4 allele.
•A joint model incorporating longitudinal mixed effects and time-event survival was applied.•The death risk of melanoma increased by 31% with one unit change of soluble PD-L1 at a ...time-point.•Approximately 30% reduction of death risk was found in melanoma patients with one unit change of soluble PD-1/PD-L1 ratio at a time-point.•Patients with a low ratio of PD-1/PD-L1 at baseline had significantly inferior OS compared to patients with a high ratio.•Dynamic change of soluble PD-1 and PD-L1 levels could be used to monitor patient response to ICBs.
Immune checkpoint PD-1 and its ligand PD-L1 lead to T cell exhaustion, and a high level of circulating soluble PD-L1 at baseline indicates a poor prognosis in melanoma and other solid tumor types. Here we show that the dynamic changes of circulating soluble PD-1 and PD-L1 across the course of immune checkpoint blockades (ICBs) and their changes associate with patient survival in melanoma in a retrospective study. A high change of soluble PD-L1 level at a time-point but not PD-1 significantly increased the mortality, whereas a high change of soluble PD-1/PD-L1 ratio significantly reduced the mortality. After the initial immunotherapy, both soluble PD-1 and PD-L1 increased. However, the change pattern of soluble PD-L1 level was particularly dependent on patients’ survival status. These findings indicate that the magnitudes of circulating soluble PD-L1 and PD-1/PD-L1 ratio changes over the time may reflect the patients’ response to ICBs or the progression of the disease and predict the survival in melanoma patients treated with ICBs.
Re: NSAID Use and Pancreatic Cancer Risk Risch, Harvey A.
Gastroenterology (New York, N.Y. 1943),
September 2018, 2018-09-00, 20180901, Letnik:
155, Številka:
3
Journal Article
Previous studies have evidenced an association between gastroesophageal reflux and esophageal adenocarcinoma (EA). It is unknown to what extent these associations vary by population, age, sex, body ...mass index, and cigarette smoking, or whether duration and frequency of symptoms interact in predicting risk. The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) allowed an in-depth assessment of these issues.
Detailed information on heartburn and regurgitation symptoms and covariates were available from five BEACON case-control studies of EA and esophagogastric junction adenocarcinoma (EGJA). We conducted single-study multivariable logistic regressions followed by random-effects meta-analysis. Stratified analyses, meta-regressions, and sensitivity analyses were also conducted.
Five studies provided 1,128 EA cases, 1,229 EGJA cases, and 4,057 controls for analysis. All summary estimates indicated positive, significant associations between heartburn/regurgitation symptoms and EA. Increasing heartburn duration was associated with increasing EA risk; odds ratios were 2.80, 3.85, and 6.24 for symptom durations of <10 years, 10 to <20 years, and ≥20 years. Associations with EGJA were slighter weaker, but still statistically significant for those with the highest exposure. Both frequency and duration of heartburn/regurgitation symptoms were independently associated with higher risk. We observed similar strengths of associations when stratified by age, sex, cigarette smoking, and body mass index.
This analysis indicates that the association between heartburn/regurgitation symptoms and EA is strong, increases with increased duration and/or frequency, and is consistent across major risk factors. Weaker associations for EGJA suggest that this cancer site has a dissimilar pathogenesis or represents a mixed population of patients.
PDF
