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Aims: To assess whether continuous positive airway pressure (CPAP) therapy reduces major adverse cardiovascular events (MACE) in patients with moderate-to-severe obstructive sleep apnoea (OSA)., Methods and Results: A total of 235 articles were recovered using MEDLINE, EMBASE and Cochrane library (inception-December 2016) and references contained in the identified articles. Seven randomized controlled trials (RCTs) were selected for final analysis. Analysis of 4268 patients demonstrated non-significant 26% relative risk reduction in MACE with CPAP [risk ratio (RR) 0.74; 95% confidence interval (CI) 0.47-1.17; P = 0.19, I2 = 48%]. A series of sensitivity analyses suggested that increased CPAP usage time yielded significant risk reduction in MACE. and stroke. Subgroup analysis revealed that CPAP adherence time ≥4 hours (h)/night reduced the risk of MACE by 57% (RR 0.43; 95% CI 0.23-0.80; P = 0.01, I2 = 0%). CPAP therapy showed no beneficial effect on myocardial infarction (MI), all-cause mortality, atrial fibrillation/flutter (AF), or heart failure (HF) (P > 0.05). CPAP had positive effect on mood and reduced the daytime sleepiness [Epworth Sleepiness Scale (ESS): mean difference (MD) -2.50, 95% CI - 3.62, -1.39; P < 0.001, I2 = 81%]., Conclusion: CPAP therapy might reduce MACE and stroke among subjects with CPAP time exceeding 4 h/night. Additional randomized trials mandating adequate CPAP time adherence are required to confirm this impression.

The US Food and Drug Administration and the Critical Path Institute's Patient-Reported Outcome (PRO) Consortium convened a cosponsored workshop on the use of PRO measures to inform the assessment of safety and tolerability in cancer clinical trials. A broad array of international stakeholders involved in oncology drug development and PRO measurement science provided perspectives on the role of PRO measures to provide complementary clinical data on the symptomatic side effects of anticancer agents. Speakers and panelists explored the utility of information derived from existing and emerging PRO measures, focusing on the PRO version of the National Cancer Institute's Common Terminology Criteria for Adverse Events. Panelists and speakers discussed potential ways to improve the collection, analysis, and presentation of PRO data describing symptomatic adverse events to support drug development and better inform regulatory and treatment decisions. Workshop participants concluded the day with a discussion of possible approaches to the patient-reported assessment of an investigational drug's overall side effect burden as a potential clinical trial end point. The Food and Drug Administration reiterated its commitment to collaborate with international drug development stakeholders to identify rigorous methods to incorporate the patient perspective into the development of cancer therapeutics., (Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Objective: To assess weight change and attempted weight loss during the 12-18 months before spontaneous conception in relation to the risk of pregnancy loss., Design: Prospective cohort study., Setting: United States, 2007-2011., Methods: Women (n = 629) who were attempting pregnancy reported at baseline any weight loss attempts over the past 12 months, and their minimum and maximum weights during that time. Follow up lasted one to six menstrual cycles and throughout pregnancy. Using bodyweight measured at 4 weeks' gestation, participants were categorised as having weight loss ≥5%, weight gain ≥5%, both, or neither, over the previous 12-18 months. Log-binomial models adjusted for potential confounders., Main Outcome Measures: Risk ratio (RR) and 95% confidence interval (CI) of pregnancy loss., Results: Attempted weight loss was reported by 44% of women and actual weight loss by 11%, but neither was consistently associated with pregnancy loss. The RR for recent weight gain ≥5% was 1.65 (CI 1.09, 2.49)., Conclusions: Weight gain over the period spanning 12-18 months pre-conception to 4 weeks' gestation may increase the risk of pregnancy loss among fertile women with prior pregnancy losses. Attempted and actual weight loss were not associated with pregnancy loss; however, replication is needed from larger studies with data on particular weight-loss methods., Tweetable Abstract: Recent weight gain before and around the time of conception may increase the risk of pregnancy loss., (© 2017 Royal College of Obstetricians and Gynaecologists.)

