Our objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative ...infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR Gram-negative infection. The primary efficacy outcome, evaluated among patients with MDR
infections, was composite clinical failure, namely, 30-day all-cause mortality, 30-day recurrence, and/or failure to resolve or improve infection signs or symptoms after C/T treatment. In total, 259 patients were included, and
was isolated in 236 (91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of
isolates, respectively. The most common infection source was the respiratory tract (62.9%). High-dose C/T was used in 71.2% of patients with a respiratory tract infection (RTI) overall but in only 39.6% of patients with an RTI who required C/T renal dose adjustment. In the primary efficacy population (
= 226), clinical failure and 30-day mortality occurred in 85 (37.6%) and 39 (17.3%) patients, respectively. New C/T MDR
resistance was detected in 3 of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and Acute Physiological and Chronic Health Evaluation II (APACHE II) score were independently associated with clinical failure (adjusted odds ratio aOR, 2.472 and 95% confidence interval CI, 1.322 to 4.625; and aOR, 1.068 and 95% CI, 1.031 to 1.106, respectively). Twenty-five (9.7%) patients experienced ≥1 adverse effect (9 acute kidney injury, 13
infection, 1 hepatotoxicity, 2 encephalopathy, and 2 gastrointestinal intolerance). C/T addresses an unmet medical need in patients with MDR Gram-negative infections.
The net tectonic rotation method is an alternative to paleomagnetic tilt corrections. The method was originally developed for sedimentary rocks and lavas, which have paleohorizontal indicators, but ...was later adapted for dikes by assuming that dikes intrude vertically. We conduct multiple numerical experiments that demonstrate geometric flaws in the net tectonic rotation method if dikes are not quite vertical prior to deformation. These flaws can impact the interpretations from the method, but the size of the impact depends on the original dike strike, dike dip, and the paleomagnetic reference direction. Our experiments show the worst behavior occurs for dikes that are approximately perpendicular to the reference declination. In addition, the results for dipping dikes of all initial strikes become increasingly distorted as the reference direction's inclination increases. Using data from two field areas in Cyprus and northern Iceland, we compare the application of net tectonic rotation to alternative techniques—relative comparisons and spatial regressions—that do not require an assumption of initially vertical dikes. We conclude with a list of questions that workers should answer prior to future application of net tectonic rotation to dikes.
Plain Language Summary
A dike is a tabular intrusion of volcanic rock. It may record the direction of Earth's magnetic field at the time of the dike's formation, and it may subsequently rotate due to tectonic processes. By analyzing the magnetic content of a dike, a geologist can therefore acquire information about Earth's tectonic history. Net tectonic rotation is a particular technique for acquiring such information. It assumes that dikes are vertical at the time of their intrusion. We perform experiments that show that if dikes are not quite vertical, the inferences from this technique will be flawed. The flaws are not systematic and in some cases can lead to egregious errors in the interpretations. We show some alternatives to this approach using real data from Cyprus and northern Iceland. We also list a series of questions for workers to consider if they wish to use this method in the future.
Key points
The net tectonic rotation method has been used to predict initial dike strikes from paleomagnetic data
The method assumes that dikes are initially vertical and can return the correct dike strike in these cases
Numerical experiments show the method returns biased answers for dipping dikes that may impact geologic interpretations
Expansions of short tandem repeats (STRs) cause many rare diseases. Expansion detection is challenging with short-read DNA sequencing data since supporting reads are often mapped incorrectly. ...Detection is particularly difficult for "novel" STRs, which include new motifs at known loci or STRs absent from the reference genome. We developed STRling to efficiently count k-mers to recover informative reads and call expansions at known and novel STR loci. STRling is sensitive to known STR disease loci, has a low false discovery rate, and resolves novel STR expansions to base-pair position accuracy. It is fast, scalable, open-source, and available at: github.com/quinlan-lab/STRling .
Abstract
Background
Delirium is common, distressing and associated with poor outcomes. Previous studies investigating the impact of delirium on cognitive outcomes have been limited by incomplete ...ascertainment of baseline cognition or lack of prospective delirium assessments. This study quantified the association between delirium and cognitive function over time by prospectively ascertaining delirium in a cohort aged ≥ 65 years in whom baseline cognition had previously been established.
Methods
For 12 months, we assessed participants from the Cognitive Function and Ageing Study II-Newcastle for delirium daily during hospital admissions. At 1-year, we assessed cognitive decline and dementia in those with and without delirium. We evaluated the effect of delirium (including its duration and number of episodes) on cognitive function over time, independently of baseline cognition and illness severity.
