Search

Prior literature has associated preoperative corticosteroid shoulder injection (CSI) with infection following shoulder surgery. A recent study found an equally elevated risk of total knee arthroplasty infection with preoperative injection of either CSI or hyaluronic acid. The implication is that violation of a joint prior to surgery, even in the absence of corticosteroid, may pose an elevated risk of infection following orthopedic surgery. The aim of the present study was to determine whether violation of the shoulder joint for Magnetic Resonance Arthrogram (MRA) poses an elevated risk of infection following shoulder arthroscopy and to compare this risk to that introduced by preoperative CSI.A national, all-payer database was queried to identify patients undergoing shoulder arthroscopy between January 2015 and October 2020. Patients were stratified into the following groups: (1) no CSI or MRA within 6 months of surgery (n = 5,000), (2) CSI within 2 weeks of surgery (n = 1,055), (3) CSI between 2 and 4 weeks prior to surgery (n = 2,575), (4) MRA within 2 weeks of surgery (n = 414), (5) MRA between 2 and 4 weeks prior to surgery (n = 1,138). Postoperative infection (septic shoulder or surgical site infection) was analyzed at 90-days, 1-year, and 2-years postoperatively. Multivariable logistic regression analysis controlled for differences among groups.MRA within 2 weeks prior to shoulder surgery was associated with an increased risk of infection at 1 year (OR, 2.17; P = 0.007), while MRA 2-4 weeks preceding surgery was not associated with an increased risk of postoperative infection at any time point. By comparison, CSI within 2 weeks prior to surgery was associated with an increased risk of postoperative infection at 90-days (OR, 1.72; P = 0.022), 1-year (OR, 1.65; P = 0.005) and 2-years (OR, 1.63; P = 0.002) following surgery. Similarly, CSI 2-4 weeks prior to surgery was associated with an increased risk of postoperative infection at 90-days (OR, 1.83; P0.001), 1-year (OR, 1.62; P0.001), and 2-years (OR, 1.79; P0.001).Preoperative CSI within 4 weeks of shoulder arthroscopy elevates the risk of postoperative infection. Needle arthrotomy for shoulder MRA elevates the risk of infection in a more limited fashion. Avoidance of MRA within 2 weeks of shoulder arthroscopy may mitigate postoperative infection risk. Additionally, the association between preoperative CSI and postoperative infection may be more attributed to medication profile than to needle arthrotomy.

To explore brain activation patterns on functional MRI (fMRI) in men with BPH and BOO before and after outlet obstruction procedures.Men age ≥45 who failed conservative BPH therapy planning to undergo BOO procedures were recruited. Eligible men underwent a concurrent fMRI/urodynamics testing before and 6 months after BOO procedure. fMRI images were obtained via 3 Tesla MRI. Significant blood-oxygen-level-dependent (BOLD) signal activated voxels (P.05) were identified at strong desire to void and (attempt at) voiding initiation pre- and post-BOO procedure.Eleven men were enrolled, of which 7 men completed the baseline scan, and 4 men completed the 6-month follow-up scan. Baseline decreased BOLD activity was observed in right inferior frontal gyrus (IFG), bilateral insula, inferior frontal gyrus (IFG) and thalamus. Significant changes in BOLD signal activity following BOO procedures were observed in the insula, IFG, and cingulate cortices.This represents a pilot study evaluating cortical activity in men with BPH and BOO. Despite limitations we found important changes in supraspinal activity in men with BPH and BOO during filling and emptying phases at baseline and following BOO procedure, with the potential to improve our understanding of neuroplasticity secondary to BPH and BOO. This preliminary data may serve as the foundation for larger future trials.

We study the problem of Nadler and Quinn from 1972, which asks whether, given an arc-like continuum $X$ and a point $x \in X$, there exists an embedding of $X$ in $\mathbb{R}^2$ for which $x$ is an accessible point. We develop the notion of a radial departure of a map $f \colon [-1,1] \to [-1,1]$, and establish a simple criterion in terms of the bonding maps in an inverse system on intervals to show that there is an embedding of the inverse limit for which a given point is accessible. Using this criterion, we give a partial affirmative answer to the problem of Nadler and Quinn, under some technical assumptions on the bonding maps of the inverse system., 23 pages, 8 figures

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers., C12292/A20861 PPRPGM-Nov20\100002

Patient satisfaction has become an increasingly important component of quality measures for both hospital reimbursement and quality assessment. Additionally, patient satisfaction influences patient behavior and patient follow-up. The purpose of this study was to identify preoperative factors associated with patient satisfaction 2 years after shoulder surgery.Electronic surveys were used to collect patient information including demographic, surgical, and social history, as well as outcome data. Satisfaction was measured 2 years after surgery using the Surgical Satisfaction Questionnaire.Multivariable linear regression identified preoperative Patient-Reported Outcomes Measurement Information System Pain Interference, annual income, and American Society of Anesthesiologists score as independent predictors of lower patient satisfaction, while total shoulder arthroplasty was an independent predictor of greater patient satisfaction. The model accounted for 15% of the variance in satisfaction scores (RPatient satisfaction 2 years after shoulder surgery is associated with preoperative patient-reported outcome scores. Lower patient satisfaction is independently predicted by greater preoperative PROMIS PI, income less than $70,000, and ASA score1, while higher patient satisfaction is predicted by total shoulder arthroplasty.

