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Background Antimicrobial resistance in Neisseria gonorrhoeae is threatening the gonorrhoea treatment, and optimizations of the current ceftriaxone-treatment regimens are crucial. We evaluated the pharmacodynamics of ceftriaxone single-dose therapy (0.125–1 g) against ceftriaxone-susceptible and ceftriaxone-resistant gonococcal strains, based on EUCAST ceftriaxone-resistance breakpoint (MIC > 0.125 mg/L), in our hollow fibre infection model (HFIM) for gonorrhoea. Methods Gonococcal strains examined were WHO F (ceftriaxone-susceptible, MIC < 0.002 mg/L), R (ceftriaxone-resistant, MIC = 0.5 mg/L), Z (ceftriaxone-resistant, MIC = 0.5 mg/L) and X (ceftriaxone-resistant, MIC = 2 mg/L). Dose-range HFIM 7 day experiments simulating ceftriaxone 0.125–1 g single-dose intramuscular regimens were conducted. Results Ceftriaxone 0.125–1 g single-dose treatments rapidly eradicated WHO F (wild-type ceftriaxone MIC). Ceftriaxone 0.5 and 1 g treatments, based on ceftriaxone human plasma pharmacokinetic parameters, eradicated most ceftriaxone-resistant gonococcal strains (WHO R and Z), but ceftriaxone 0.5 g failed to eradicate WHO X (high-level ceftriaxone resistance). When simulating oropharyngeal gonorrhoea, ceftriaxone 0.5 g failed to eradicate all the ceftriaxone-resistant strains, while ceftriaxone 1 g eradicated WHO R and Z (low-level ceftriaxone resistance) but failed to eradicate WHO X (high-level ceftriaxone resistance). No ceftriaxone-resistant mutants were selected using any ceftriaxone treatments. Conclusions Ceftriaxone 1 g single-dose intramuscularly cure most of the anogenital and oropharyngeal gonorrhoea cases caused by the currently internationally spreading ceftriaxone-resistant gonococcal strains, which should be further confirmed clinically. A ceftriaxone 1 g dose (±azithromycin 2 g) should be recommended for first-line empiric gonorrhoea treatment. This will buy countries some time until novel antimicrobials are licensed. Using ceftriaxone 1 g gonorrhoea treatment, the EUCAST ceftriaxone-resistance breakpoint is too low. [ABSTRACT FROM AUTHOR]

Objective To conduct a multicenter case series characterizing the clinical characteristics at presentation and pancreatic volume changes of patients with checkpoint inhibitor-associated autoimmune diabetes (CIADM). Research Design and Methods Electronic medical records were reviewed with 36 consecutive patients identified with CIADM, as defined by (1) previous immune checkpoint inhibitor (ICI) therapy, (2) new-onset hyperglycemia (blood glucose level ≥ 11.1 mmol/L and/or glycosylated hemoglobin ≥ 6.5%), and (3) insulin deficiency [C-peptide <0.4 nmol/L or diabetic ketoacidosis (DKA)] within 1 month of presentation. Pancreatic volume was available and measured using computed tomography volumetry for 17 patients with CIADM and 3 sets of control patients: 7 with ICI-related pancreatitis, 13 with asymptomatic ICI-related lipase elevation, and 11 ICI-treated controls for comparison. Results All patients had either anti-programmed cell death protein 1 or anti-programmed cell death ligand 1 therapy. Median time from ICI commencement to CIADM diagnosis was 15 weeks. At presentation, 25 (69%) had DKA, 27 (84%) had low C-peptide, and, by 1 month, 100% had low C-peptide. Traditional type 1 diabetes autoantibodies were positive in 15/35 (43%). Lipase was elevated in 13/27 (48%) at presentation. In 4 patients with longitudinal lipase testing, elevated levels peaked 1 month prior to CIADM diagnosis. Pancreatic volume was lower pre-ICI in CIADM patients compared with controls and demonstrated a mean decline of 41% from pretreatment to 6 months post-CIADM diagnosis. Conclusion Pronounced biochemical and radiologic changes occur during CIADM pathogenesis. Rapid loss of C-peptide is a distinct characteristic that can be used to aid diagnosis as autoantibodies are often negative. [ABSTRACT FROM AUTHOR]

Background Extended spectrum beta-lactamase producing Enterobacterales (ESBL-PE) present a risk to public health by limiting the efficacy of multiple classes of beta-lactam antibiotics against infection. International travellers may acquire these organisms and identifying individuals at high risk of acquisition could help inform clinical treatment or prevention strategies. Methods We used data collected from a cohort of 528 international travellers enrolled in a multicentre US-based study to derive a clinical prediction rule (CPR) to identify travellers who developed ESBL-PE colonization, defined as those with new ESBL positivity in stool upon return to the United States. To select candidate features, we used data collected from pre-travel and post-travel questionnaires, alongside destination-specific data from external sources. We utilized LASSO regression for feature selection, followed by random forest or logistic regression modelling, to derive a CPR for ESBL acquisition. Results A CPR using machine learning and logistic regression on 10 features has an internally cross-validated area under the receiver operating characteristic curve (cvAUC) of 0.70 (95% confidence interval 0.69–0.71). We also demonstrate that a four-feature model performs similarly to the 10-feature model, with a cvAUC of 0.68 (95% confidence interval 0.67–0.69). This model uses traveller's diarrhoea, and antibiotics as treatment, destination country waste management rankings and destination regional probabilities as predictors. Conclusions We demonstrate that by integrating traveller characteristics with destination-specific data, we could derive a CPR to identify those at highest risk of acquiring ESBL-PE during international travel. [ABSTRACT FROM AUTHOR]