Hepatitis C virus (HCV) infection is a serious worldwide healthcare issue. Its association with various liver diseases including hepatocellular carcinoma (HCC) is well studied. However, the study on the relationship between HCV infection and the development of insulin resistance and diabetes is very limited. Current research has already elucidated some underlying mechanisms, especially on the regulation of metabolism and insulin signalling by viral proteins. More studies have emerged recently on the correlation between HCV infection-derived miRNAs and diabetes and insulin resistance. However, no studies have been carried out to directly address if these miRNAs, especially circulating miRNAs, have causal effects on the development of insulin resistance and diabetes. Here, we proposed a new perspective that circulating miRNAs can perform regulatory functions to modulate gene expression in peripheral tissues leading to insulin resistance and diabetes, rather than just a passive factor associated with these pathological processes. The detailed rationales were elaborated through comprehensive literature review and bioinformatic analyses. miR-122 was identified to be one of the most potential circulating miRNAs to cause insulin resistance. This result along with the idea about the driver function of circulating miRNAs will promote further investigations that eventually lead to the development of novel strategies to treat HCV infection-associated extrahepatic comorbidities., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Medical marijuana patients often believe that specific strains are more efficacious at treating their conditions. The goals of this investigation were to determine: (1) how many strains of cannabis are there; (2) which strains are used by medical cannabis (MC) patients; and (3) are there any differences in the strains used by patient condition? Study I involved quantifying the number of strains listed in the online database leafly.com and categorizing these by whether the strain name included a gustatory component. MC patients (N = 455) from New England completed an anonymous online survey about their medical history and strain preferences in Study II. There were 1,987 strains listed. Hybrids were significantly more likely than Cannabis indica strains to have a gustatory title. Strain preferences were highly state/dispensary specific with one-fifth of MC patients in Maine preferring Mother of Berries (M.O.B., 21.5%). Many respondents mentioned that they had developed a time-dependent pattern with sativa use during the day and an indica for nighttime use and for improving sleep. There is some general consistency across dispensaries in that hybrid strains and C. indica were most common. Further longitudinal and controlled investigations are necessary to identify the strains that are most efficacious for specific conditions.

BACKGROUND Breast metaplastic squamous cell carcinoma (SCC) is a rare primary breast carcinoma, and overexpression of HER2 in this carcinoma is extremely uncommon. CASE REPORT We presented a case of a 48-year-old Asian female with breast metaplastic SCC. Fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) of the lesion were taken prior to surgical resection. FNAB smears demonstrated highly atypical squamous cells and a diagnosis positive for malignancy was rendered. CNB and a surgical resection specimen revealed invasive squamous carcinoma with keratin pearl formation and intercellular bridges. Further study demonstrated this was an unusual metaplastic SCC case with basal-HER2 (+) phenotype. HER2 has been linked to poor prognosis and response to therapy. CONCLUSIONS The pathological diagnosis of the breast metaplastic SCC was made initially by FNAB and CNB. Identification of basal-HER2 (+) phenotype was critical for selection of hormonal therapies and chemotherapy.

Objective: To investigate the safety and efficacy of percutaneous coronary interventions (PCI) versus coronary artery bypass graft (CABG) surgery for left main coronary artery (LMCA) disease., Methods: Six randomised controlled trials (RCTs) were reviewed by searching PubMed/Medline, Embase and the Cochrane Library. Estimates were pooled according to random effects model. Binary outcomes were reported as risk ratio (RR) and continuous outcomes were reported as mean difference (MD) with 95% confidence interval (CI)., Results: 3794 patients were randomised into PCI and CABG arms. Mean age of the total population was 64.7 years, 74.4% were male and mean Logistic EURO score (LES) was 2.9. When compared with CABG, patients treated with PCI had reduced risk of major adverse cardiovascular events (MACE) at 30 days: (RR: 0.55; 95% CI, 0.41-0.75; p<0.001; I 2 =0) but similar risk at 1year (RR: 1.15; 95% CI, 0.92-1.45; p=0.22; I 2 =0). Five years MACE rates favoured CABG (RR: 1.32; 95% CI, 1.13-1.53; p<0.001; I 2 =0) driven by a higher rate of target vessel revascularisation (TVR) (RR: 1.71; 95%CI, 1.38-2.12; p<0.001; I 2 =0) and myocardial infarction (MI) (RR: 1.97; 95%CI, 1.28-3.04; p<0.001; I 2 =22). Percutaneous coronary intervention was comparatively a safer procedure with lower rates of periprocedural adverse events including MI, stroke, bleeding events and need for blood transfusions., Conclusion: Percutaneous coronary intervention reduced MACE at 30days with comparable MACE at 1year. However, CABG was a more effective modality when considering mid- to long-term outcomes. PCI is a safer procedure with regards to periprocedural adverse events., (Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