BackgroundAsthma is a leading cause of childhood morbidity in the U.S. and a significant public health concern. The prenatal period is a critical window during which environmental influences, including maternal occupational exposures, can shape child respiratory health. Cleaning chemicals are commonly encountered in occupational settings, yet few studies have examined the potential link between prenatal occupational exposures to cleaning chemicals and risk of childhood wheeze and asthma.MethodsWe evaluated the potential influence of maternal occupational exposure to cleaning chemicals during pregnancy on pediatric asthma and wheeze at child age 4–6 years in 453 mother-child pairs from two longitudinal pregnancy cohorts, TIDES and GAPPS, part of the ECHO prenatal and early childhood pathways to health (ECHO-PATHWAYS) consortium. Maternal occupational exposure to cleaning chemicals was defined based on reported occupation and frequency of occupational use of chemicals during pregnancy. Child current wheeze and asthma outcomes were defined by parental responses to a widely-used, standardized respiratory outcomes questionnaire administered at child age 4–6 years. Multivariable Poisson regression with robust standard errors was used to estimate relative risk (RR) of asthma in models adjusted for confounding. Effect modification by child sex was assessed using product interaction terms.ResultsOverall, 116 mothers (25.6%) reported occupational exposure to cleaning chemicals during pregnancy, 11.7% of children had current wheeze, and 10.2% had current asthma. We did not identify associations between prenatal exposure to cleaning chemicals and current wheeze [RRadjusted 1.03, 95% confidence interval (CI): 0.56, 1.90] or current asthma (RRadjusted 0.89, CI: 0.46, 1.74) in the overall sample. Analyses of effect modification suggested an adverse association among females for current wheeze (RR 1.82, CI: 0.76, 4.37), compared to males (RR 0.68, CI: 0.29, 1.58), though the interaction p-value was >0.05.ConclusionWe did not observe evidence of associations between maternal prenatal occupational exposure to cleaning chemicals and childhood wheeze or asthma in the multi-site ECHO-PATHWAYS consortium. We leveraged longitudinal U.S. pregnancy cohorts with rich data characterization to expand on limited and mixed literature. Ongoing research is needed to more precisely characterize maternal occupational chemical exposures and impacts on child health in larger studies.

Supplementary Table 2. Results of the statistical analyses in BRCA mutation carriers.

Supplementary Table 1. The 3,248 SNPs included in the study

Supplementary Table 3. Results of the statistical analyses of SNPs from project 12 in BRCA-mutation carriers affected or non-affected with breast cancer and according to their estrogen receptor status.

Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes.Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.

ZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimer’s Disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis. Co-immunoprecipitation of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17’s binding partners are enriched for RNA splicing proteins. ZCCHC17 knockdown results in widespread RNA splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression correlates with cognitive resilience in AD patients, and we uncover an APOE4 dependent negative correlation of ZCCHC17 expression with tangle burden. Furthermore, a majority of ZCCHC17 interactors also co-IP with known tau interactors, and we find significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons. These results demonstrate ZCCHC17’s role in neuronal RNA processing and its interaction with pathology and cognitive resilience in AD, and suggest that maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology.SignificanceAbnormal RNA processing is an important component of AD pathophysiology. We show here that ZCCHC17, a previously identified putative master regulator of synaptic dysfunction in AD, plays a role in neuronal RNA processing, and illustrate that ZCCHC17 dysfunction is sufficient to explain some of the splicing abnormalities seen in AD brain tissue, including synaptic gene splicing abnormalities. Using data from human patients, we demonstrate that ZCCHC17 mRNA levels correlate with cognitive resilience in the setting of AD pathology. These results suggest that maintenance of ZCCHC17 function may be a therapeutic strategy for supporting cognitive function in AD patients, and motivate future work examining a possible role of abnormal RNA processing in AD-related cognitive decline.

The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) framework for classifying variants uses six evidence categories related to the splicing potential of variants: PVS1 (null variant in a gene where loss-of-function is the mechanism of disease), PS3 (functional assays show damaging effect on splicing), PP3 (computational evidence supports a splicing effect), BS3 (functional assays show no damaging effect on splicing), BP4 (computational evidence suggests no splicing impact), and BP7 (silent change with no predicted impact on splicing). However, the lack of guidance on how to apply such codes has contributed to variation in the specifications developed by different Clinical Genome Resource (ClinGen) Variant Curation Expert Panels. The ClinGen Sequence Variant Interpretation (SVI) Splicing Subgroup was established to refine recommendations for applying ACMG/AMP codes relating to splicing data and computational predictions. Our study utilised empirically derived splicing evidence to: 1) determine the evidence weighting of splicing-related data and appropriate criteria code selection for general use, 2) outline a process for integrating splicing-related considerations when developing a gene-specific PVS1 decision tree, and 3) exemplify methodology to calibrate bioinformatic splice prediction tools. We propose repurposing of the PVS1_Strength code to capture splicing assay data that provide experimental evidence for variants resulting in RNA transcript(s) with loss of function. Conversely BP7 may be used to capture RNA results demonstrating no impact on splicing for both intronic and synonymous variants, and for missense variants if protein functional impact has been excluded. Furthermore, we propose that the PS3 and BS3 codes are applied only for well-established assays that measure functional impact that is not directly captured by RNA splicing assays. We recommend the application of PS1 based on similarity of predicted RNA splicing effects for a variant under assessment in comparison to a known Pathogenic variant. The recommendations and approaches for consideration and evaluation of RNA assay evidence described aim to help standardise variant pathogenicity classification processes and result in greater consistency when interpreting splicing-based evidence.