We analyze early-venture fundraising from dispersed, endogenously informed investors. An entrepreneur chooses a payoff-maximizing offering, and investors communicate their information by either contributing capital or abstaining. The entrepreneur uses the information conveyed by fundraising amounts to decide whether or not to undertake a risky venture. His decision threshold hedges investors against bad projects, creating a "loser's blessing" that encourages contributing without information. Making the offering less attractive to investors mitigates the loser's blessing but can give rise to a winner's curse. Both tensions reduce financing efficiency. Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online. [ABSTRACT FROM AUTHOR]

The Department of Defense (DoD) is increasingly dependent on highly technological weapon systems, but the human is still at the heart of our war-fighting efforts. In order to maintain an effective fighting force, we must optimize and sustain human performance, which is defined as the successful completion of a specified task within an available performance capacity that meets or exceeds the mission demands. When health and performance are optimized and sustained, the costs of warfighter care and disability compensation are reduced and the quality of life is enhanced. Therefore, we propose that the Military Health System (MHS) reshape its focus on disease and injury treatment and prevention to embrace health enhancement for optimal human performance in a technology-rich battle space. This commentary develops a high-level strategy and policy framework to enable the MHS to optimize health and human performance for all DoD warfighters. We conducted a review of human performance literature, assessed existing health programs across the services, and conducted interviews with MHS and Line representatives. We found that the MHS has thus far met warfighter needs in a haphazard fashion. We propose an orchestrated approach to warfighter health and performance across the DoD and a more substantial partnership between Total Force Fitness and the MHS. We provide a notional concept for how the parts of this system could interact and a strategic framework for the delivery of health and performance to the warfighter. [ABSTRACT FROM AUTHOR]

The article explores the proliferation of plot-twist documentaries, and addresses the concern about the detrimental effects of excessive fictionalizing to the ability of documentary films to represent reality truthfully. Topics discussed include cognitive and epistemic value of documentaries, viewers' expectations of storytelling and narration, and pluralistic view of the value of documentary.

Background: Antiextractable nuclear antigens (anti-ENAs) are regarded as diagnostic tests with no established value for serial monitoring. We therefore sought to establish the stability over time of anti-ENAs in a large diagnostic immunopathology laboratory. Methods: A retrospective review of all patients who had a serial anti-ENA ordered at the Westmead Hospital (Sydney, Australia) was performed over 24 months. Anti-ENA characterization was performed using line immunoassay, and historical data were available from 2013 onward. The earliest available densitometry readings were compared with the latest available to examine for a change in quantitation or qualitative (serostatus) result (from negative to positive, and vice versa). Medical records were examined for clinical correlations. Results: A total of 283 patients (24.1%) had serial testing of anti-ENA in the audit period, with each patient having an average of 3.9 ± 2.9 tests each. Most patients were diagnosed with systemic lupus erythematosus or primary Sjögren's syndrome. About 25% and 58% of patients had a qualitative and quantitative change, respectively, in at least 1 anti-ENA in the study period. Changes in anti-ENA levels correlated with erythrocyte sedimentation rate and disease activity. Increasing duration between serial tests increased the probability of observing a change in anti-ENA levels. Conclusion: Certain anti-ENAs are dynamic autoantibodies that may have significance for monitoring disease activity. Laboratories may consider reporting quantitative results. Further disease- and autoantibody-specific studies are required to determine the clinical significance of changes in anti-ENAs. [ABSTRACT FROM AUTHOR]

Background: Myelin oligodendrocyte glycoprotein antibodies (MOG Ab) are essential in the diagnosis of MOG Ab–associated disease (MOGAD). Live cell-based assays (CBAs) are the gold standard for MOG Ab detection with improved sensitivity and specificity over fixed CBAs. A number of testing centers have used flow cytometry for its high throughput and quantitative utility. Presently, there is increasing demand to translate these research-based methods into an accredited routine diagnostic setting. Methods: A flow cytometry live CBA was used to detect MOG Ab in patients with demyelination. Serostatuses were compared between a research-based assay and a streamlined diagnostic assay. Inter-laboratory validation of the streamlined assay was performed in an accredited diagnostic laboratory. Further streamlining was performed by introducing a borderline serostatus range and reducing the number of controls used to determine the positivity threshold. Results: High serostatus agreement (98%–100%) was observed between streamlined and research-based assays. Intra- and inter-assay imprecision was improved in the streamlined assay (mean intra- and inter-assay CV = 7.3% and 27.8%, respectively) compared to the research-based assay (mean intra- and inter-assay CV = 11.8% and 33.6%, respectively). Borderline positive and clear positive serostatuses were associated with confirmed phenotypes typical of MOGAD. Compared to using 24 controls, robust serostatus classification was observed when using 13 controls without compromising analytical performance (93%–98.5% agreement). Conclusions: Flow cytometry live CBAs show robust utility in determining MOG Ab serostatus. Streamlining and standardizing use of this assay for diagnostics would improve the accuracy and reliability of routine testing to aid diagnosis and treatment of patients with demyelination. [ABSTRACT FROM AUTHOR]

The American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions have recently released their joint guideline on coronary artery revascularization [[1]]. Considering that only 26% of patients in the revascularization arm underwent CABG, one can hardly consider this trial as an adequate comparison of CABG plus OMT versus OMT alone. The largest trial to date is the ISCHEMIA trial, which randomized patients with SIHD to revascularization or OMT in patients with moderate to severe ischaemia. [Extracted from the article]

An editorial is presented on cardiac mortality in patients randomised to elective coronary revascularisation plus medical therapy or medical therapy alone. Topics include natural history studies demonstrating the extent of obstructive CAD correlating with an increased incidence of myocardial infarction (MI); and early medical therapy consisting of nitrates and beta-blockers with or without aspirin.