Results
Eighty two of 205 participants recruited developed delirium in hospital (40%). One-year outcome data were available for 173 participants: 18 had a new dementia diagnosis, 38 had died. Delirium was associated with cognitive decline (−1.8 Mini-Mental State Examination points 95% CI –3.5 to –0.2) and an increased risk of new dementia diagnosis at follow up (OR 8.8 95% CI 1.9–41.4). More than one episode and more days with delirium (>5 days) were associated with worse cognitive outcomes.
Conclusions
Delirium increases risk of future cognitive decline and dementia, independent of illness severity and baseline cognition, with more episodes associated with worse cognitive outcomes. Given that delirium has been shown to be preventable in some cases, we propose that delirium is a potentially modifiable risk factor for dementia.
As anthropogenic changes continue to ecologically stress wildlife, obtaining measures of gene flow and genetic diversity are crucial for evaluating population trends and considering management and ...conservation strategies for small, imperiled populations. In our study, we conducted a molecular assessment to expand on previous work to elucidate patterns of diversity and connectivity in the remaining disjunct Eastern Massasauga Rattlesnake (Sistrurus catenatus) hibernacula in Illinois. We assayed genetic data for 327 samples collected during 1999-2015 from the Carlyle Lake study area across 21 microsatellite loci. We found hibernacula formed distinct genetic clusters corresponding to the three main study areas (Dam Recreation Areas, Eldon Hazlet State Park, and South Shore State Park). Genetic structuring and low estimates of dispersal indicated that connectivity among these study areas is limited and each is demographically independent. Hibernacula exhibited moderate levels of heterozygosity (0.60-0.73), but estimates of effective population size (5.2-41.0) were low and track census sizes generated via long-term mark-recapture data. Hibernacula at Carlyle Lake, which represent the only Eastern Massasauga remaining in Illinois, are vulnerable to future loss of genetic diversity through lack of gene flow as well as demographic and environmental stochastic processes. Our work highlights the need to include population-level genetic data in recovery planning and suggests that recovery efforts should focus on managing the three major study areas as separate conservation units in order to preserve and maintain long-term adaptive potential of these populations. Specific management goals should include improving connectivity among hibernacula, maintaining existing wet grassland habitat, and minimizing anthropogenic sources of mortality caused by habitat management (e.g., mowing, prescribed fire) and recreational activities. Our molecular study provides additional details about demographic parameters and connectivity at Carlyle Lake that can be used to guide recovery of Eastern Massasauga in Illinois and throughout its range.
We present the design of a portable coronagraph, CATEcor (where CATE stands for Continental-America Telescope Eclipse), that incorporates a novel “shaded-truss” style of external occultation and ...serves as a proof-of-concept for that family of coronagraphs. The shaded-truss design style has the potential for broad application in various scientific settings. We conceived CATEcor itself as a simple instrument to observe the corona during the darker skies available during a partial solar eclipse, or for students or interested amateurs to detect the corona under ideal noneclipsed conditions. CATEcor is therefore optimized for simplicity and accessibility to the public. It is implemented using an existing dioptric telescope and an adapter rig that mounts in front of the objective lens, restricting the telescope aperture and providing external occultation. The adapter rig, including occulter, is fabricated using fusion deposition modeling (FDM; colloquially “3D printing”), greatly reducing cost. The structure is designed to be integrated with moderate care and may be replicated in a university or amateur setting. While CATEcor is a simple demonstration unit, the design concept, process, and trades are useful for other more sophisticated coronagraphs in the same general family, which might operate under normal daytime skies outside the annular-eclipse conditions used for CATEcor.
Previous research has identified a number of patient and operative factors associated with anastomotic leak after colectomy; however, a study that examines these factors on a national level with ...direct coding for anastomotic leak is lacking.
The purpose of this work was to identify risk factors associated with anastomotic leak on a national level and quantify the additional morbidity and mortality experienced by these patients.
We performed a retrospective analysis of patients who underwent segmental colectomy with anastomosis from the 2012 American College of Surgeons National Surgical Quality Improvement Program colectomy procedure-targeted database. Anastomotic leak was defined as minor leak requiring percutaneous intervention or major leak requiring laparotomy. Multivariate logistic regression was used to determine predictors of anastomotic leak and its impact on postoperative outcomes.
This study was conducted at a tertiary university department.
