Coronaviruses (CoVs) are positive-sense RNA viruses that can emerge from endemic reservoirs and infect zoonotically, causing significant morbidity and mortality. CoVs encode an endoribonuclease ...designated EndoU that facilitates evasion of host pattern recognition receptor MDA5, but the target of EndoU activity was not known. Here, we report that EndoU cleaves the 5′-polyuridines fromnegative-sense viral RNA, termed PUN RNA, which is the product of polyA-templated RNA synthesis. Using a virus containing an EndoU catalytic-inactive mutation, we detected a higher abundance of PUN RNA in the cytoplasm compared to wildtype–infected cells. Furthermore, we found that transfecting PUN RNA into cells stimulates a robust, MDA5-dependent interferon response, and that removal of the polyuridine extension on the RNA dampens the response. Overall, the results of this study reveal the PUN RNA to be a CoV MDA5-dependent pathogen-associated molecular pattern (PAMP). We also establish a mechanism for EndoU activity to cleave and limit the accumulation of this PAMP. Since EndoU activity is highly conserved in all CoVs, inhibiting this activity may serve as an approach for therapeutic interventions against existing and emerging CoV infections.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
We explain when and how staggered difference-in-differences regression estimators, commonly applied to assess the impact of policy changes, are biased. These biases are likely to be relevant for a ...large portion of research settings in finance, accounting, and law that rely on staggered treatment timing, and can result in Type-I and Type-II errors. We summarize three alternative estimators developed in the econometrics and applied literature for addressing these biases, including their differences and tradeoffs. We apply these estimators to re-examine prior published results and show, in many cases, the alternative causal estimates or inferences differ substantially from prior papers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IMPORTANCE: Chronic opioid use imposes a substantial burden in terms of morbidity and economic costs. Whether opioid-naive patients undergoing surgery are at increased risk for chronic opioid use is ...unknown, as are the potential risk factors for chronic opioid use following surgery. OBJECTIVE: To characterize the risk of chronic opioid use among opioid-naive patients following 1 of 11 surgical procedures compared with nonsurgical patients. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of administrative health claims to determine the association between chronic opioid use and surgery among privately insured patients between January 1, 2001, and December 31, 2013. The data concluded 11 surgical procedures (total knee arthroplasty TKA, total hip arthroplasty, laparoscopic cholecystectomy, open cholecystectomy, laparoscopic appendectomy, open appendectomy, cesarean delivery, functional endoscopic sinus surgery FESS, cataract surgery, transurethral prostate resection TURP, and simple mastectomy). Multivariable logistic regression analysis was performed to control for possible confounders, including sex, age, preoperative history of depression, psychosis, drug or alcohol abuse, and preoperatice use of benzodiazepines, antipsychotics, and antidepressants. EXPOSURES: One of the 11 study surgical procedures. MAIN OUTCOMES AND MEASURES: Chronic opioid use, defined as having filled 10 or more prescriptions or more than 120 days’ supply of an opioid in the first year after surgery, excluding the first 90 postoperative days. For nonsurgical patients, chronic opioid use was defined as having filled 10 or more prescriptions or more than 120 days’ supply following a randomly assigned “surgery date.” RESULTS: The study included 641 941 opioid-naive surgical patients (169 666 men; mean SD age, 44.0 12.8 years), and 18 011 137 opioid-naive nonsurgical patients (8 849 107 men; mean SD age, 42.4 12.6 years). Among the surgical patients, the incidence of chronic opioid in the first preoperative year ranged from 0.119% for Cesarean delivery (95% CI, 0.104%-0.134%) to 1.41% for TKA (95% CI, 1.29%-1.53%) The baseline incidence of chronic opioid use among the nonsurgical patients was 0.136% (95% CI, 0.134%-0.137%). Except for cataract surgery, laparoscopic appendectomy, FESS, and TURP, all of the surgical procedures were associated with an increased risk of chronic opioid use, with odds ratios ranging from 1.28 (95% CI, 1.12-1.46) for cesarean delivery to 5.10 (95% CI, 4.67-5.58) for TKA. Male sex, age older than 50 years, and preoperative history of drug abuse, alcohol abuse, depression, benzodiazepine use, or antidepressant use were associated with chronic opioid use among surgical patients. CONCLUSIONS AND RELEVANCE: In opioid-naive patients, many surgical procedures are associated with an increased risk of chronic opioid use in the postoperative period. A certain subset of patients (eg, men, elderly patients) may be particularly vulnerable.