In most bird species, females disperse prior to their first breeding attempt, while males remain close to the place they hatched. While explanations for such female bias in natal dispersal have focused on the resource-defense based monogamous mating system that is prevalent in most birds, the factors shaping dispersal decisions are often more complex. Studying species with different social and mating systems can help illuminate the various factors shaping sex biased dispersal. Here, we use genetic approaches to determine whether females and/or males disperse in great-tailed grackles (Quiscalus mexicanus), which have a mating system where the males hold breeding territories that multiple females might choose to place their nest in, but females forage independently of these breeding territories across a wider area. We find that for individuals caught at a single site in Arizona, (i) the average relatedness among all female dyads, but not of males, is higher than average relatedness among other individuals at the site; (ii) that female close relatives are found within shorter distances from each other than pairs of unrelated females, but male close relatives at larger distances than pairs of unrelated males; and (iii) we find a decline in relatedness with increasing spatial distances for females, but not for males. Our findings show that great-tailed grackles offer opportunities to understand how divergent social and mating systems might shape natal philopatry and dispersal, given their reversal of the usual sex-bias in dispersal with females associating with genetic relatives while males are not.

Multiple demethylation-inhibiting (DMI) fungicides are used to control pecan scab, caused by Venturia effusa. To compare the efficacy of various DMI fungicides on V. effusa, field trials were conducted at multiple locations applying fungicides to individual pecan terminals. In vitro assays were conducted to test the sensitivity of V. effusa isolates from multiple locations to various concentrations of tebuconazole. Both studies confirmed high levels of resistance to tebuconazole. To investigate the mechanism of resistance, two copies of the CYP51 gene, CYP51A and CYP51B, of resistant and sensitive isolates were sequenced and scanned for mutations. In the CYP51A gene, mutation at codon 444 (G444D), and in the CYP51B gene, mutations at codon 357 (G357H) and 177 (I77T/I77L) were found in resistant isolates. Expression analysis of CYP51A and CYP51B revealed enhanced expression in the resistant isolates compared to the sensitive isolates. There were 3.0- and 1.9-fold increases in gene expression in the resistant isolates compared to the sensitive isolates for the CYP51A and CYP51B genes, respectively. Therefore, two potential mechanisms—multiple point mutations and gene over expression in the CYP51 gene of V. effusa isolates—were revealed as likely reasons for the observed resistance in isolates of V. effusa to tebuconazole.

ObjectiveChronic stress can undermine psychological and physiological health. We sought to evaluate three stress management interventions among clergy, accounting for intervention preferences.MethodsUnited Methodist clergy in North Carolina enrolled in a partially randomized, preference-based waitlist control trial. The interventions were: mindfulness-based stress reduction (MBSR), Daily Examen prayer practice, and Stress Proofing (stress inoculation plus breathing skills). The intervention period spanned 12 weeks with a 12-week follow-up. Daily text message data were collected to assess practice across the 24 weeks. Co-primary outcomes were symptoms of stress using the Calgary Symptoms of Stress Inventory and 48-hour ambulatory heart rate variability (HRV) at 12-weeks post-intervention compared to waitlist control. Survey data were collected at 0, 12 and 24 weeks, with HRV collected at 0 and 12 weeks.Results255 participants (mean age=54 years old; 91% white; 48% female) were randomized and initiated an intervention (n=184) or waitlist control (n=71). Compared to waitlist control, lower stress symptoms were found for MBSR participants [Mean Difference (MD)=-0.30, 95% CI:-0.41,-0.20;ppp=.036).ConclusionsMBSR demonstrated robust improvement in self-reported and objective physical correlates of stress whereas Stress Proofing and Daily Examen resulted in improvements in self-reported correlates of stress only. These brief practices were sustainable and beneficial for an occupational sample during the COVID pandemic.RegistrationClinicalTrials.govidentifier:NCT04625777(https://clinicaltrials.gov/ct2/show/NCT04625777)

Introduction Like many helping professionals in emotional labor occupations, clergy experience high rates of mental and physical comorbidities. Regular stress management practices may reduce stress-related symptoms and morbidity, but more research is needed into what practices can be reliably included in busy lifestyles and practiced at a high enough level to meaningfully reduce stress symptoms. Methods and analysis The overall design is a preference-based randomized waitlist control trial. United Methodist clergy in North Carolina will be eligible to participate. The intervention and waitlist control groups will be recruited by email. The interventions offered are specifically targeted to clergy preference and include mindfulness-based stress reduction, Daily Examen, and stress inoculation training. Surveys will be conducted at 0, 12, and 24 weeks with heart rate data collected at 0 and 12 weeks. The primary outcomes for this study are self-reported symptoms of stress and heart rate at week 12 for each intervention compared to waitlist control; the secondary outcome is symptoms of anxiety comparing each intervention vs waitlist control. Ethics and dissemination Ethical approval was obtained from the Duke University Campus IRB (2019-0238). The results will be made available to researchers, funders, and members of the clergy community. Strengths and limitations of this study While evidence-based stress reduction practices such as mindfulness-based stress reduction (MBSR) exist, a wider variety of practices should be tested to appeal to different individuals. Clergy in particular may prefer, and consequently enact, spiritual practices like the Daily Examen, and individuals such as clergy who spend most of their time thinking and feeling may prefer experiential-based practices like stress inoculation training. If efficacious, the Daily Examen and stress inoculation training practices have high feasibility in that they require few minutes per day. This study is limited by the inclusion of Christian clergy of only one denomination. Trial registration ClinicalTrials.gov NCT04625777. November 12, 2020.