The evidence to support implantable cardioverter defibrillator (ICD) in subjects with nonischemic cardiomyopathy (NICM) for primary prevention of sudden cardiac death (SCD) is not robust. This meta-analysis intends to assess the impact of routine ICD implantation for primary prevention of mortality due to SCD in NICM based on all the published randomized clinical trials (RCTs). Six RCTs were selected using PubMed/Medline, EMBASE, and CENTRAL from inception to December 2016. Outcomes were calculated as random-effects relative risk (RR) and risk difference (RD) with 95% confidence interval (CI). Patients were randomized to ICD arm and control arm (usual care, medical treatment, and anti-arrhythmic drugs). ICD significantly reduced all-cause mortality in NICM patients (RR, 0.74, 95% CI, 0.56-0.97, P  = .03, I 2 = 40). Mortality benefit was achieved due to a significant reduction in sudden cardiac death (SCD) (RR, 0.47, 95% CI, 0.30-0.73, P  < .001, I 2 = 0). There were no statistical differences between two groups with regard to risk of noncardiac mortality, non-SCD, cardiac arrest, cardiac transplant, sustained ventricular tachycardia (VT), and VT requiring medical treatment. Our results support efficacy of ICDs at reducing all-cause mortality due to a reduction in SCD.

Wernicke's Aphasia (WA) is characterized by an individual speaking fluent gibberish without the ability to understand anything that is said to them or anything they attempt to read. It is caused by damage to the left posterior temporoparietal cortex, also known as Wernicke's area. An additional intriguing symptom of WA patients is their apparent obliviousness to their own lack of understanding despite their intact reasoning or other cognitive abilities. Their only deficit seems to be in the basic rules of language that define word meaning, also known as phonology. Growing out of a project in an undergraduate class, we devised a phonology-free approach to communicating with WA patients that attempts to answer the questions of whether WA patients know that they do not understand what is said to them, that others do not understand what they have said, and if these patients are distressed by this lack of communication. We here describe the process and the resulting method.

Intrinsically disordered (ID) regions of the transcription factor proteins have much larger frequency of phosphorylation sites than ordered regions, suggesting an important role in their regulatory capacity. Consistent with this phenomenon, most of the functionally known phosphorylation sites in the steroid receptor family of transcription factors are located in the ID N-terminal domain that contains a powerful activation function (AF1) region. In this study, we determined the structural and functional consequences of functionally known phosphorylation residues (Ser203, 211, and 226) located in the human glucocorticoid receptor's (GR's) ID AF1 domain. We report the relative importance of each phosphorylation site in inducing a functionally active ordered conformation in GR's ID AF1 domain. Our data demonstrate a mechanism through which ID domain of the steroid receptors and other similar transcription factors may adopt a functionally active conformation under physiological conditions.

Long-term persistent infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. However, molecular mechanisms of HPV16 E6/E7 induction of lung cancer are not fully understood. Using bi-directional genetic manipulation and four well-established lung cancer cell lines, we showed HPV16 E6/E7 downregulated expression of liver kinase B1 at both protein and messenger RNA levels; liver kinase B1 downregulated hypoxia-inducible factor 2α at protein level but not at messenger RNA level, and hypoxia-inducible factor 2α upregulated vascular endothelial growth factor at both protein and messenger RNA levels. This is the first study to show hypoxia-inducible factor 2α as a downstream effector of liver kinase B1 in lung cancer cells. Our results indicate that HPV16 E6/E7 indirectly upregulated the expression of vascular endothelial growth factor by inhibition of liver kinase B1 expression and upregulation of hypoxia-inducible factor 2α expression, thus propose a human papillomavirus-liver kinase B1-hypoxia-inducible factor 2α-vascular endothelial growth factor axis for the tumorigenesis of lung cancer. Our study also provides new evidence to support the critical role of liver kinase B1 in the pathogenesis of human papillomavirus-related lung cancer and suggests novel therapeutic targets.