Treatment options for Achromobacter xylosoxidans are limited. Eight cystic fibrosis patients with A. xylosoxidans were treated with 12 cefiderocol courses. Pretreatment in vitro resistance was seen in 3 of 8 cases. Clinical response occurred after 11 of 12 treatment courses. However, microbiologic relapse was observed after 11 of 12 treatment courses, notably without emergence of resistance. [ABSTRACT FROM AUTHOR]

The American Physical Therapy Association's Vision Statement of 2013 asserts that physical therapists optimize movement in order to improve the human experience. In accordance with this vision, physical therapists strive to be recognized as experts in movement analysis. However, there continues to be no accepted method to conduct movement analysis, nor an agreement of key terminology to describe movement observations. As a result, the Academy of Neurologic Physical Therapy organized a task force that was charged with advancing the state of practice with respect to these issues, including the development of a proposed method for movement analysis of tasks. This paper presents the work of the Task Force, which includes (1) development of a method for conducting movement analysis within the context of the movement continuum during 6 core tasks (sitting, sit to stand, standing, walking, step up/down, and reach/grasp/manipulate); (2) glossary of movement constructs that can provide a common language for movement analysis across a range of tasks: symmetry, speed, amplitude, alignment, verticality, stability, smoothness, sequencing, timing, accuracy, and symptom provocation; and (3) recommendations for task and environmental variations that can be systematically applied. The expectation is that this systematic framework and accompanying terminology will be easily adapted to additional patient or client-specific tasks, contribute to development of movement system diagnostic labels, and ultimately improve consistency across patient/client examination, evaluation, and intervention for the physical therapy profession. Next steps should include validation of this framework across patient/client groups and settings. [ABSTRACT FROM AUTHOR]

The authors comment on the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial, published in April 2020. Topics discussed include the study finding on patients with chronic coronary syndromes (CCS), problems in downplaying periprocedural myocardial infarction, and prognostic implications of myocardial infarctions in ISCHEMIA.

Aims  The REFLECT I trial investigated the safety and effectiveness of the TriGuard™ HDH (TG) cerebral embolic deflection device in patients undergoing transcatheter aortic valve replacement (TAVR). Methods and results  This prospective, multicentre, single-blind, 2:1 randomized (TG vs. no TG) study aimed to enrol up to 375 patients, including up to 90 roll-in patients. The primary combined safety endpoint (VARC-2 defined early safety) at 30 days was compared with a performance goal. The primary efficacy endpoint was a hierarchical composite of (i) all-cause mortality or any stroke at 30 days, (ii) National Institutes of Health Stroke Scale (NIHSS) worsening at 2–5 days or Montreal Cognitive Assessment worsening at 30 days, and (iii) total volume of cerebral ischaemic lesions detected by diffusion-weighted magnetic resonance imaging at 2–5 days. Cumulative scores were compared between treatment groups using the Finkelstein–Schoenfeld method. A total of 258 of the planned, 375 patients (68.8%) were enrolled (54 roll-in and 204 randomized). The primary safety outcome was met compared with the performance goal (21.8% vs. 35%, P  < 0.0001). The primary hierarchical efficacy endpoint was not met (mean efficacy score, higher is better: −5.3 ± 99.8 TG vs. 11.8 ± 96.4 control, P  = 0.31). Covert central nervous system injury was numerically lower with TG both in-hospital (46.1% vs. 60.3%, P  = 0.0698) and at 5 days (61.7 vs. 76.2%, P  = 0.054) compared with controls. Conclusion  REFLECT I demonstrated that TG cerebral protection during TAVR was safe in comparison with historical TAVR data but did not meet the predefined effectiveness endpoint compared with unprotected TAVR controls. [ABSTRACT FROM AUTHOR]

Non-fundamental demand shocks have significant effects on asset prices, but observing these shocks is challenging. We use the exchange-traded fund (ETF) primary market to study non-fundamental demand. Unique to the ETF market, specialized arbitrageurs called authorized participants correct violations of the law of one price between an ETF and its underlying assets by creating or redeeming ETF shares. We show theoretically and empirically that creation and redemption activities (ETF flows) provide signals of non-fundamental demand shocks. A portfolio that is short high-flow ETFs and long low-flow ETFs earns excess returns of 1.1–2.0% per month, consistent with non-fundamental demand distorting asset prices away from fundamental values. Moreover, we show non-fundamental demand imposes non-trivial costs on investors, leading to underperformance. [ABSTRACT FROM AUTHOR]

Background: Patients with human papillomavirus-related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy.Methods: In 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided.Results: Fifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation-related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03).Conclusions: Deescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy. [ABSTRACT FROM AUTHOR]