The majority of women do not meet the recommended levels of exercise during their pregnancies, frequently due to a lack of time. High-intensity interval training offers a potential solution, providing an effective, time-efficient exercise modality. This exercise modality has not been studied in pregnancy therefore, the objective of this study was to evaluate fetal response to a high-intensity interval training resistance circuit in the late second and early third trimesters of pregnancy. Fourteen active, healthy women with uncomplicated, singleton pregnancies participated in a high-intensity interval training resistance circuit between 28 + 0/7 and 32 + 0/7 weeks. A Borg rating of perceived exertion of 15–17/20 and an estimated heart rate of 80%–90% of maternal heart-rate maximum was targeted. Fetal well-being was evaluated continuously with fetal heart-rate tracings and umbilical artery Doppler velocimetry conducted pre-and post-exercise. Fetal heart rate tracings were normal throughout the exercise circuit. Post-exercise, umbilical artery end-diastolic flow was normal and significant decreases were observed in the mean systolic/diastolic ratios, pulsatility indexes and resistance indexes. Therefore, in a small cohort of active pregnant women, a high-intensity interval training resistance circuit in the late second and early third trimesters of pregnancy appears to be a safe exercise modality with no acute, adverse fetal effects but further study is required. Novelty: High-intensity interval training, at an intensity in excess of current recommendations, does not appear to be associated with any adverse fetal effects in previously active pregnant women. High-intensity interval training is an enjoyable and effective exercise modality in previously active pregnant women.

As of November 14, 2022, monkeypox (mpox) cases had been reported from more than 110 countries, including 29,133 cases in the United States.* Among U.S. cases to date, 95% have occurred among males (1). After the first confirmed U.S. mpox case on May 17, 2022, limited supplies of JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic) were made available to jurisdictions for persons exposed to mpox. JYNNEOS vaccine was approved by the Food and Drug Administration (FDA) in 2019 as a 2-dose series (0.5 mL per dose, administered subcutaneously) to prevent smallpox and mpox disease.

As of October 28, 2022, a total of 28,244* monkeypox (mpox) cases have been reported in the United States during an outbreak that has disproportionately affected gay, bisexual, and other men who have sex with men (MSM) (1). JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic), administered subcutaneously as a 2-dose (0.5 mL per dose) series (with doses administered 4 weeks apart), was approved by the Food and Drug Administration (FDA) in 2019 to prevent smallpox and mpox disease (2); an FDA Emergency Use Authorization issued on August 9, 2022, authorized intradermal administration of 0.1 mL per dose, increasing the number of persons who could be vaccinated with the available vaccine supply

This study used high-resolution real-data WRF simulations of Hurricane Ivan (2004) to document the structure of potentially tornadic supercells embedded in tropical cyclone (TC) rainbands. The simulated TC track and intensity matched well with observations post landfall, and the simulated TC structure closely replicated the observed shape and rainbands, as evident by an assessment of observed composite and simulated radar reflectivity. TC tornado surrogates (TCT-Ss) were identified and calibrated using thresholds based on percentile values of maximum updraft helicity (UHmax) and simulated radar reflectivity. Although the magnitude of UHmax generally decreased as the simulated TC moved inland, sensitivity testing revealed that a threshold based on the 99.95% percentile value of UHmax achieved optimal TCT-S coverage and agreement with observed TC tornado (TCT) tracks on domains with 3-km and 1-km grid spacings. Three cells were identified at three different stages of the TC inland evolution and were found to have hook appendages resembling supercells found in midlatitudes. The cells produced storm tops of 13 km, with rotating cores with depths of 4 km above ground level. Although results in this study are unique to Hurricane Ivan, the authors believe the use of convection-allowing models and UH-based surrogate methodologies can be applied to other TC cases.

Human monkeypox is caused by Monkeypox virus (MPXV), an Orthopoxvirus, previously rare in the United States (1). The first U.S. case of monkeypox during the current outbreak was identified on May 17, 2022 (2). As of September 28, 2022, a total of 25,341 monkeypox cases have been reported in the United States.* The outbreak has disproportionately affected gay, bisexual, and other men who have sex with men (MSM) (3). JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic), administered subcutaneously as a 2-dose (0.5 mL per dose) series with doses administered 4 weeks apart, was approved by the Food and Drug Administration (FDA) in 2019 to prevent smallpox and monkeypox infection (4). U.S. distribution of JYNNEOS vaccine as postexposure prophylaxis (PEP) for persons with known exposures to MPXV began in May 2022. A U.S. national vaccination strategy

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

This brief methods paper is being published concomitantly with “Preliminary Incidence and Trends of Infections Caused by Pathogens Transmitted Commonly Through Food— Foodborne Diseases Active Surveillance Network, 10 U.S. Sites, 2016–2021” in Morbidity and Mortality Weekly Reports (MMWR). That article describes the application of the new model described here to analyze trends and evaluate progress towards the prevention of infection from enteric pathogens in the United States.

Microcystins are toxic chemicals generated by certain freshwater cyanobacteria. These chemicals can accumulate to dangerous levels during harmful algal blooms. When exposed to microcystins, humans are at risk of hepatic injury, including liver failure. Here, we describe a method to detect microcystins in human plasma by using immunocapture followed by a protein phosphatase inhibition assay. At least 279 microcystins have been identified, and most of these compounds share a common amino acid, the Adda side chain. We targeted this Adda side chain using a commercial antibody and extracted microcystins from human samples for screening and analysis. To quantitate the extracted microcystins, we fortified plasma with microcystin-LR, one of the most well-studied, commonly detected, and toxic microcystin congeners. The quantitation range for the detection of microcystin in human plasma using this method is 0.030–0.50 ng/mL microcystin-LR equivalents. This method detects unconjugated and conjugated forms (cysteine and glutathione) of microcystins. Quality control sample accuracies varied between 98.9% and 114%, with a precision of 7.18–15.8%. Finally, we evaluated plasma samples from a community health surveillance project of Florida residents living or working near harmful algae blooms.

