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Ann R Falsey1,2, Kenneth L Becker3, Andrew J Swinburne2, Eric S Nylen3, Richard H Snider3, Maria A Formica2, Patricia A Hennessey2, Mary M Criddle2, Derick R Peterson4, Edward E Walsh1,21Department of Medicine, University of Rochester, 2Rochester General Hospital, Rochester, NY, 3Veterans Affairs Medical Center and George Washington University, Washington DC, 4Biostatistics and Computational Biology, University of Rochester, Rochester, NY, USABackground: Serum procalcitonin levels have been used as a biomarker of invasive bacterial infection and recently have been advocated to guide antibiotic therapy in patients with chronic obstructive pulmonary disease (COPD). However, rigorous studies correlating procalcitonin levels with microbiologic data are lacking. Acute exacerbations of COPD (AECOPD) have been linked to viral and bacterial infection as well as noninfectious causes. Therefore, we evaluated procalcitonin as a predictor of viral versus bacterial infection in patients hospitalized with AECOPD with and without evidence of pneumonia.Methods: Adults hospitalized during the winter with symptoms consistent with AECOPD underwent extensive testing for viral, bacterial, and atypical pathogens. Serum procalcitonin levels were measured on day 1 (admission), day 2, and at one month. Clinical and laboratory features of subjects with viral and bacterial diagnoses were compared.Results: In total, 224 subjects with COPD were admitted for 240 respiratory illnesses. Of these, 56 had pneumonia and 184 had AECOPD alone. A microbiologic diagnosis was made in 76 (56%) of 134 illnesses with reliable bacteriology (26 viral infection, 29 bacterial infection, and 21 mixed viral bacterial infection). Mean procalcitonin levels were significantly higher in patients with pneumonia compared with AECOPD. However, discrimination between viral and bacterial infection using a 0.25 ng/mL threshold for bacterial infection in patients with AECOPD was poor.Conclusion: Procalcitonin is useful in COPD patients for alerting clinicians to invasive bacterial infections such as pneumonia but it does not distinguish bacterial from viral and noninfectious causes of AECOPD.Keywords: virus, bacterial infection, procalcitonin, chronic obstructive pulmonary disease, bronchitis

Imagine you want to do something as simple as schedule a teeth cleaning for your child, but in the process you encounter a significant stumbling block. There are no dentists [...]

Background: There is a consensus on the limited value of the QTc interval prolongation as a surrogate marker of drug cardiotoxicity and as a risk stratifier in inherited long QT syndrome (LQTS) patients.Objective: We investigated the interest of repolarization morphology in the acquired and the inherited LQTS.Methods: We analyzed 2 retrospective electrocardiographic (ECG) datasets from healthy on/off moxifloxacin and from genotyped KCNH2 patients. We measured QT, RR, and T-peak to T-end intervals, early repolarization duration (ERD) and late repolarization duration, T-roundness, T-amplitude, left (αL) and right slopes of T-waves. We designed multivariate logistic models to predict the presence of the KCNH2 mutation or moxifloxacin while adjusting for the level of QTc prolongation and the level of heart rate in LQT2 patients. Independent learning and validation sets were used. A list of 4,874 ECGs from 411 healthy individuals, 293 from 143 LQT2 carriers and 150 noncarrier family members were analyzed.Results: In the moxifloxacin model, ERD was associated with the presence of the drug (odds ratio = 1.15 per ms increase, confidence interval 1.04 to 1.26, P = .0001) after adjustment for QTc. The model for the LQT2 revealed that left slope was associated with the presence of the KCNH2 mutation (odds ratio = 0.38 per 1.5 μV/ms decrease, confidence interval 0.23 to 0.64, P = .0002). Only T-roundness complemented QTc in the model investigating cardiac events in LQT2.Conclusions: These observations demonstrate that the phenotypic expression of KCNH2 mutations and the effect of IKr-inhibitory drug on the surface electrocardiogram are specific. Future research should investigate whether this phenomenon is linked to different level/form of loss functions of Ikr channels, and whether they could result in different arrhythmogenic mechanisms. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to test the hypothesis that social support is an important predictor of mortality in a frail older population receiving formal long-term care services.Research Design and Methods: The analysis is based on 3138 individuals enrolled in 28 Programs of All-Inclusive Care for the Elderly (PACE). Information about the enrollees is obtained from dataPACE. Semiparametric Cox proportional hazards models are estimated to assess the importance of individual risk factors, program effect, and social support.Results: The introduction of the social support variables into the mortality model containing the sociodemographic, health needs, and the PACE-site indicator variables results in a significant improvement of the overall model fit. Several social support variables are statistically significant predictors of mortality. Controlling for all participant and caregiver characteristics, participants whose caregiver is a spouse have a significantly lower risk of mortality (hazard ratio = 0.63) compared with those whose caregiver is not a spouse. Furthermore, caregivers' assistance with meals confers a significantly lower risk of morality (hazard ratio = 0.66) compared with no assistance with meals.Conclusions: This study shows that certain aspects of informal caregiving are important factors enhancing survival in a population of frail, nursing home-certifiable individuals enrolled in a health program that already provides extensive services, including personal care, chores, and meals. Further research to better differentiate between the affective versus the instrumental dimensions of social support is needed to guide programs on how to balance the use of resources to provide both the necessary formal services and the support for the informal caregivers. [ABSTRACT FROM AUTHOR]