We report the discovery of a new ultrashort period (USP) transiting hot Jupiter from the Next Generation Transit Survey (NGTS). NGTS-10b has a mass and radius of |$2.162\, ^{+0.092}_{-0.107}$|   M J and |$1.205\, ^{+0.117}_{-0.083}$|   R J and orbits its host star with a period of 0.7668944 ± 0.0000003 d, making it the shortest period hot Jupiter yet discovered. The host is a 10.4 ± 2.5 Gyr old K5V star (T eff = 4400 ± 100 K) of Solar metallicity ([Fe/H] = −0.02 ± 0.12 dex) showing moderate signs of stellar activity. NGTS-10b joins a short list of USP Jupiters that are prime candidates for the study of star–planet tidal interactions. NGTS-10b orbits its host at just 1.46 ± 0.18 Roche radii, and we calculate a median remaining inspiral time of 38 Myr and a potentially measurable orbital period decay of 7 s over the coming decade, assuming a stellar tidal quality factor |$Q^{\prime }_{\rm s}$| =2 × 107. [ABSTRACT FROM AUTHOR]

Diffuse and focal epicardial coronary disease and coronary microvascular abnormalities may exist side-by-side. Identifying the contributions of each of these three players in the coronary circulation is a difficult task. Yet identifying coronary microvascular dysfunction (CMD) as an additional player in patients with coronary artery disease (CAD) may provide explanations of why symptoms may persist frequently following and why global coronary flow reserve may be more prognostically important than fractional flow reserve measured in a single vessel before percutaneous coronary intervention. This review focuses on the challenges of identifying the presence of CMD in the context of diffuse non-obstructive CAD and obstructive CAD. Furthermore, it is going to discuss the pathophysiology in this complex situation, examine the clinical context in which the interaction of the three components of disease takes place and finally look at non-invasive diagnostic methods relevant for addressing this question. [ABSTRACT FROM AUTHOR]

We use administrative data from the Internal Revenue Service to examine long-term impacts of childhood Medicaid eligibility expansions on outcomes in adulthood at each age from 19 to 28. Greater Medicaid eligibility increases college enrolment and decreases fertility, especially through age 21. Starting at age 23, females have higher contemporaneous wage income, although male increases are imprecise. Together, both genders have lower mortality. These adults collect less from the earned income tax credit and pay more in taxes. Cumulatively from ages 19 to 28, at a 3% discount rate, the federal government recoups 58 cents of each dollar of its "investment" in childhood Medicaid. [ABSTRACT FROM AUTHOR]

Aims Transcatheter aortic valve replacement (TAVR) is now an established therapy for intermediate-risk surgical candidates with symptomatic, severe aortic stenosis. The clinical impact of new-onset left bundle branch block (LBBB) after TAVR remains controversial and has not been studied in intermediate-risk patients. We therefore sought to analyse outcomes associated with new LBBB in a large cohort of intermediate-risk patients treated with TAVR. Methods and results A total of 2043 patients underwent TAVR in the PARTNER II trial and S3 intermediate-risk registry and survived to hospital discharge. Patients were excluded from the current analysis due to baseline conduction disturbances, pre-existing permanent pacemaker (PPM), and new PPM during the index hospitalization. Clinical outcomes at 2 years were compared between patients with and without persistent, new-onset LBBB at hospital discharge, and multivariable analysis was performed to identify predictors of mortality. Among 1179 intermediate-risk patients, new-onset LBBB at discharge occurred in 179 patients (15.2%). Patients with new LBBB were similar to those without except for more frequent diabetes and more frequent treatment with SAPIEN 3 vs. SAPIEN XT. At 2 years, new LBBB was associated with increased rates of all-cause mortality (19.3% vs. 10.8%, P  = 0.002), cardiovascular mortality (16.2% vs. 6.5%, P  < 0.001), rehospitalization, and new PPM implantation. By multivariable analysis, new LBBB remained an independent predictor of 2-year all-cause [hazard ratio (HR) 1.98, 95% confidence interval (95% CI) 1.33, 2.96; P  < 0.001] and cardiovascular (HR 2.66 95% CI 1.67, 4.24; P  < 0.001) mortality. New LBBB was also associated with worse left ventricular systolic function at 1 and 2-year follow-up. Conclusions In a large cohort of intermediate-risk patients from the PARTNER II trial and registry, persistent, new-onset LBBB occurred in 15.2% of patients without baseline conduction disturbances or pacemaker. New LBBB was associated with adverse clinical outcomes at 2 years, including all-cause and cardiovascular mortality, rehospitalization, new pacemaker implantation, and worsened left ventricular systolic function. Clinical Trial Registration ClinicalTrials.gov #NCT01314313 and NCT03222128. [ABSTRACT FROM AUTHOR]