ROS1 tyrosine kinase inhibitors (TKIs) have demonstrated significant clinical benefit for ROS1+ NSCLC patients. However, TKI resistance inevitably develops through ROS1 kinase domain (KD) modification or another kinase driving bypass signaling. While multiple TKIs have been designed to target ROS1 KD mutations, less is known about bypass signaling in TKI-resistant ROS1+ lung cancers.Utilizing a primary, patient-derived TPM3-ROS1 cell line (CUTO28), we derived an entrectinib-resistant line (CUTO28-ER). We evaluated proliferation and signaling responses to TKIs, and utilized RNA sequencing, whole exome sequencing, and fluorescence in situ hybridization to detect transcriptional, mutational, and copy number alterations, respectively. We substantiated in vitro findings using a CD74-ROS1 NSCLC patient's tumor samples. Last, we analyzed circulating tumor DNA (ctDNA) from ROS1+ NSCLC patients in the STARTRK-2 entrectinib trial to determine the prevalence of MET amplification.CUTO28-ER cells did not exhibit ROS1 KD mutations. MET TKIs inhibited proliferation and downstream signaling and MET transcription was elevated in CUTO28-ER cells. CUTO28-ER cells displayed extrachromosomal (ecDNA) MET amplification without MET activating mutations, exon 14 skipping, or fusions. The CD74-ROS1 patient samples illustrated MET amplification while receiving ROS1 TKI. Finally, two of 105 (1.9%) entrectinib-resistant ROS1+ NSCLC STARTRK-2 patients with ctDNA analysis at enrollment and disease progression displayed MET amplification.Treatment with ROS1-selective inhibitors may lead to MET-mediated resistance. The discovery of ecDNA MET amplification is noteworthy, as ecDNA is associated with more aggressive cancers. Following progression on ROS1-selective inhibitors, MET gene testing and treatments targeting MET should be explored to overcome MET-driven resistance.

BACKGROUND Poa annua is a pervasive grassy, self‐pollinating, weed that has evolved resistance to 10 different herbicide modes‐of‐action, third most of all weed species. We investigated constitutive overexpression of genes associated with non‐target site resistance (NTSR) in POAAN‐R3 and the response of those genes when treated with trifloxysulfuron despite the biotype having a known target site mutation in acetolactate synthase (ALS). RESULTS Despite having an ALS target site mutation, POAAN‐R3 still had a transcriptomic response to herbicide application that differed from a susceptible biotype. We observed differential expression of genes associated with transmembrane transport and oxidation–reduction activities, with differences being most pronounced prior to herbicide treatment. CONCLUSIONS In the P. annua biotype we studied with confirmed target site resistance to ALS inhibitors, we also observed constitutive expression of genes regulating transmembrane transport, as well as differential expression of genes associated with oxidative stress after treatment with trifloxysulfuron. This accumulation of mechanisms, in addition to the manifestation of target site resistance, could potentially increase the chance of survival when plants are challenged by different modes of action., In Poa annua with target‐site resistance to ALS inhibitors, we observed constitutive expression of genes regulating transmembrane‐transport, and differential expression of genes associated with oxidative stress after treatment with trifloxysulfuron. © 2021 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The Trier Social Stress Test (TSST) is a widely used, reliable, and ecologically valid method for inducing acute stress under controlled conditions. Traditionally, the TSST is administered with staff physically present with participants, which limits the participant populations that can be exposed to the TSST. We describe an adaptation of the TSST to remote, online delivery over video-conferencing, which we call the internet-delivered Trier Social Stress Test (iTSST). This adaption has participants use wearable, self-administered ECG monitors received and returned via mail. Fifty participants were recruited to take part in a pilot study evaluating stress-reduction interventions and completed the iTSST at two occasions separated by approximately 12 weeks. Perceived stress and heart rate variability (HRV) were measured during both administrations of the iTSST. Forty-one participants completed both assessments and were included in the set of analyses. Both administrations were characterized by an increase in self-reported stress and reduction in self-reported relaxation from the resting phase to the speech task, which returned to baseline during recovery. In terms of HRV, we observed a significant parasympathetic response to the iTSST in 90% of participants, evidenced by a decrease in RMSSD and increase in heart rate from resting to the speech task, which recovered during the recovery phase. In terms of repeatability, there was little evidence of habituation and the iTSST elicited a stress response during both the initial administration and the 12-week follow-up. While the utility is limited by the lack of a measure of sympathetic and HPA-axis activity, the iTSST represents a promising research tool when physically interacting with participants is not feasible.

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E−18). Nine other genes were associated with a p-value, Dennis et al. investigate potential breast cancer associations with rare germline copy number variants (CNVs) by conducting a genome-wide analysis in a large breast cancer case-control dataset. The authors detected associations with exonic deletions in established breast cancer susceptibility genes and suggestive associations for a number of non-coding CNVs.

The U.S. COVID-19 Forecast Hub aggregates forecasts of the short-term burden of COVID-19 in the United States from many contributing teams. We study methods for building an ensemble that combines forecasts from these teams. These experiments have informed the ensemble methods used by the Hub. To be most useful to policy makers, ensemble forecasts must have stable performance in the presence of two key characteristics of the component forecasts: (1) occasional misalignment with the reported data, and (2) instability in the relative performance of component forecasters over time. Our results indicate that in the presence of these challenges, an untrained and robust approach to ensembling using an equally weighted median of all component forecasts is a good choice to support public health decision makers. In settings where some contributing forecasters have a stable record of good performance, trained ensembles that give those forecasters higher weight can also be helpful.