PURPOSE: This study was designed to determine the relationship between musculoskeletal disorder symptoms and vibration in dental hygiene students as a pilot for a larger scale study. METHODS: A custom-designed questionnaire was distributed to three intact student groups: those accepted for admission, those at the end of the first year, and graduating students at the end of the second year. Data were analyzed using tabular and multivariate analysis. Students increased their use of ultrasonic instruments from 0.2 to 2.8 to 7.3 hours per week over the three years. Dental hygiene students with symptoms of numbness in the upper extremities used ultrasonic scalers a mean of 8.2 hours per week compared to 2.8 hours of use by students with no upper extremity numbness. These students also used manual instruments 10.1 hours and 4.8 hours per week, respectively. RESULTS: Logistic regression revealed a significant association between hours of use of ultrasonics and upper extremity numbness/tingling, with an odds ratio of 1.10 for each increased hour of use (95% CI 1.01-1.19; chi-square = 4.9). A similar result was found for manual instrument use. CONCLUSION: Results indicate that musculoskeletal disorder symptoms may increase with the use of ultrasonic and/or manual instruments. [ABSTRACT FROM AUTHOR]

Objectives: Phase 3 licensing trials for the recently approved respiratory syncytial virus (RSV) vaccines did not include many residents of long-term care facilities (LTCF). Our primary objective was to assess humoral immune responses in LTCF residents, age 60 and older, to the RSV vaccines, and demonstrate noninferiority to antibody responses in community-dwelling (CD) adults who were representative of the phase 3 trial participants in whom the vaccines were highly efficacious., Design: Prospective non-randomized intervention trial of RSV vaccines in LTCF residents., Setting and Participants: Research clinic and 2 LTCFs. Adults ≥60 years old, free of immunosuppression and planning to receive an RSV vaccine were eligible., Methods: LTCF and CD participants received either the GSK or Pfizer RSV vaccine in equal numbers. Blood was collected before and 30 days after vaccination. Total immunoglobulin (Ig)G to the prefusion F protein of RSV group A (F A ) and B (F B ), and neutralizing activity were measured, and geometric mean titer (GMT) and geometric mean fold rise (GMFR) calculated. Intercurrent respiratory illnesses were tracked., Results: A total of 76 LTCF residents and 76 CD adults were enrolled. Day 30 blood was unavailable from 3 residents and 3 had RSV infection and vaccination was deferred, leaving data for 76 CD and 70 LTCF adults for analysis. Serum IgG GMFR prefusion F A (9.9 vs 12.5, P = .14), prefusion F B (8.7 vs 11.0, P = .17) were not statistically different in CD and LTCF cohorts, respectively, and also equivalent for GMFR in viral neutralization titers (12.8 vs. 15.5, P = .32). As measured by GMT or GMFR, RSV vaccine responses of LTCF residents met noninferiority criteria compared with the CD cohort., Conclusions and Implications: This small immunobridging study demonstrates robust antibody responses to RSV vaccines in LTCF residents providing support for their use in this high-risk population., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The use of occupational exoskeletons has grown fast in manufacturing industries in recent years. One major scenario of exoskeleton use in manufacturing is to assist overhead, power hand tool operations. This preliminary work aimed to determine the effects of arm-supporting exoskeletons on shoulder muscle activity and human-hand tool coupling in simulated overhead tasks with axially applied vibration. An electromagnetic shaker capable of producing the random vibration spectrum specified in ISO 10819 was hung overhead to deliver vibrations. Two passive, arm-supporting exoskeletons, with one (ExoVest) transferring load to both the shoulder and pelvic region while the second one (ExoStrap) transferring load primarily to the pelvic region, were used in testing. Testing was also done with the shaker placed in front of the body to better understand the posture and exoskeleton engagement effects. The results collected from 6 healthy male subjects demonstrate the dominating effects of the overhead working posture on increased shoulder muscle activities. Vibration led to higher muscle activities in both agonist and antagonist shoulder muscles to a less extent. Exoskeleton use reduced the anterior deltoid and serratus anterior activities by 27% to 43%. However, wearing the ExoStrap increased the upper trapezius activities by 23% to 38% in the overhead posture. Furthermore, an increased human-shaker handle coupling was observed in the OH posture when wearing the ExoVest, indicating a more demanding neuromuscular control.