Although invasive ductal breast cancer (IDC) represents the most common histological type of breast cancer, minor subtypes exist such as mucinous breast cancer (MuBC). MuBC are distinguished by tumor cells floating in extracellular mucin. MuBC patients are generally older and associated with a favorable prognosis. To unravel the molecular architecture of MuBC, we applied low-pass whole-genome sequencing and microscopic evaluation of stromal tumor infiltrating lymphocytes to 30 MuBC from a retrospective institutional cohort. We further analyzed two independent datasets from the International Cancer Genomics Consortium and The Cancer Genome Atlas. Genomic data (n = 26 MuBC, n = 535 estrogen receptor [ER] positive/HER2-negative IDC), methylation data (n = 28 MuBC, n = 529 ER-positive/HER2-negative IDC), and transcriptomic data (n = 27 MuBC, n = 467 ER-positive/HER2-negative IDC) were analyzed. MuBC was characterized by low tumor infiltrating lymphocyte levels (median = 0.0%, average = 3.4%, 95% confidence interval = 1.9% to 4.9%). Compared with IDC, MuBC had a lower genomic instability (P = .01, two-sided Mann-Whitney U test) and a decreased prevalence of PIK3CA mutations (39.7% in IDC vs 6.7% in MuBC, P = .01 in the International Cancer Genomics Consortium; and 34.8% vs 0.0%, P = .02 in The Cancer Genome Atlas, two-sided Fisher's exact test). Finally, our report identifies aberrant DNA methylation of MUC2 as a possible cause of extracellular production of mucin in MuBC. [ABSTRACT FROM AUTHOR]

Mucinous carcinoma of the breast (MCB) is a rare histologic form of estrogen receptor (ER)-positive/HER2-negative breast cancer (BC) characterized by tumor cells floating in lakes of mucin. We assessed the genomic landscape of 32 MCBs by whole-exome sequencing and/or RNA-sequencing. GATA3 (23.8%), KMT2C (19.0%), and MAP3K1 (14.3%) were the most frequently mutated genes in pure MCBs. In addition, two recurrent but not pathognomonic fusion genes, OAZ1-CSNK1G2 and RFC4-LPP, were detected in 3/31 (9.7%) and 2/31 (6.5%) samples, respectively. Compared with ER-positive/HER2-negative common forms of BC, MCBs displayed lower PIK3CA and TP53 mutation rates and fewer concurrent 1q gains and 16q losses. Clonal decomposition analysis of the mucinous and ductal components independently microdissected from five mixed MCBs revealed that they are clonally related and evolve following clonal selection or parallel evolution. Our findings indicate that MCB represents a genetically distinct ER-positive/HER2-negative form of BC. [ABSTRACT FROM AUTHOR]

Aims Studies have suggested relationships between obesity and cardiovascular disease (CVD) morbidity. However, little is known about whether substantial weight reduction affects the risk of CVD-related acute care use in obese patients with CVD. The objective of this study was to determine whether bariatric surgery is associated with decreased risk of CVD-related acute care use. Methods and results We performed a self-controlled case series study of obese adults with CVD who underwent bariatric surgery, using population-based emergency department (ED), and inpatient samples in California, Florida, and Nebraska from 2005 to 2011. The primary outcome was ED visit or unplanned hospitalization for CVD. We used conditional logistic regression to compare the risk during sequential 12-month periods, using pre-surgery months 13–24 as the reference period. We identified 11 106 obese adults with CVD who underwent bariatric surgery. During the reference period, 20.6% [95% confidence interval (CI), 19.8–21.3%] of patients had an ED visit or unplanned hospitalization for CVD. The risk did not significantly change in the subsequent 12-month pre-surgery period [adjusted odds ratio (aOR) 0.98; 95% CI, 0.93–1.04; P = 0.42]. By contrast, in the first 12-month period after bariatric surgery, the risk significantly decreased (aOR 0.91; 95% CI, 0.86–0.96; P = 0.002). The risk remained reduced in the subsequent 13–24 months post-bariatric surgery (aOR 0.84; 95% CI, 0.79–0.89; P < 0.001). There was no reduction in the risk in separate obese populations that underwent non-bariatric surgery (i.e. cholecystectomy, hysterectomy). By CVD category, the risk of acute care use for coronary artery disease (CAD), heart failure (HF), and hypertension decreased after bariatric surgery, whereas that of dysrhythmia and venous thromboembolism transiently increased (Bonferroni corrected P < 0.05 for all comparisons). Conclusion Bariatric surgery is associated with a lower risk of overall CVD-related ED visit or unplanned hospitalization. The decline was mainly driven by reduced risk of acute care use for CAD, HF, and hypertension after bariatric surgery. [ABSTRACT FROM AUTHOR]

Background Patients with cognitive impairment associated with schizophrenia may benefit from treatments targeting dysfunctional glutamatergic neurotransmission. BI 409306, a potent and selective phosphodiesterase 9 inhibitor, was assessed in patients with schizophrenia using a learn-and-confirm adaptive trial design. Methods This double-blind, parallel-group trial randomized patients 2:1:1:1:1 to once-daily placebo or BI 409306 (10, 25, 50, or 100 mg) for 12 weeks. Stage 1 (learn) assessed change from baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) scores (week 12) to identify ≥1 meaningful endpoints for stage 2 (confirm). If no domains showed efficacy, change from baseline in Measurements and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) composite scores (week 12) was the primary endpoint. The key secondary endpoint was change from baseline in Schizophrenia Cognition Rating Scale (SCoRS) total score. Safety was monitored. Results Five hundred eighteen patients were randomized. In stage 1, CANTAB did not differentiate between BI 409306 and placebo (n = 120), so the primary endpoint of change from baseline in MCCB composite score was analyzed in 450 patients in stage 2. There was no significant difference between BI 409306 (1.2–2.8) and placebo (2.5) in MCCB composite score change. BI 409306 did not significantly improve change from baseline in SCoRS total score (−3.1 to −2.0) vs placebo (−2.5). Adverse events were dose-dependent, increasing from 33.3% (10 mg) to 53.5% (100 mg), vs 36.4% for placebo. Conclusion The primary endpoint of cognitive function improvement was not met. BI 409306 was well-tolerated, with an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Background: Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after invasive ductal cancer (IDC). Here, we aimed at evaluating the prevalence, levels, and composition of tumor-infiltrating lymphocytes (TILs) and their association with clinico-pathological and outcome variables in ILC, and to compare them with IDC.Methods: We considered two patient series with TIL data: a multicentric retrospective series (n = 614) and the BIG 02-98 study (n = 149 ILC and 807 IDC). We compared immune subsets identified by immuno-histochemistry in the ILC (n = 159) and IDC (n = 468) patients from the Nottingham series, as well as the CIBERSORT immune profiling of the ILC (n = 98) and IDC (n = 388) METABRIC and The Cancer Genome Atlas patients. All ILC/IDC comparisons were done in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors. All statistical tests were two-sided.Results: TIL levels were statistically significantly lower in ILC compared with IDC (fold-change = 0.79, 95% confidence interval = 0.70 to 0.88, P < .001). In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors. In the univariate analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although they did not reach statistical significance in the latter. The Nottingham series revealed that the levels of intratumoral but not total CD8+ were statistically significantly lower in ILC compared with IDC. Comparison of the CIBERSORT profiles highlighted statistically significant differences in terms of immune composition.Conclusions: This study shows differences between the immune infiltrates of ER-positive/HER2-negative ILC and IDC in terms of prevalence, levels, localization, composition, and clinical associations. [ABSTRACT FROM AUTHOR]