A prior epidemiological study identified a reduction in opioid overdose deaths in US states that legalized medical cannabis (MC). One theory to explain this phenomenon is a potential substitution effect of MC for opioids. This study evaluated whether this substitution effect of MC for opioids also applies to other psychoactive medications. New England dispensary members ( n = 1,513) completed an online survey about their medical history and MC experiences. Among respondents that regularly used opioids, over three-quarters (76.7%) indicated that they reduced their use since they started MC. This was significantly ( p < 0.0001) greater than the patients that reduced their use of antidepressants (37.6%) or alcohol (42.0%). Approximately two-thirds of patients decreased their use of anti-anxiety (71.8%), migraine (66.7%), and sleep (65.2%) medications following MC which significantly ( p < 0.0001) exceeded the reduction in antidepressants or alcohol use. The patient's spouse, family, and other friends were more likely to know about their MC use than was their primary care provider. In conclusion, a majority of patients reported using less opioids as well as fewer medications to treat anxiety, migraines, and sleep after initiating MC. A smaller portion used less antidepressants or alcohol. Additional research is needed to corroborate these self-reported, retrospective, cross-sectional findings using other data sources.

Study Question: Are maternal preconception lipid levels associated with fecundability?, Summary Answer: Fecundability was reduced for all abnormal female lipid levels including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total triglyceride levels., What Is Known Already: Subfecundity affects 7-15% of the population and lipid disorders are hypothesized to play a role since cholesterol acts as a substrate for the synthesis of steroid hormones. Evidence illustrating this relationship at the mechanistic level is mounting but few studies in humans have explored the role of preconception lipids in fecundity., Study Design, Size, Duration: A secondary analysis of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial (2007-2011), a block-randomized, double-blind, placebo-controlled trial., Participants/materials, Setting, Methods: A total of 1228 women, with 1-2 prior pregnancy losses and without a diagnosis of infertility, attempting pregnancy for up to six menstrual cycles were recruited from clinical sites in Utah, New York, PA and Colorado. Time to pregnancy was the number of menstrual cycles to pregnancy as determined by positive hCG test or ultrasound. Individual preconception lipoproteins were measured at baseline, prior to treatment randomization and dichotomized based on clinically accepted cut-points as total cholesterol ≥200 mg/dl, LDL-C ≥130 mg/dl, HDL-C <50 mg/dl and triglycerides ≥150 mg/dl., Main Results and the Role of Chance: There were 148 (12.3%) women with elevated total cholesterol, 94 (7.9%) with elevated LDL-C, 280 (23.2%) with elevated triglycerides and 606 (50.7%) with low HDL-C. The fecundability odds ratio (FOR) was reduced for all abnormal lipids before and after confounder adjustment, indicating reduced fecundability. Total cholesterol ≥200 mg/dl was associated with 24% (FOR: 0.76, 95% CI: 0.59, 0.97) and 29% (FOR: 0.71, 95% CI: 0.55, 0.93) reduced fecundability for hCG-detected and ultrasound-confirmed pregnancy, respectively, compared with total cholesterol <200 mg/dl. There was a 19-36% decrease in the probability of conception per cycle for women with abnormal lipoprotein levels, though additional adjustment for central adiposity and BMI attenuated observed associations., Limitations, Reasons for Caution: Although the FOR is a measure of couple fecundability, we had only measures of female lipid levels and can therefore not confirm the findings from a previous study indicating the independent role of male lipids in fecundity. The attenuated estimates and decreased precision after adjustment for central adiposity and obesity indicate the complexity of potential causal lipid pathways, suggesting other factors related to obesity besides dyslipidemia likely contribute to reduced fecundability., Wider Implications of the Findings: Our results are consistent with one other study relating preconception lipid concentrations to fecundity and expand these findings by adding critically important information about individual lipoproteins. As lipid levels are modifiable they may offer an inexpensive target to improve female fecundability., Study Funding and Competing Interest(s): This study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have declared that no conflicts of interest exist., Trial Registration Number: #NCT00467363., (Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Online health information is being used more ubiquitously by the general population. However, this information typically favors only a small percentage of readers, which can result in suboptimal medical outcomes for patients., Objective: The readability of online patient education materials regarding the topic of congestive heart failure was assessed through six readability assessment tools., Methods: The search phrase "congestive heart failure" was employed into the search engine Google. Out of the first 100 websites, only 70 were included attending to compliance with selection and exclusion criteria. These were then assessed through six readability assessment tools., Results: Only 5 out of 70 websites were within the limits of the recommended sixth-grade readability level. The mean readability scores were as follows: the Flesch-Kincaid Grade Level (9.79), Gunning-Fog Score (11.95), Coleman-Liau Index (15.17), Simple Measure of Gobbledygook (SMOG) index (11.39), and the Flesch Reading Ease (48.87)., Conclusion: Most of the analyzed websites were found to be above the sixth-grade readability level recommendations. Efforts need to be made to better tailor online patient education materials to the general population.