Background: Nutritional impairment is associated with treatment toxicity and worse overall survival in patients with cancer. We aimed to (1) evaluate the association of nutritional impairment with psychological health and quality of life (QOL) and (2) examine which measures of nutrition had the strongest association with psychological health and QOL among older adults receiving cancer treatment with palliative intent., Methods: This secondary analysis was performed on baseline data from a nationwide cluster randomized clinical trial (ClinicalTrials.gov identifier: NCT02107443; PI: Mohile). Adults age ≥70 with advanced cancer and ≥1 geriatric assessment (GA) impairment were enrolled from 2014 to 2017. In line with geriatric oncology standards, we defined nutritional impairment as Mini Nutritional Assessment Short Form (MNA-SF) ≤11, body mass index (BMI) <21 kg/m 2 , or >10% involuntary weight loss in the past 6 months. We conducted multivariable linear regressions to evaluate the association of nutritional impairment with each measure of psychological health and QOL: Geriatric Depression Scale (GDS-15, range 0-15), Generalized Anxiety Disorder-7 (GAD-7, range 0-21), NCCN Distress Thermometer (NCCN DT, range 0-10), and Functional Assessment of Cancer Therapy-General (FACT-G, range 0-108). Analyses were adjusted for patient demographics, clinical characteristics, and GA., Results: Among 541 patients, the mean age was 77 (range 70-96) and 60% had nutritional impairment. Mean baseline scores: GDS-15 3.1 (SD 2.7), GAD-7 2.9 (SD 4.0), NCCN DT 2.9 (SD 2.7), and FACT-G 80 (SD 15). In the adjusted model, compared to those with no nutritional impairment, older adults with nutritional impairment had greater depression (β = 0.79, 95% CI 0.36-1.23) and anxiety severity (β = 0.86, 95% CI 0.19-1.53), and worse QOL (β = -6.31, 95% CI -8.62 to -4.00). Of the measures of nutrition, MNA-SF ≤11 demonstrated the strongest associations with depression, anxiety, distress, and QOL., Conclusion: Nutritional impairment is associated with impaired psychological health and worse QOL. Clinicians should use the MNA-SF to screen older adults for nutritional impairment and offer tailored supportive interventions., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Americans consume diets that fall short of dietary recommendations, and the cost of healthier diets is often cited as a barrier to dietary change. We conducted a nonrandomized crossover trial with meals provided utilizing 2 diets: Dietary Approaches to Stop Hypertension (DASH) and whole food, plant-based (WFPB), and thus had intake data from baseline and both intervention diets., Objectives: Using actual diet records, describe food costs of baseline diets of individuals with type 2 diabetes (T2DM) as well as therapeutic DASH and WFPB diets., Methods: Three-day food records were collected and analyzed for each 7-d diet phase: baseline, DASH, and WFPB. Nutrient content was analyzed using the Nutrient Data System for Research and cost was determined using Fillet, an application to manage menu pricing. Food costs were calculated for each diet as consumed and adjusted to a standardized 1800 kcal/d. Ingredient-only costs of food away from home (FAFH) were approximated and analyzed. Costs were analyzed using linear mixed-effect models as a function of diet., Results: Fifteen subjects enrolled; 12 completed all dietary phases. The baseline, DASH, and WFPB diets, as consumed, cost $15.72/d (95% CI; $13.91, $17.53), $12.74/d ($11.23, $14.25), and $9.78/d ($7.97, $11.59), respectively. When adjusted to an 1800 kcal/d intake, the baseline, DASH, and WFPB diets cost $15.69/d ($13.87, $17.52), $14.92/d ($13.59, $16.26), and $11.96/d ($10.14, $13.78), respectively. When approximated ingredient-only costs of FAFH were analyzed, as consumed baseline [$11.01 ($9.53, $12.49)] and DASH diets [$11.81 ($10.44, $13.18)] had similar costs; WFPB diet [$8.83 ($7.35, $10.31)] cost the least., Conclusions: In this short-term study with meals provided, the food costs of plant-predominant diets offering substantial metabolic health benefits were less than or similar to baseline food costs of adults with insulin-treated T2DM. Longer-term data without meal provision are needed for more generalizable results. This trial was registered at clinicaltrials.gov as NCT04048642., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Maternal iron deficiency (ID) and environmental lead (Pb) exposure are co-occurring insults that both affect the neurodevelopment of offspring. Few studies have investigated how ID affects brain-region-specific Pb accumulations using human-relevant Pb concentrations. Furthermore, how these Pb exposures impact blood and brain Fe levels remains unclear. Importantly, we also wanted to determine whether the use of blood Pb levels as a surrogate for the brain Pb burden is affected by underlying iron status. We exposed virgin Swiss Webster female mice to one of six conditions differing by iron diet and Pb water concentration (0 ppm, 19 ppm, or 50 ppm lead acetate) and used Inductively Coupled Plasma Mass Spectrometry to measure the maternal and offspring circulating, stored, and brain Pb levels. We found that maternal ID rendered the offspring iron-deficient anemic and led to a region-specific depletion of brain Fe that was exacerbated by Pb in a dose-specific manner. The postnatal iron deficiency anemia also exacerbated cortical and hippocampal Pb accumulation. Interestingly, BPb levels only correlated with the brain Pb burden in ID pups but not in IN offspring. We conclude that ID significantly increases the brain Pb burden and that BPb levels alone are insufficient as a clinical surrogate to make extrapolations on the brain Pb burden.