This study uses information gleaned from the front matter, or preliminaries, of Spanish Golden Age texts to model the social networks underpinning the early modern publication industry. Using a data-driven approach, we examine the historical and political conditions that influenced the process of approval, censorship, and publication in the Spanish Empire, with a particular focus on the concept of geography, as it relates to the process of community formation and composition. We find that the literary publishing scene was dominated by a small group of authors, generally tied to Madrid, but highly published across Iberian cultural and political capitals. These authors, together with the powerful literary patrons who they relied upon for support, served as local bridges between communities that formed primarily at the local level. Regionally, we find groups of literate bureaucrats, clergymen, printers, and booksellers working together to fulfill the legal requirements for publication as dictated by the Spanish crown. Finally, we see how certain individuals tend to stand out at the regional level as gatekeepers to the publication industry, interacting equally with high- and lowprofile individuals to approve and publish texts. [ABSTRACT FROM AUTHOR]

Summary: Molecular dynamics (MD) determines the physical motions of atoms of a biological macromolecule in a cell-like environment and is an important method in structural bioinformatics. Traditionally, measurements such as root mean square deviation, root mean square fluctuation, radius of gyration, and various energy measures have been used to analyze MD simulations. Here, we present MD-TASK, a novel software suite that employs graph theory techniques, perturbation response scanning, and dynamic cross-correlation to provide unique ways for analyzing MD trajectories. [ABSTRACT FROM AUTHOR]

Background: Encephalitis is parenchymal brain inflammation, commonly due to herpes simplex virus (HSV). Key host inflammatory mediators and their relationship to blood-brain barrier (BBB) permeability, neuroimaging changes, and disease outcome are poorly understood.Methods: We measured levels of 38 mediators in serum (n = 78) and cerebrospinal fluid (n = 37) specimens from patients with encephalitis, including 17 with disease due to HSV infection. Outcome measures were Glasgow coma and outcome scores; CSF to serum albumin ratio, reflecting BBB permeability; and, in patients with HSV infection, magnetic resonance imaging-based temporal lobe volume.Results: Serum interleukin 1 receptor antagonist (IL-1RA) levels were elevated in patients with a good outcome (P= .004). Among patients infected with HSV, the ratio of CSF IL-1β to IL-1RA was associated with a worse outcome (P= .009); a ratio of ≥0.55 pg/mL had high specificity and sensitivity for a poor outcome (100% and 83%;P= .015). Temporal lobe volume had a negative correlation with serum IL-1RA level (P= .012) and a positive correlation with serum IL-1α level (P= .0003) and CSF IL-1β level (P= .007). A normal coma score was associated with an elevated interleukin 10 (IL-10) level in serum specimens from HSV-infected patients (P= .007) and CSF specimens from all patients (P= .016); the IL-10 level correlated inversely with BBB permeability (P= .005).Conclusions: A proinflammatory cytokine response is associated with greater clinical severity, BBB permeability, and neuroimaging damage during encephalitis. IL-1 antagonists should be investigated as adjunctive treatment in encephalitis. [ABSTRACT FROM AUTHOR]

Background: The oral infant rotavirus vaccine, Rotarix, was introduced in England and Wales in July 2013. We estimated the impact on laboratory-confirmed rotavirus infections and hospitalizations for all-cause acute gastroenteritis (AGE) during the first year after introduction.Methods: We extracted data on laboratory-confirmed rotavirus infections (July 2000 through June 2015) and all-cause AGE-associated hospitalizations (July 2007 through June 2014) for all age groups using national databases (LabBase2 and HES). We determined the ratio of the rate during the 2013-2014 rotavirus season to the rate during the prevaccination era.Results: In infants, there was a 77% decline (rate ratio [RR], 0.23; 95% confidence interval [CI], .16-.32) in laboratory-confirmed rotavirus infections and a 26% decline (RR, 0.74; 95% CI, .65-.84) in all-cause AGE-associated hospitalizations in 2013-2014, compared with the prevaccination era. Large reductions were also observed in older children, adults, and older adults. We estimated that 10 884 laboratory-confirmed infections and 50 427 all-cause AGE-associated hospital admissions were averted in 2013-2014. Similar reductions have been observed for laboratory-confirmed rotavirus infections during the 2014-2015 season.Conclusions: The rapid declines in rotavirus infection and AGE in vaccinated and unvaccinated age groups within 1 year of introducing an infant rotavirus vaccination program are far greater than expected and than previously reported by other countries. [ABSTRACT FROM AUTHOR]