Primary dysmenorrhea, or painful menstruation in the absence of pelvic pathology, is a common, and often debilitating, gynecological condition that affects between 45 and 95% of menstruating women. ...Despite the high prevalence, dysmenorrhea is often poorly treated, and even disregarded, by health professionals, pain researchers, and the women themselves, who may accept it as a normal part of the menstrual cycle. This review reports on current knowledge, particularly with regards to the impact and consequences of recurrent menstrual pain on pain sensitivity, mood, quality of life and sleep in women with primary dysmenorrhea.
Comprehensive literature searches on primary dysmenorrhea were performed using the electronic databases PubMed, Google Scholar and the Cochrane Library. Full-text manuscripts published between the years 1944 and 2015 were reviewed for relevancy and reference lists were cross-checked for additional relevant studies. In combination with the word 'dysmenorrhea' one or more of the following search terms were used to obtain articles published in peer-reviewed journals only: pain, risk factors, etiology, experimental pain, clinical pain, adenomyosis, chronic pain, women, menstrual cycle, hyperalgesia, pain threshold, pain tolerance, pain sensitivity, pain reactivity, pain perception, central sensitization, quality of life, sleep, treatment, non-steroidal anti-inflammatory drugs.
Women with dysmenorrhea, compared with women without dysmenorrhea, have greater sensitivity to experimental pain both within and outside areas of referred menstrual pain. Importantly, the enhanced pain sensitivity is evident even in phases of the menstrual cycle when women are not experiencing menstrual pain, illustrating that long-term differences in pain perception extend outside of the painful menstruation phase. This enhanced pain sensitivity may increase susceptibility to other chronic pain conditions in later life; dysmenorrhea is a risk factor for fibromyalgia. Further, dysmenorrheic pain has an immediate negative impact on quality of life, for up to a few days every month. Women with primary dysmenorrhea have a significantly reduced quality of life, poorer mood and poorer sleep quality during menstruation compared with their pain-free follicular phase, and compared with the menstruation phase of pain-free control women. The prescribed first-line therapy for menstrual pain remains non-steroidal anti-inflammatory drugs, which are effective in relieving daytime and night-time pain.
Further study is needed to determine whether effectively blocking dysmenorrheic pain ameliorates risk for the development of chronic pain disorders and to explore whether it is possible to prevent the development-and not just treat-severe dysmenorrheic pain in adolescent girls. In conclusion, we demonstrate the extensive multi-factorial impact of dysmenorrhea and we encourage and direct researchers to necessary future studies.
Baker talks about the American Genetic Association (AGA) and Journal of Heredity's efforts to improve data archiving. The AGA recognizes that the primary data underlying the conclusions of an article ...are critical to the verifiability and transparency of the scientific enterprise. With the advent of electronic archiving, these data can now be preserved in usable form for decades into the future. For this reason, Journal of Heredity has previously endorsed the principles of the Joint Data Archiving Policy by encouraging all authors to archive primary data in an appropriate public archive, on a voluntary basis. By agreement of the AGA Council, they are updating the journal's instructions to Authors to conform with the expectation of mandatory data archiving adopted by other leading journals in evolution and genetics. As of Jan 1, 2013, the primary data underlying the analyses and conclusions of a manuscript must be submitted to a public archive as a condition of publication in Journal of Heredity.