Aims: There is limited research regarding insulin dosing changes following adoption of plant-based diets. We conducted a nonrandomized crossover trial utilizing two plant-based diets (Dietary Approaches to Stop Hypertension, or DASH, and Whole Food, Plant-Based, or WFPB) to assess acute changes in insulin requirements and associated markers among individuals with insulin-treated type 2 diabetes., Methods: Participants (n = 15) enrolled in a 4-week trial with sequential, one-week phases: Baseline, DASH 1, WFPB, and DASH 2. Each diet was ad libitum and meals were provided., Results: Compared to baseline, daily insulin usage was 24%, 39%, and 30% lower after DASH 1, WFPB, and DASH 2 weeks respectively (all p < 0.01). Insulin resistance (HOMA-IR) was 49% lower (p < 0.01) and the insulin sensitivity index was 38% higher (p < 0.01) at the end of the WFPB week before regressing toward baseline during DASH 2. Total, LDL, and HDL cholesterol, leptin, urinary glucose, and hsCRP decreased to a nadir at the end of the WFPB week before increasing during DASH 2., Conclusions: Adopting a DASH or WFPB diet can result in significant, rapid changes in insulin requirements, insulin sensitivity, and related markers among individuals with insulin-treated type 2 diabetes, with larger dietary changes producing larger benefits., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests or personal relationships that could have appeared to influence the work reported in this paper: [TMC receives royalties from general interest books about plant-based nutrition (Benbella Books and Penguin Random House). In addition, he has received income from a medical practice focused on lifestyle medicine (Thomas Campbell, MD PLLC). EKC has no conflicts other than those of her spouse (TMC). SDW has received consulting honoraria from Medtronic Diabetes and Ascencia Diabetes. None of the other authors declare any conflicts]., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Estrogenic endocrine disrupting chemicals (EEDC) have been suspected to impact offspring in a transgenerational manner via modifications of the germline epigenome in the directly exposed generations. A holistic assessment of the concentration/ exposure duration-response, threshold level, and critical exposure windows (parental gametogenesis and embryogenesis) for the transgenerational evaluation of reproduction and immune compromise concomitantly will inform the overall EEDC exposure risk. We conducted a multigenerational study using the environmental estrogen, 17α-ethinylestradiol (EE2), and the marine laboratory model fish Oryzias melastigma (adult, F0) and their offspring (F1-F4) to identify transgenerationally altered offspring generations and phenotype persistence. Three exposure scenarios were used: short parental exposure, long parental exposure, and a combined parental and embryonic exposure using two concentrations of EE2 (33ng/L, 113ng/L). The reproductive fitness of fish was evaluated by assessing fecundity, fertilization rate, hatching success, and sex ratio. Immune competence was assessed in adults via a host-resistance assay. EE2 exposure during both parental gametogenesis and embryogenesis was found to induce concentration/ exposure duration-dependent transgenerational reproductive effects in the unexposed F4 offspring. Furthermore, embryonic exposure to 113 ng/L EE2 induced feminization of the directly exposed F1 generation, followed by subsequent masculinization of the F2 and F3 generations. A sex difference was found in the transgenerationally impaired reproductive output with F4 females being sensitive to the lowest concentration of EE2 (33 ng/L) upon long-term ancestral parent exposure (21 days). Conversely, F4 males were affected by ancestral embryonic EE2 exposure. No definitive transgenerational impacts on immune competence were identified in male or female offspring. In combination, these results indicate that EEDCs can be transgenerational toxicants that may negatively impact the reproductive success and population sustainability of fish populations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Anterior cruciate ligament (ACL) repair had previously been considered the standard of care for a ruptured ACL; however, ACL reconstruction has became the standard of care because of poor midterm outcomes after ACL repair. Recently, studies have suggested that the treatment paradigm should shift back to ACL repair., Purpose/hypothesis: The purpose of this study was to evaluate the outcomes of ACL repair augmented with suture tape in a high-demand military population. We hypothesized that for proximal ACL avulsions, ACL repair with suture tape augmentation would lead to acceptable failure rates, satisfactory knee stability, excellent functional outcomes, and high rates of return to preinjury activity levels., Study Design: Case series; Level of evidence, 2., Methods: Patients who were treated