The space mission PLATO will usher in a new era of exoplanetary science by expanding our current inventory of transiting systems and constraining host star ages, which are currently highly uncertain. This capability might allow PLATO to detect changes in planetary system architecture with time, particularly because planetary scattering due to Lagrange instability may be triggered long after the system was formed. Here, we utilize previously published instability time-scale prescriptions to determine PLATO's capability to detect a trend of decreasing planet frequency with age for systems with equal-mass planets. For two-planet systems, our results demonstrate that PLATO may detect a trend for planet masses which are at least as massive as super-Earths. For systems with three or more planets, we link their initial compactness to potentially detectable frequency trends in order to aid future investigations when these populations will be better characterized. [ABSTRACT FROM AUTHOR]

Background: Data on home-based records (HBRs) practices within national immunization programmes are nonexistent, making it difficult to determine whether current efforts of immunization programmes related to basic recording of immunization services are appropriately focused. Methods: During January 2014, WHO and the United Nations Children's Fund sent a one-page questionnaire to 195 countries to obtain information on HBRs including type of record used, number of records printed, whether records were provided free-of-charge or required by schools, whether there was a stock-out and the duration of any stock-outs that occurred, as well as the total expenditure for printing HBRs during 2013. Results: A total of 140 countries returned a completed HBR questionnaire. Two countries were excluded from analysis because they did not use a HBR during 2013. HBR types varied across countries (vaccination only cards, 32/138 [23.1%]; vaccination plus growth monitoring records, 31/138 [22.4%]; child health books, 48/138 [34.7%]; combination of these, 27/138 [19.5%] countries). HBRs were provided free-of-charge in 124/138 (89.8%) respondent countries. HBRs were required for school entry in 62/138 (44.9%) countries. Nearly a quarter of countries reported HBR stock-outs during 2013. Computed printing cost per record was

Does language choice attract foreign direct investment ( FDI), and if so, how? We argue that language-a dynamic instrument for reducing transaction costs-can influence investors' decision to allocate capital. Potential host countries attract investments by coordinating their domestic language policies-especially those in education-to match the language of the potential FDI investor. We subject our argument to three different tests: (i) a cross-sectional sample of all global Organization for Economic Co-operation and Development investments that employs a newly constructed language-in-education measurement; (ii) a newly assembled time-series cross-sectional data set of all Chinese FDI abroad; and (iii) a detailed case study that uses process tracing to explain Chinese FDI in Indonesia. The results from these tests demonstrate a significant and robust relationship between language and FDI. [ABSTRACT FROM AUTHOR]

Background. Meropenem plus levofloxacin treatment was shown to be a promising combination in our in vitro hollow fiber infection model. We strove to validate this finding in a murine Pseudomonas pneumonia model. Methods. A dose-ranging study with meropenem and levofloxacin alone and in combination against Pseudomonas aeruginosa was performed in a granulocytopenic murine pneumonia model. Meropenem and levofloxacin were administered to partially humanize their pharmacokinetic profiles in mouse serum. Total and resistant bacterial populations were estimated after 24 hours of therapy. Pharmacokinetic profiling of both drugs was performed in plasma and epithelial lining fluid, using a population model. Results. Meropenem and levofloxacin penetrations into epithelial lining fluid were 39.3% and 64.3%, respectively. Both monotherapies demonstrated good exposure responses. An innovative combination-therapy analytic approach demonstrated that the combination was statistically significantly synergistic (a = 2.475), as was shown in the hollow fiber infection model. Bacterial resistant to levofloxacin and meropenem was seen in the control arm. Levofloxacin monotherapy selected for resistance to itself. No resistant subpopulations were observed in any combination therapy arm. Conclusions. The combination of meropenem plus levofloxacin was synergistic, producing good bacterial kill and resistance suppression. Given the track record of safety of each agent, this combination may be worthy of clinical trial. [ABSTRACT FROM AUTHOR]

BACKGROUND: A low-cost virtual reality system that translates movements of the hand, fingers, and thumb into game play was designed to provide a flexible and motivating approach to increasing adherence to home-based rehabilitation. OBJECTIVE: Effectiveness depends on adherence, so did patients use the intervention to the recommended level? If not, what reasons did they give? The purpose of this study was to investigate these and related questions. DESIGN: A prospective cohort study, plus qualitative analysis of interviews, was conducted. METHODS: Seventeen patients recovering from stroke recruited to the intervention arm of a feasibility trial had the equipment left in their homes for 8 weeks and were advised to use it 3 times a day for periods of no more than 20 minutes. Frequency and duration of use were automatically recorded. At the end of the intervention, participants were interviewed to determine barriers to using it in the recommended way. RESULTS: Duration of use and how many days they used the equipment are presented for the 13 participants who successfully started the intervention. These figures were highly variable and could fall far short of our recommendations. There was a weak positive correlation between duration and baseline reported activities of daily living. Participants reported familiarity with technology and competing commitments as barriers to use, although they appreciated the flexibility of the intervention and found it motivating. LIMITATIONS: The small sample size limits the conclusions that can be drawn. CONCLUSIONS: Level of use is variable and can fall far short of recommendations. Competing commitments were a barrier to use of the equipment, but participants reported that the intervention was flexible and motivating. It will not suit everyone, but some participants recorded high levels of use. Implications for practice are discussed. [ABSTRACT FROM AUTHOR]