Let $X$ be a smooth fan and denote its set of endpoints by $E(X)$. Let $E$ be one of the following spaces: the natural numbers, the irrational numbers, or the product of the Cantor set with the natural numbers. We prove that there is a smooth fan $X$ such that $E(X)$ is homeomorphic to $E$ and for every homeomorphism $h \colon X \to X$, the restriction of $h$ to $E(X)$ is the identity. On the other hand, we also prove that if $X$ is any smooth fan such that $E(X)$ is homeomorphic to complete Erd\H{o}s space, then $X$ is necessarily homeomorphic to the Lelek fan; this adds to a 1989 result by W{\l}odzimierz Charatonik., Comment: 15 pages, 4 figures

We examine maternal microvascular function after preeclampsia, identifying heightened endothelium-dependent and endothelium-independent microvascular reactivity following severe disease. Our study represents a noteworthy addition to the existing literature with the use of a novel imaging modality, vascular perturbation, postpartum time point, and patient population with differentiation of preeclampsia into severe and nonsevere subtypes. These results represent a novel addition to the growing clinical and academic understanding of maternal health outcomes following preeclampsia.

Background The Bundled Payment for Care Improvement initiative is a program designed by Center for Medicare and Medicaid Services in an attempt to increase the value of care delivered to Medicare recipients by rewarding providers who can deliver more cost-efficient, high-value care. This article reports the results of a coordinated care redesign program in an independent, medium-sized private-practice orthopedic group. Methods A committee of stakeholders worked to redesign care protocols for patients receiving upper and lower joint replacement procedures. These protocols included preoperative, intraoperative, and postoperative care. Baseline metrics for post-acute care and readmissions were compared to the same metrics after initiating care redesign. Results Incidence of discharge to inpatient facilities decreased as did length of stay at these facilities. Home health utilization and readmission rates were lowered. Average cost of the 90-day episodes decreased to a statistically significant degree. Conclusions These initial results indicate that coordinated care redesign in the private practice setting can yield higher value care with decreased utilization of high-cost care, particularly in the post-acute period.

MXenes are atomically layered carbides and nitrides of transition metals that have potential for micro-devices applications in energy storage, conversion, and transport. This emerging family of materials is typically studied as nanosheets or ultra-thin films, for which the internal defects are mostly nanoscale flake-flake interface separation type. However, micro-devices applications would require thicker films, which exhibit very high density of microscale pores. Electrical conductivity of thicker MXenes is significantly lower than nanosheets, and the physics of defect size and density control are also different and less understood. Current art is to perform high temperature annealing to improve the electrical conductivity, which can structurally alter or degrade MXene. The key contribution of this study is a room-temperature annealing process that exploits the synergy between electrical pulses and compressive mechanical loading. Experimental results indicate over a 90% increase in electrical conductivity, which reflects a decrease in void size and density. In the absence of compressive loading, the same process resulted in a conductivity increase of approximately 75%. Analytical spectroscopy and microscopy indicated that the proposed multi-stimuli process kept the MXene composition intact while significantly decreasing the void size and density.

The aim of this paper is to outline the impact Coronavirus disease (COVID)-19 has had on health research in New Zealand. We used data from the University of Otago, Christchurch, a research intensiv...

Preeclampsia is a hypertensive pregnancy complication with an unknown etiology and high maternal burden worldwide. Burgeoning research has linked preeclampsia to adverse maternal health outcomes remote from pregnancy; however, the intermediary mechanisms responsible for this association have not been sufficiently established. In the present narrative review, we summarize leading evidence of structural and functional cardiovascular changes associated with prior preeclampsia, and how these changes may be linked to future maternal disease. KEY POINTS: · Prior preeclampsia is associated with subclinical structural and functional vascular changes remote from pregnancy.. · Maternal cardiac adaptations to preeclampsia may have long-term implications on cardiovascular health.. · Clinicians have an opportunity to minimize maternal disease risk following preeclampsia..

Background Pathogen detection has changed with increased use of culture-independent diagnostic tests (CIDTs). CIDTs do not yield isolates, which are necessary to detect outbreaks using whole-genome sequencing. The Foodborne Diseases Active Surveillance Network (FoodNet) monitors clinical laboratory testing practices to improve interpretation of surveillance data and assess availability of isolates. We describe changes in practices over 8 years. Methods During 2012–2019, 10 FoodNet sites collected standardized data about practices in clinical laboratories (range, 664–723 laboratories) for select enteric pathogens. We assessed changes in practices. Results During 2012–2019, the percentage of laboratories that used only culture methods decreased, with the largest declines for Vibrio (99%–57%) and Yersinia (99%–60%). During 2019, the percentage of laboratories using only CIDTs was highest for Shiga toxin–producing Escherichia coli (43%), Campylobacter (34%), and Vibrio (34%). From 2015 to 2019, the percentage of laboratories that performed reflex culture after a positive CIDT decreased, with the largest declines for Shigella (75%–42%) and Salmonella (70%–38%). The percentage of laboratories that routinely submitted isolates to a public health laboratory decreased for all bacterial pathogens examined from 2015 to 2019. Conclusions By increasing use of CIDTs and decreasing reflex culture, clinical laboratories have transferred the burden of isolate recovery to public health laboratories. Until technologies allow for molecular subtyping directly from a patient specimen, state public health laboratories should consider updating enteric disease reporting requirements to include submission of isolates or specimens. Public health laboratories need resources for isolate recovery.