with ACL repair by a single surgeon between March 2017 and June 2019 and who had a minimum of 2 years of follow-up were included. Intraoperatively, all patients first underwent an arthroscopic examination. If an ACL avulsion of the proximal insertion with adequate remaining tissue was visualized, then ACL repair was performed. The primary outcome assessed was ACL repair failure, defined as reruptures or clinical instability requiring revision to ACL reconstruction. Analysis of the risk factors for ACL repair failure was conducted, with age at surgery, sex, body mass index, level of competition, and tobacco use evaluated., Results: Included were 46 patients (32 male and 14 female; mean age, 28.3 ± 8.4 years) who underwent ACL repair with suture tape augmentation. There were 12 cases of failure (26.1%; 8 male and 4 female). The mean time from injury to surgery in the failure group was 164.1 ± 59.4 days compared to 107.3 ± 98.0 days in the nonfailure group ( P = .02). According to multivariate regression analysis, patients aged ≤17 and ≥35 years, elite/competitive/operational patients, and current smokers had a higher chance of ACL repair failure. The mean time to pass a military physical fitness test was 5.0 months. There were no complications other than ACL repair failure., Conclusion: Primary arthroscopic ACL repair with suture tape augmentation resulted in unacceptably high failure rates at a minimum of 2 years of follow-up in a highly active military population. Age ≤17 and ≥35 years, elite level of competition, time from injury to surgery, and active tobacco use were independent risk factors for ACL repair failure., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: B.J.M. has received grant support from Arthrex and education payments from Smith & Nephew. L.Z. has received grant support from Arthrex and hospitality payments from Stryker. K.S.M. has received grant support from Arthrex and Zimmer Biomet and education payments from Smith & Nephew. C.R.B. has received education payments and speaking fees from Arthrex and honoraria from the Musculoskeletal Transplant Foundation. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2023.)

Background: The correlates of coronavirus disease 2019 (COVID-19) illness severity following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are incompletely understood., Methods: We assessed peripheral blood gene expression in 53 adults with confirmed SARS-CoV-2 infection clinically adjudicated as having mild, moderate, or severe disease. Supervised principal components analysis was used to build a weighted gene expression risk score (WGERS) to discriminate between severe and nonsevere COVID-19., Results: Gene expression patterns in participants with mild and moderate illness were similar, but significantly different from severe illness. When comparing severe versus nonsevere illness, we identified >4000 genes differentially expressed (false discovery rate < 0.05). Biological pathways increased in severe COVID-19 were associated with platelet activation and coagulation, and those significantly decreased with T-cell signaling and differentiation. A WGERS based on 18 genes distinguished severe illness in our training cohort (cross-validated receiver operating characteristic-area under the curve [ROC-AUC] = 0.98), and need for intensive care in an independent cohort (ROC-AUC = 0.85). Dichotomizing the WGERS yielded 100% sensitivity and 85% specificity for classifying severe illness in our training cohort, and 84% sensitivity and 74% specificity for defining the need for intensive care in the validation cohort., Conclusions: These data suggest that gene expression classifiers may provide clinical utility as predictors of COVID-19 illness severity., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Risk stratification in long QT syndrome (LQTS) patients is important for optimizing patient care and informing clinical decision making. We developed a risk prediction algorithm with prediction of 5-year absolute risk of the first life-threatening arrhythmic event [defined as aborted cardiac arrest, sudden cardiac death, or appropriate implantable cardioverter defibrillator (ICD) shock] in LQTS patients, accounting for individual risk factors and their changes over time., Methods: Rochester-based LQTS Registry included the phenotypic cohort consisting of 1,509 LQTS patients with a QTc ≥ 470 ms, and the genotypic cohort including 1,288 patients with single LQT1, LQT2, or LQT3 mutation. We developed two separate risk prediction models which included pre-specified time-dependent covariates of beta-blocker use, syncope (never, syncope while off beta blockers, and syncope while on beta blockers), and sex by age < and ≥13 years, baseline QTc, and genotype (for the genotypic cohort only). Follow-up started from enrollment in the registry and was censored at patients' 50s birthday, date of death due to reasons other than