Objectives To identify trends in concurrent use of a benzodiazepine and an opioid and to identify the impact of these trends on admissions to hospital and emergency room visits for opioid ...overdose.Design Retrospective analysis of claims data, 2001-13.Setting Administrative health claims database.Participants 315 428 privately insured people aged 18-64 who were continuously enrolled in a health plan with medical and pharmacy benefits during the study period and who also filled at least one prescription for an opioid.Interventions Concurrent benzodiazepine/opioid use, defined as an overlap of at least one day in the time periods covered by prescriptions for each drug. Main outcome measures Annual percentage of opioid users with concurrent benzodiazepine use; annual incidence of visits to emergency room and inpatient admissions for opioid overdose.Results 9% of opioid users also used a benzodiazepine in 2001, increasing to 17% in 2013 (80% relative increase). This increase was driven mainly by increases among intermittent, as opposed to chronic, opioid users. Compared with opioid users who did not use benzodiazepines, concurrent use of both drugs was associated with an increased risk of an emergency room visit or inpatient admission for opioid overdose (adjusted odds ratio 2.14, 95% confidence interval 2.05 to 2.24; P<0.001) among all opioid users. The adjusted odds ratio for an emergency room visit or inpatient admission for opioid overdose was 1.42 (1.33 to 1.51; P<0.001) for intermittent opioid users and 1.81 (1.67 to 1.96; P<0.001) chronic opioid users. If this association is causal, elimination of concurrent benzodiazepine/opioid use could reduce the risk of emergency room visits related to opioid use and inpatient admissions for opioid overdose by an estimated 15% (95% confidence interval 14 to 16).Conclusions From 2001 to 2013, concurrent benzodiazepine/opioid use sharply increased in a large sample of privately insured patients in the US and significantly contributed to the overall population risk of opioid overdose.
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We report on Bayesian parameter estimation of the mass and equatorial radius of the millisecond pulsar PSR J0030+0451, conditional on pulse-profile modeling of Neutron Star Interior Composition ...Explorer X-ray spectral-timing event data. We perform relativistic ray-tracing of thermal emission from hot regions of the pulsar's surface. We assume two distinct hot regions based on two clear pulsed components in the phase-folded pulse-profile data; we explore a number of forms (morphologies and topologies) for each hot region, inferring their parameters in addition to the stellar mass and radius. For the family of models considered, the evidence (prior predictive probability of the data) strongly favors a model that permits both hot regions to be located in the same rotational hemisphere. Models wherein both hot regions are assumed to be simply connected circular single-temperature spots, in particular those where the spots are assumed to be reflection-symmetric with respect to the stellar origin, are strongly disfavored. For the inferred configuration, one hot region subtends an angular extent of only a few degrees (in spherical coordinates with origin at the stellar center) and we are insensitive to other structural details; the second hot region is far more azimuthally extended in the form of a narrow arc, thus requiring a larger number of parameters to describe. The inferred mass M and equatorial radius Req are, respectively, 1.34 − 0.16 + 0.15 M and 12.71 − 1.19 + 1.14 km , while the compactness GM R eq c 2 = 0.156 − 0.010 + 0.008 is more tightly constrained; the credible interval bounds reported here are approximately the 16% and 84% quantiles in marginal posterior mass.
The accurate assessment of sleep is critical to better understand and evaluate its role in health and disease. The boom in wearable technology is part of the digital health revolution and is ...producing many novel, highly sophisticated and relatively inexpensive consumer devices collecting data from multiple sensors and claiming to extract information about users’ behaviors, including sleep. These devices are now able to capture different biosignals for determining, for example, HR and its variability, skin conductance, and temperature, in addition to activity. They perform 24/7, generating overwhelmingly large data sets (big data), with the potential of offering an unprecedented window on users’ health. Unfortunately, little guidance exists within and outside the scientific sleep community for their use, leading to confusion and controversy about their validity and application. The current state-of-the-art review aims to highlight use, validation and utility of consumer wearable sleep-trackers in clinical practice and research. Guidelines for a standardized assessment of device performance is deemed necessary, and several critical factors (proprietary algorithms, device malfunction, firmware updates) need to be considered before using these devices in clinical and sleep research protocols. Ultimately, wearable sleep technology holds promise for advancing understanding of sleep health; however, a careful path forward needs to be navigated, understanding the benefits and pitfalls of this technology as applied in sleep research and clinical sleep medicine.
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