Preeclampsia (PE) is a hypertensive obstetrical complication associated with increased cardiovascular disease risk. Carotid artery functional assessments allow for identification of subclinical vascular dysfunction. This cross-sectional study measured carotid artery functional indices in healthy women with a recent pregnancy complicated by PE, versus women with a prior uncomplicated pregnancy. Women with a history of PE (N = 30) or an uncomplicated pregnancy (N = 30), were recruited between 6 months and 5 years postpartum. Left and right carotid artery ultrasound measured carotid intima media thickness, plaque burden, peak systolic velocity, end diastolic flow velocity and carotid far-wall circumferential strain (FWCS). Carotid FWCS is inversely related to vessel stiffness, where a decrease in FWCS indicates increased vessel stiffness. Right-side FWCS did not differ between women with a history of PE versus normotensive pregnancy. Left carotid artery FWCS was lower in formerly preeclamptic women after adjustment for diameter, pulse pressure, and heart rate compared to women following an uncomplicated pregnancy (3.35 ± 1.08 × 10

Graphical Abstract Models for gut-mediated bacterial conjugation and plasmid transfer. Depiction of conjugative elements (Left, Top), current in silico models (Left, Middle), experimental in vitro models (Left, Bottom), and in vivo animal models (Right) for bacterial conjugation in the gut. Arthropods; spring tails (Folsomia candida), fleas (Alphitobius diaperinus), fruit flies (Drosophila melanogaster), house flies (Musca domestica), beetles (Xenopsylla cheopis); Rhabditidae; nematodes (Caenorhabditis elegans); Phasianidae; chickens (Gallus gallus). Leporidae; rabbits (Oryctolagus cuniculus). Muridae; mice (Mus musculus), rats (Mus rattus).

Primary ciliary defects cause a group of developmental conditions known as ciliopathies. Here, we provide mechanistic insight into ciliary ubiquitin processing in cells and for mouse model lacking the ciliary protein Mks1. In vivo loss of Mks1 sensitises cells to proteasomal disruption, leading to abnormal accumulation of ubiquitinated proteins. We identified UBE2E1, an E2 ubiquitin-conjugating enzyme that polyubiquitinates β-catenin, and RNF34, an E3 ligase, as novel interactants of MKS1. UBE2E1 and MKS1 colocalised, and loss of UBE2E1 recapitulates the ciliary and Wnt signalling phenotypes observed during loss of MKS1. Levels of UBE2E1 and MKS1 are co-dependent and UBE2E1 mediates both regulatory and degradative ubiquitination of MKS1. We demonstrate that processing of phosphorylated β-catenin occurs at the ciliary base through the functional interaction between UBE2E1 and MKS1. These observations suggest that correct β-catenin levels are tightly regulated at the primary cilium by a ciliary-specific E2 (UBE2E1) and a regulatory substrate-adaptor (MKS1).

The intensities from genotyping array data can be used to detect copy number variants (CNVs) but a high level of noise in the data and overlap between different copy-number intensity distributions produces unreliable calls, particularly when only a few probes are covered by the CNV. We present a novel pipeline (CamCNV) with a series of steps to reduce noise and detect more reliably CNVs covering as few as three probes. The pipeline aims to detect rare CNVs (below 1% frequency) for association tests in large cohorts. The method uses the information from all samples to convert intensities to z-scores, thus adjusting for variance between probes. We tested the sensitivity of our pipeline by looking for known CNVs from the 1000 Genomes Project in our genotyping of 1000 Genomes samples. We also compared the CNV calls for 1661 pairs of genotyped replicate samples. At the chosen mean z-score cut-off, sensitivity to detect the 1000 Genomes CNVs was approximately 85% for deletions and 65% for duplications. From the replicates, we estimate the false discovery rate is controlled at ∼10% for deletions (falling to below 3% with more than five probes) and ∼28% for duplications. The pipeline demonstrates improved sensitivity when compared to calling with PennCNV, particularly for short deletions covering only a few probes. For each called CNV, the mean z-score is a useful metric for controlling the false discovery rate.

Cornus kousa (Asian dogwood), an East Asia native tree, is the most economically important species of the dogwood genus, owing to its desirable horticultural traits and ability to hybridize with North America‐native dogwoods. To assess the species genetic diversity and to better inform the ongoing and future breeding efforts, we assembled an herbarium and arboretum collection of 131 noncultivated C. kousa specimens. Genotyping and capillary electrophoresis analyses of our C. kousa collection with the newly developed genic and published nuclear genomic microsatellites permitted assessment of genetic diversity and evolutionary history of the species. Regardless of the microsatellite type used, the study yielded generally similar insights into the C. kousa diversity with subtle differences deriving from and underlining the marker used. The accrued evidence pointed to the species distinct genetic pools related to the plant country of origin. This can be helpful in the development of the commercial cultivars for this important ornamental crop with increased pyramided utility traits. Analyses of the C. kousa evolutionary history using the accrued genotyping datasets pointed to an unsampled ancestor population, possibly now extinct, as per the phylogeography of the region. To our knowledge, there are few studies utilizing the same gDNA collection to compare performance of genomic and genic microsatellites. This is the first detailed report on C. kousa species diversity and evolutionary history inference.

The composition of arbuscular mycorrhizal fungal (AMF) communities should reflect not only responses to host and soil environments, but also differences in functional roles and costs vs. benefits among arbuscular mycorrhizal fungi. The coffee agroecosystem allows exploration of the effects of both light and soil fertility on AMF communities, because of the variation in shade and soil nutrients farmers generate through field management. We used high-throughput ITS2 sequencing to characterize the AMF communities of coffee roots in 25 fields in Costa Rica that ranged from organic management with high shade and no chemical fertilizers to conventionally managed fields with minimal shade and high N fertilization, and examined relationships between AMF communities and soil and shade parameters with partial correlations, NMDS, PERMANOVA, and partial least squares analysis. Gigasporaceae and Acaulosporaceae dominated coffee AMF communities in terms of relative abundance and richness, respectively. Gigasporaceae richness was greatest in conventionally managed fields, while Glomeraceae richness was greatest in organic fields. While total AMF richness and root colonization did not differ between organic and conventionally managed fields, AMF community composition did; these differences were correlated with soil nitrate and shade. OTUs differing in relative abundance between conventionally managed and organic fields segregated into four groups: Gigasporaceae associated with high light and nitrate availability, Acaulosporaceae with high light and low nitrate availability, Acaulosporaceae and a single relative of Rhizophagus fasciculatus with shade and low nitrate availability, and Claroideoglomus/Glomus with conventionally managed fields but uncorrelated with shade and soil variables. The association of closely related taxa with similar shade and light availabilities is consistent with phylogenetic trait conservatism in AM fungi.