sudden cardiac death, or last contact, whichever occurred first. The predictive models were externally validated in an independent cohort of 1,481 LQTS patients from Pavia, Italy., Results: In Rochester dataset, there were 77 endpoints in the phenotypic cohort during a median follow-up of 9.0 years, and 47 endpoints in the genotypic cohort during a median follow-up of 9.8 years. The time-dependent extension of Harrell's generalized C-statistics for the phenotypic model and genotypic model were 0.784 (95% CI: 0.740-0.827) and 0.785 (95% CI: 0.721-0.849), respectively, in the Rochester cohort. The C-statistics obtained from external validation in the Pavia cohort were 0.700 (95% CI: 0.610-0.790) and 0.711 (95% CI: 0.631-0.792) for the two models, respectively. Based on the above models, an online risk calculator estimating a 5-year risk of life-threatening arrhythmic events was developed., Conclusion: This study developed two risk prediction algorithms for phenotype and genotype positive LQTS patients separately. The estimated 5-year absolute risk can be used to quantify a LQTS patient's risk of developing life-threatening arrhythmic events and thus assisting in clinical decision making regarding prophylactic ICD therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Peterson, Pagan, Bagnardi, Mazzanti, McNitt, Rich, Seplaki, Kutyifa, Polonsky, Barsheshet, Kukavica, Rosero, Goldenberg, Priori and Zareba.)

Incubation of craving is a well-documented phenomenon referring to the intensification of drug craving over extended abstinence. The neural adaptations that occur during forced abstinence following chronic drug taking have been a topic of intense study. However, little is known about the transcriptomic changes occurring throughout this window of time. To define gene expression changes associated with morphine consumption and extended abstinence, male and female rats underwent 10 days of morphine self-administration. Separate drug-naive rats self-administered sucrose in order to compare opioid-induced changes from those associated with natural, non-drug rewards. After one or 30 days of forced abstinence, rats were tested for craving, or nucleus accumbens shell tissue was dissected for RNA sequencing. Morphine consumption was predictive of drug seeking after extended (30 days) but not brief (1 day) abstinence in both sexes. Extended abstinence was also associated with robust sex- and reinforcer-specific changes in gene expression, suggesting sex differences underlying incubation of morphine and sucrose seeking respectively. Importantly, these changes in gene expression occurred without re-exposure to drug-paired cues, indicating that chronic morphine causes long-lasting changes in gene expression that prime the system for increased craving. These findings lay the groundwork for identifying specific therapeutic targets for curbing opioid craving without impacting the natural reward system in males and females., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: Women with congenital long QT syndrome (LQTS) experience increased cardiac event risk after the onset of adolescence, perhaps stemming from the known modulating effects of sex hormones on the cardiac potassium channels., Objective: We hypothesized that the effect of sex hormones on cardiac ion channel function may modify electrocardiographic (ECG) parameters associated with the propensity for ventricular tachyarrhythmias during the menstrual cycle in women with LQTS., Methods: We prospectively enrolled 65 women with congenital LQTS (type 1 LQTS [LQT1], n = 24 [36.9%]; type 2 LQTS [LQT2], n = 20 [30.8%]) and unaffected female relatives (n = 21 [32.3%]). Patients underwent three 7-day ECG recordings during their menstrual cycles. Simultaneous saliva testing of sex hormone levels was conducted on the first day of each 7-day ECG recording cycle., Results: The mean age was 35 ± 8 years, without a significant difference among the groups. In women with LQT2, linear mixed effects models showed significant inverse correlations of the corrected QT interval with progesterone levels (P < .001) and with the progesterone to estradiol ratio (P < .001). Inverse relationships of the R-R interval with estradiol levels (P = .003) and of the T-wave duration with testosterone levels (P = .014) were also observed in women with LQT2. In contrast, no significant associations were observed between ECG parameters and sex hormone levels in women with LQT1 or unaffected relatives., Conclusion: This is the first study to prospectively assess correlations between repolarization dynamics and sex hormone levels during the menstrual cycle in women with congenital LQTS. Our findings show genotype-specific unique corrected QT dynamics during the menstrual cycle that may affect the propensity for ventricular tachyarrhythmia in women with LQTS, particularly women with LQT2., (Copyright © 2022. Published by Elsevier Inc.)