This study includes 13,684 patients who underwent segmental colectomy with anastomosis at American College of Surgeons National Surgical Quality Improvement Program-affiliated hospitals in 2012.
The primary outcome studied was anastomotic leak.
The overall leak rate was 3.8%. Male sex, steroid use, smoking, open approach, operative time, and preoperative chemotherapy were associated with increased anastomotic leaks and diverting ileostomy with decreased incidence of leaks on multivariate analysis. Increased length of stay (13 vs 5 days; p < 0.001) and increased 30-day mortality (6.8% vs 1.6%; p < 0.001) were also seen in patients who experienced leaks. These patients also experienced increased readmission rates (43.5% vs 8.3%; p < 0.001) and were 37 times more likely to require reoperation as a complication of their primary procedure (p < 0.001).
The main limitations of this study include its retrospective nature and the limited 30-day outcomes recorded in the American College of Surgeons National Surgical Quality Improvement Program database.
This study identified patient and operative risk factors for anastomotic leak on a national scale. It also demonstrates that these patients have increased morbidity and 30-day mortality rates, experience multiple readmissions to the hospital, and have a higher likelihood of requiring further operative intervention.
Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication ...from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.
To examine the associations between depression in fathers of 1-year-old children and specific positive and negative parenting behaviors discussed by pediatric providers at well-child visits.
We ...performed a cross-sectional secondary analysis by using interview data from 1746 fathers of 1-year-old children in the Fragile Families and Child Wellbeing Study. Positive parenting behaviors included fathers' reports of playing games, singing songs, and reading stories to their children ≥ 3 days in a typical week. Negative parenting behavior included fathers' reports of spanking their 1-year-old children in the previous month. Depression was assessed by using the World Health Organization Composite International Diagnostic Interview Short Form. Weighted bivariate and multivariate analyses of parenting behaviors were performed while controlling for demographics and paternal substance abuse.
Overall, 7% of fathers had depression. In bivariate analyses, depressed fathers were more likely than nondepressed fathers to report spanking their 1-year-old children in the previous month (41% compared with 13%; P < .01). In multivariate analyses, depressed fathers were less likely to report reading to their children ≥ 3 days in a typical week (adjusted odds ratio: 0.38 95% confidence interval: 0.15-0.98) and much more likely to report spanking (adjusted odds ratio: 3.92 95% confidence interval: 1.23-12.5). Seventy-seven percent of depressed fathers reported talking to their children's doctor in the previous year.
Paternal depression is associated with parenting behaviors relevant to well-child visits. Pediatric providers should consider screening fathers for depression, discussing specific parenting behaviors (eg, reading to children and appropriate discipline), and referring for treatment if appropriate.
In addition to their well-defined roles in replenishing depleted endoplasmic reticulum (ER) Ca(2+) reserves, molecular components of the store-operated Ca(2+) entry pathway regulate breast cancer ...metastasis. A process implicated in cancer metastasis that describes the conversion to a more invasive phenotype is epithelial-mesenchymal transition (EMT). In this study we show that EGF-induced EMT in MDA-MB-468 breast cancer cells is associated with a reduction in agonist-stimulated and store-operated Ca(2+) influx, and that MDA-MB-468 cells prior to EMT induction have a high level of non-stimulated Ca(2+) influx. The potential roles for specific Ca(2+) channels in these pathways were assessed by siRNA-mediated silencing of ORAI1 and transient receptor potential canonical type 1 (TRPC1) channels in MDA-MB-468 breast cancer cells. Non-stimulated, agonist-stimulated and store-operated Ca(2+) influx were significantly inhibited with ORAI1 silencing. TRPC1 knockdown attenuated non-stimulated Ca(2+) influx in a manner dependent on Ca(2+) influx via ORAI1. TRPC1 silencing was also associated with reduced ERK1/2 phosphorylation and changes in the rate of Ca(2+) release from the ER associated with the inhibition of the sarco/endoplasmic reticulum Ca(2+)-ATPase (time to peak Ca(2+)(CYT) = 188.7 ± 34.6 s (TRPC1 siRNA) versus 124.0 ± 9.5 s (non-targeting siRNA); P<0.05). These studies indicate that EMT in MDA-MB-468 breast cancer cells is associated with a pronounced remodeling of Ca(2+) influx, which may be due to altered ORAI1 and/or TRPC1 channel function. Our findings also suggest that TRPC1 channels in MDA-MB-468 cells contribute to ORAI1-mediated Ca(2+) influx in non-stimulated cells.
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