Introduction. Seizures are neurological emergencies with short- and long-term adverse effects in pre-term infants. They may present with or without abnormal movements (clinical versus subclinical). Thus, the true incidence of seizures may be under-reported. Current research indicates that most seizures occur in the first few days of life, are associated with intraventricular hemorrhage (IVH), and show low response to anticonvulsant drugs. The purpose of this study was to evaluate incidence, etiology, clinical antecedents, mortality, and response to treatment of seizures in extremely pre-term infants. Methods. This is a retrospective cohort study of pre-term infants < 29 weeks gestation from January 2011 to December 2013. Presence or absence of seizure was the outcome. Data extraction included demographics, medications, co-morbidities, mortality, and details of seizures. A multivariable prediction model was developed to evaluate risk for seizures. Results. Analysis included 269 pre-term infants. Incidence of EEG-confirmed seizures was 40% (108/269); 49% were clinical and 51% were subclinical. Seizures occurred in 72% of infants ≤ 24 weeks, 57% of those 25-26 weeks, and 23% of those 27-28 weeks. Most seizures (85%) occurred after day eight of life. Mortality was 14% in those with seizures versus 5% in those without (p = 0.019). The model showed seizures were associated significantly with gestational age and medications, while controlling for sex, APGAR score, and co-morbidities, including IVH. At discharge, anticonvulsants were continued in 66% (72/108) of infants with seizures. Conclusion. The incidence of seizures was highest in infants born most premature. Contrary to previous research, nearly two-thirds of pre-term infants with seizures did not have IVH or cystic periventricular leukomalacia; apnea of prematurity was a common presentation of subclinical seizures; and the majority of treated infants responded to Phenobarbital. These findings need be explored in future research.

Given the numerous health benefits of exercise, understanding how exercise capacity is regulated is a question of paramount importance. Circulating interleukin 6 (IL-6) levels surge during exercise and IL-6 favors exercise capacity. However, neither the cellular origin of circulating IL-6 during exercise nor the means by which this cytokine enhances exercise capacity has been formally established yet. Here we show through genetic means that the majority of circulating IL-6 detectable during exercise originates from muscle and that to increase exercise capacity, IL-6 must signal in osteoblasts to favor osteoclast differentiation and the release of bioactive osteocalcin in the general circulation. This explains why mice lacking the IL-6 receptor only in osteoblasts exhibit a deficit in exercise capacity of similar severity to the one seen in mice lacking muscle-derived IL-6 (mIL-6), and why this deficit is correctable by osteocalcin but not by IL-6. Furthermore, in agreement with the notion that IL-6 acts through osteocalcin, we demonstrate that mIL-6 promotes nutrient uptake and catabolism into myofibers during exercise in an osteocalcin-dependent manner. Finally, we show that the crosstalk between osteocalcin and IL-6 is conserved between rodents and humans. This study provides evidence that a muscle-bone-muscle endocrine axis is necessary to increase muscle function during exercise in rodents and humans.

Two experiments were conducted to evaluate the effects of including liquid lactose (LL) and molasses (M) in swine diets on pellet quality and pig performance. In experiment 1, a total of 194 nursery pigs (DNA 241 × 600, initially 6.7 ± 0.4 kg at 27 d of age) were used in a 33-d experiment evaluating the effects of LL (SweetLac 63; Westway Feed Products, Tomball, TX) or cane molasses on nursery pig performance and pellet quality. Pelleted experimental diets were fed from d 0 to 21, and a common pelleted diet fed from d 21 to 33. Dietary treatments consisted of a control diet containing 19.1% total sugars from whey powder and whey permeate and experimental diets with a percentage of whey permeate replaced by either 5% or 10% LL or 9.4% cane molasses (5 LL, 10 LL, and 9.4 M, respectively). Hot pellet temperature and production rate decreased (P < 0.05) from the control to 9.4 M treatments with 5 LL and 10 LL having intermediate effects. Pellet durability index (PDI) increased (P < 0.05) in 5 LL, 10 LL, and 9.4 M, respectively. From d 0 to 7, pigs fed the 10 LL and 9.4 M treatment had the best G:F followed by the control and 5 LL treatments. From d 0 to 21, ADFI had a marginally significant improvement (P < 0.10) in pigs fed up to 10 LL in the diet. Fecal consistency scores at d 7 were also firmer (P < 0.05) in pigs fed 9.4 M compared with pigs fed the control or 5 LL treatments with pigs fed the 10 LL treatment being intermediate. There was no evidence for differences in fecal consistency scores for d 14. In experiment 2, a total of 289 finishing pigs (DNA 241 × 600; initially 53.5 ± 0.5 kg BW) were used in a 53-d experiment evaluating the effects of LL on pellet quality and finishing pig performance. Experimental diets were fed in pelleted form from d 0 to 53 divided into three phases. Dietary treatments were a corn-soybean meal control diet with 0%, 2.5%, 5%, and 7.5% LL added in the place of corn. PDI improved (linear, P < 0.01) with increasing inclusion of LL. There were no differences in ADG, ADFI, final BW, or carcass characteristics. Pigs fed diets with increasing levels of LL tended to have improved (quadratic, P = 0.070) G:F.