Background: Increasingly, integrated healthcare systems such as the United States Veterans Health Administration (VHA) are employing chiropractors. However, little is known about chiropractor employee clinical productivity which may be important for resource planning and monitoring care delivery. With its history of delivering chiropractic care and its enterprise-level assessment metrics, the VHA is an ideal setting to study a chiropractic workforce. We aim to assess characteristics of chiropractors employed by the VHA and explore associations between these characteristics and clinical productivity., Methods: This was a cross-sectional and serial analyses of VHA administrative data. Characteristics of the chiropractor workforce were evaluated from fiscal year (FY) 2016 to FY2019. Productivity was calculated using the VHA productivity measure, the quotient of an individual's total work relative value units (wRVUs) per FY divided by the direct clinical full-time equivalent (FTE) worked. A multivariable regression model was used to analyze the association between productivity and characteristics of the chiropractor and VHA facility., Results: From FY2016 to FY2019, the number of chiropractor employees increased from 102 to 167. In FY2019, the typical chiropractor employee was male, white, and 45.9 years old with 5.2 years of VHA experience. In FY2019, the VHA chiropractor workforce was 25.1% female, 79% white, and 20.4% Veteran. The productivity measure of a chiropractor was 3040 in FY2019. A higher facility complexity measure, presence of 3 chiropractor employees at a facility, and older age of the providers were the only characteristics studied that had a significant impact on productivity after adjusting for other covariates., Conclusion: Provider characteristics and productivity metrics of the VHA chiropractor employee workforce are presented. The productivity measure provides an initial benchmarking that may be relevant to future modeling of chiropractor personnel in VHA and other healthcare systems., (© 2022. The Author(s).)

Background: Respiratory syncytial virus (RSV) causes acute respiratory illness (ARI) and triggers exacerbations of cardiopulmonary disease. Estimates of incidence in hospitalized adults range widely, with few data on incidence in adults with comorbidities that increase the risk of severity. We conducted a prospective, population-based, surveillance study to estimate incidence of RSV hospitalization among adults overall and those with specific comorbidities., Methods: Hospitalized adults aged ≥18 years residing in the surveillance area with ≥2 ARI symptoms or exacerbation of underlying cardiopulmonary disease were screened during the 2017-2018, 2018-2019, and 2019-2020 RSV seasons in 3 hospitals in Rochester, New York and New York City. Respiratory specimens were tested for RSV using polymerase chain reaction assays. RSV incidence per 100 000 was adjusted by market share., Results: Active and passive surveillance identified 1099 adults hospitalized with RSV. Annual incidence during 3 seasons ranged from 44.2 to 58.9/100 000. Age-group-specific incidence ranged from 7.7 to 11.9/100 000, 33.5 to 57.5/100 000, and 136.9 to 255.6/100 000 in patients ages 18-49, 50-64, and ≥65 years, respectively. Incidence rates in patients with chronic obstructive pulmonary disease, coronary artery disease, and congestive heart failure were 3-13, 4-7, and 4-33 times, respectively, the incidence in patients without these conditions., Conclusions: We found a high burden of RSV hospitalization in this large prospective study. Notable was the high incidence among older patients and those with cardiac conditions. These data confirm the need for effective vaccines to prevent RSV infection in older and vulnerable adults., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background and Purpose: Genome-wide association studies (GWAS) of late hematuria following prostate cancer radiotherapy identified single nucleotide polymorphisms (SNPs) near AGT, encoding angiotensinogen. We tested the hypothesis that patients taking angiotensin converting enzyme inhibitors (ACEi) have a reduced risk of late hematuria. We additionally tested genetically-defined hypertension., Materials and Methods: Prostate cancer patients undergoing potentially-curative radiotherapy were enrolled onto two multi-center observational studies, URWCI (N = 256) and REQUITE (N = 1,437). Patients were assessed pre-radiotherapy and followed prospectively for development of toxicity for up to four years. The cumulative probability of hematuria was estimated by the Kaplan-Meier method. Multivariable grouped relative risk models assessed the effect of ACEi on time to hematuria adjusting for clinical factors and stratified by enrollment site. A polygenic risk score (PRS) for blood pressure was tested for association with hematuria in REQUITE and our Radiogenomics Consortium GWAS., Results: Patients taking ACEi during radiotherapy had a reduced risk of hematuria (HR 0.51, 95%CI 0.28 to 0.94, p = 0.030) after adjusting for prior transurethral prostate and/or bladder resection, heart disease, pelvic node radiotherapy, and bladder volume receiving 70 Gy, which are associated with hematuria. A blood pressure PRS was associated with hypertension (odds ratio per standard deviation 1.38, 95%CI 1.31 to 1.46, n = 5,288, p < 0.001) but not hematuria (HR per standard deviation 0.96, 95%CI 0.87 to 1.06, n = 5,126, p = 0.41)., Conclusions: Our study is the first to show a radioprotective effect of ACEi on bladder in an international, multi-site study of patients receiving pelvic radiotherapy. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects the bladder., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The effectiveness of implantable cardioverter-defibrillators (ICDs) on reducing mortality has not been well studied in patients with long QT syndrome (LQTS)., Objectives: This study aimed to assess the survival benefits of ICDs in the overall LQTS population and in subgroups defined by ICD indications., Methods: This study included 3,035 patients (597 with ICD) from the Rochester LQTS Registry with a QTc ≥470 milliseconds or confirmed LQTS mutation. Using multivariable Cox proportional hazards models, the risk of all-cause mortality, all-cause mortality before age 50 years, and sudden cardiac death (SCD) were estimated as functions of time-dependent ICD therapy. Indication subgroups examined included patients with: 1) nonfatal cardiac arrest; 2) syncope while on beta-blockers; and 3) a QTc ≥500 milliseconds and syncope while off beta-blockers., Results: During the 118,837 person-years of follow-up, 389 patients died (137 before age 50 years, and 116 experienced SCD). In the entire population, patients with ICDs had a lower risk of death (HR: 0.54; 95% CI: 0.34-0.86), death before age 50 years (HR: 0.29; 95% CI: 0.14-0.61), and SCD (HR: 0.22; 95% CI: 0.09-0.55) than patients without ICDs did. Patients with ICDs also had a lower risk of mortality among the 3 indication subgroups (HR: 0.14; 95% CI: 0.06-0.34; HR: 0.27; 95% CI: 0.10-0.72; and HR: 0.42; 95% CI: 0.19-0.96, respectively)., Conclusions: ICD therapy was associated with a lower risk of all-cause mortality, all-cause mortality before age 50 years, and SCD in the LQTS population, as wells as with a lower risk of all-cause mortality in indication subgroups. This study provides evidence supporting ICD implantation in patients with high-risk LQTS., Competing Interests: Funding Support and Author Disclosures The study was performed with support from National Institutes of Health grants HL-33843, HL-51618, and HL-123483. Dr Zareba has received research grant support from Biotronik and LivaNova; and has received consulting honoraria for Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Experiencing some early life adversity can have an "inoculating" effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown, and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal days 2 to 9 and their dams were exposed to a low-resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions. High levels of impulsivity are associated with substance abuse, but in males, LBN reduced impulsive choice compared to controls. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. These effects of LBN on addiction-related behaviors were not found in females. Because the nucleus accumbens (NAc) mediates these behaviors, we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced the frequency of spontaneous excitatory postsynaptic currents in males, but a similar effect was not observed in females. Only in males did LBN prevent a morphine-induced increase in the AMPA/NMDA ratio. RNA sequencing was performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients., Competing Interests: The authors declare no competing interest.

Many premature babies who are born with neonatal respiratory distress syndrome (RDS) go on to develop Bronchopulmonary Dysplasia (BPD) and later Post-Prematurity Respiratory Disease (PRD) at one year corrected age, characterized by persistent or recurrent lower respiratory tract symptoms frequently related to inflammation and viral infection. Transcriptomic profiles were generated from sorted peripheral blood CD8+ T cells of preterm and full-term infants enrolled with consent in the NHLBI Prematurity and Respiratory Outcomes Program (PROP) at the University of Rochester and the University at Buffalo. We identified outcome-related gene expression patterns following standard methods to identify markers for oxygen utilization and BPD as outcomes in extremely premature infants. We further identified predictor gene sets for BPD based on transcriptomic data adjusted for gestational age at birth (GAB). RNA-Seq analysis was completed for CD8+ T cells from 145 subjects. Among the subjects with highest risk for BPD (born at <29 weeks gestational age (GA); n=72), 501 genes were associated with oxygen utilization. In the same set of subjects, 571 genes were differentially expressed in subjects with a diagnosis of BPD and 105 genes were different in BPD subjects as defined by physiologic challenge. A set of 92 genes could predict BPD with a moderately high degree of accuracy. We consistently observed dysregulation of TGFB, NRF2, HIPPO , and CD40 -associated pathways in BPD. Using gene expression data from both premature and full-term subjects (n=116), we identified a 28 gene set that predicted the PRD status with a moderately high level of accuracy, which also were involved in TGFB signaling. Transcriptomic data from sort-purified peripheral blood CD8+ T cells from 145 preterm and full-term infants identified sets of molecular markers of inflammation associated with independent development of BPD in extremely premature infants at high risk for the disease and of PRD among the preterm and full-term subjects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bhattacharya, Mereness, Baran, Misra, Peterson, Ryan, Reynolds, Pryhuber and Mariani.)