Background. Killing of bacterial pathogens by granulocytes is a saturable process, as previously demonstrated. There is virtually no quantitative information about how granulocytes interact with antimicrobial chemotherapy to kill bacterial cells.Methods. We performed a dose-ranging study with the aminoglycoside plazomicin against Pseudomonas aeruginosa ATCC27853 in a granulocyte-replete murine pneumonia model. Plazomicin was administered in a humanized fashion (ie, administration of decrementing doses 5 times over 24 hours, mimicking a human daily administration profile). Pharmacokinetic profiling was performed in plasma and epithelial lining fluid. All samples were simultaneously analyzed with a population model. Mouse cohorts were treated for 24 hours; other cohorts treated with the same therapy were observed for another 24 hours after therapy cessation, allowing delineation of the therapeutic effect necessary to reduce the bacterial burden to a level below the half-saturation point.Results. The mean bacterial burden (±SD) at which granulocyte-mediated kill was half saturable was 2.45 × 106 ± 6.84 × 105 colony-forming units of bacteria per gram of tissue (CFU/g). Higher levels of plazomicin exposure reduced the bacterial burden to <5 log10 CFU/g, allowing granulocytes to kill an additional 1.0–1.5 log CFU/g over the subsequent 24 hours.Conclusions. For patients with large bacterial burdens (eg, individuals with ventilator-requiring hospital-acquired pneumonia), it is imperative to kill ≥2 log10 CFU/g early after treatment initiation, to allow the granulocytes to contribute optimally to bacterial clearance. [ABSTRACT FROM AUTHOR]

Objective. Emergency department (ED) visits for opioid overdose provide an important marker of acute morbidity. We sought to evaluate national trends of ED visits for opioid overdose. Design, Setting, and Participants. The National Hospital Ambulatory Medical Care Survey, 1993-2010, was used to identify ED visits for opioid overdose. Outcome Measures. Outcome measures were national ED visit rates for opioid overdose per 100,000 U.S. population and per 100,000 ED visits. Results. From 1993 to 2010, there were approximately 731,000 ED visits (95% CI, 586,000-877,000 visits) for opioid overdose, representing an overall rate of 14 ED visits (95% CI, 12-17 visits) per 100,000 population and 37 ED visits (95% CI, 31-45 visits) per 100,000 ED visits. Of these, 41% (95% CI, 33-50%) were for prescription opioid overdose. Between 1993 and 2010, the national visit rate increased from 7 to 27 per 100,000 population (+307%; Ptrend = 0.03), and from 19 to 63 per 100,000 ED visits (+235%; Ptrend < 0.001). Stratified analyses of the visit rate per population showed upward, but nonsignificant, trends across multiple demographic groups and U.S. regions. In stratified analyses of the visit rate per 100,000 ED visits, the rate increased significantly in several groups: age <20 years (+1188%; Ptrend = 0.002), age 20-29 years (+155%; Ptrend = 0.04), age ⩾50 years (+231%; Ptrend = 0.04), female (+234%; Ptrend = 0.001), male (+80%; Ptrend = 0.04), whites (+187%; Ptrend < 0.001), and patients in the South (+371%; Ptrend < 0.001). Conclusion. In a nationally representative database of U.S. ED visits, we found that the ED visit rate for opioid overdose quadrupled from 1993 to 2010. Our findings suggest that previous prevention measures may not be adequate. [ABSTRACT FROM AUTHOR]

The article talks about the cultural theology of salvation through reference of variety of ancient Jewish and Christian sources that refer to a sexual liaison between Satan and Eve, a union that resulted in the birth of Cain. It mentions about the features of the Adam and Eve narratives as the tradition that Eve consorted with Satan; and also presents sources for the tradition of Eve's sexual seduction as the Greek and Latin Lives of Adam and Eve.

Pathogenic germline variants in checkpoint kinase 2 (CHEK2), which plays pivotal roles in DNA damage response and cell cycle regulation, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic and genomic characteristics of 33 BCs from CHEK2 germline mutation carriers (16 high-risk variants and 17 low-risk p.Ile157Thr variants). CHEK2 -associated BCs from patients with high-risk germline variants were largely hormone receptor-positive (87%, 13/15), and 81% (13/16) exhibited loss of heterozygosity (LOH) of the CHEK2 wild-type allele. Conversely, CHEK2 -associated BCs from patients with the low-risk p.Ile157Thr variant displayed less-frequent loss of heterozygosity (5/17, 29%) and higher levels of CHEK2 protein expression than those with high-risk germline variants. CHEK2 -associated BCs lacked a dominant mutational signature 3, a genomics feature of homologous recombination DNA repair deficiency (HRD). Our findings indicate that CHEK2 -associated BCs are generally hormone receptor-positive and lack HRD-related mutational signatures, recapitulating the features of ATM -associated BCs. Specific CHEK2 germline variants may have a distinct impact on tumor biology. [ABSTRACT FROM AUTHOR]