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Therapeutic Area: CVD Prevention – Primary and Secondary Background: Engaging in physical activity (PA) is an important modifiable risk factor to improve health in hypertension. However, the association between PA and outcomes in high-risk hypertension remains understudied. The aim of this study was to examine the relationship between the intensity and amount of PA and outcomes in SPRINT. SPRINT investigated the benefit of intensive blood pressure treatment on cardiovascular outcomes and all-cause mortality among individuals with high-risk hypertension. Methods: This analysis included 8,320 (age 67.8±9.3, 34.9% women) participants from SPRINT on whom data was available on self-reported PA. Vigorous-intensity PA (VPA) included activities associated with sweating, increased heart rate or breathing. Moderate-Intensity PA (MPA) included activities such as brisk walking, climbing stairs or vacuuming. VPA was categorized into 2 groups based on frequency of “rarely or never” and ≥1 times/month. MPA was also categorized into 2 groups based on average duration/day of

Therapeutic Area: Obesity Background: Many people who try to lose weight fail to achieve sustained weight loss and instead experience cycles of weight loss and weight gain, a phenomenon referred to as “weight cycling”. Such intra-individual body weight variability (BWV) has been linked to increased risk for cardiovascular (CV) disease and death, independent of other risk factors. The aim of this study was to examine the association between BWV and body weight change (BWC) with outcomes SPRINT. SPRINT enrolled individuals with high-risk hypertension but without diabetes mellitus (DM), to investigate the benefit of intensive (versus standard) blood pressure treatment on CV outcomes and all-cause mortality. Methods: In this analysis, we included a total of 8,714 SPRINT participants (age 67.8±9.4 years, 35.1% women) on whom data was available on serial weight during the study period. BWV was defined as the intra-individual average successive variability (ASV). BWC was defined as baseline weight minus exit weight. Using multivariate Cox regression models, we examined the hazard ratios (HR) associated with BWV and BWC (both as continuous variables), for all-cause mortality and the primary outcome [defined as the composite of myocardial infarction (MI), other acute coronary syndromes, stroke, acute decompensated heart failure (HF), or death from CV causes]. Results: Over a median follow-up of 3.9 years, the BWV and BWC [mean ± standard deviation (SD)] among participants were 3.12±3.04 and 1.01±6.97 kilogram respectively. Each 1 unit SD of BWV was significantly associated with a higher risk for all-cause mortality, primary outcome, MI and HF [HR (95% CI)]: 1.22(1.14–1.30; p

Empathy is the cornerstone of the patient–physician relationship and is consistently ranked by patients as one of the most important factors in the quality of their care. In this paper we examine the degree to which perceived physician empathy is associated with the characteristics of the caregiver (parent or legal guardian) and physician in pediatric orthopedic surgery. This was a cross-sectional survey study of 200 English-speaking caregivers of pediatric patients at a large children's hospital. The Consultation and Relational Empathy (CARE) Measure was used to measure perceived physician empathy. Only if the caregiver felt carefully listened to by the physician ( p -value < 0.001), and if the physician showed respect for what the caregiver had to say ( p -value = 0.007) were statistically significant and positively associated with perceived physician empathy. The most significant determinant of perceived physician empathy is whether the caregiver felt listened to during the encounter. Other factors such as caregiver demographics, health literacy, self-rated mental health, wait time, and time spent with the physician do not significantly affect perceived physician empathy.

Background: Insufficiency of hip capsular structures has recently gained recognition as a cause of pre-arthritic hip pain, leading to hip joint instability and progressive chondrolabral injury. An accurate evaluation of capsular integrity can help orthopedic surgeons plan capsular management prior to hip arthroscopy. Indications: The proposed iliofemoral bounce test is meant to be applied preoperatively for identification of hip capsular integrity when microinstability is suspected or in the setting of revision hip arthroscopy. Technique Description: After induction of general anesthesia and complete muscle relaxation, the patient is placed in a supine figure-four position by placing the foot of the pathologic hip on the contralateral knee. Two examination techniques are performed: (1) The examiner places one hand on the patient’s contralateral anterior superior iliac spine and applies consecutive downward pressure in a “rocking” manner to the pelvis; (2) the examiner applies a preload and release force to the flexed knee (examined hip), with the contralateral pelvis stabilized, and observes the response of the knee to this loads. Results: Technique 1: The expected physiologic response in a preserved joint is a “bounce” of the contralateral hip (examined hip), evidenced by an up-and-down movement of the knee in response to the rocking movement applied. This movement reflects the integrity and functionality of the hip capsule ligaments’ elastic recoil forces, allowing the hip to remain in a stable state in response to destabilizing forces. In contrast, when capsular insufficiency is present, a lack of bouncing will be observed due to unrestricted external rotation of the hip to constrain the hip joint. Technique 2: In a preserved joint capsule, the knee will return to its preload position, while in capsular insufficiency, no bouncing of the knee will be observed. Discussion/Conclusion: The iliofemoral bounce test is a novel, dynamic, and reproducible examination technique for clinicians to evaluate patient’s true hip capsular integrity and for preoperative identification of the proper capsular management, either with a less invasive capsulotomy or performing a capsular closure, plication or even reconstruction, when necessary.

Background: We investigated in older adult non-cardiac surgical patients whether receipt of perioperative non-steroidal anti-inflammatory drugs (NSAIDs) is associated with increased incidence of postoperative cardiovascular complications., Methods: We retrospectively extracted the information for patients with age ≥  65 years who had inpatient non-cardiac surgery with a duration of ≥  1 h from the American College of Surgeons-National Surgical Quality Improvement Program registry data acquired at the University of Washington Medical Center. We compared patients who received NSAIDs perioperatively to those who did not receive NSAIDs, on the two composite outcomes: (1) the incidence of postoperative cardiovascular complications within 30 days of the surgery, and (2) the incidence of combined postoperative gastrointestinal and renal complications, and length of postoperative hospital stay. We used separate multivariable logistic regression models to analyze the two composite outcomes and a Poisson regression model for the length of hospital stay., Results: The receipt of perioperative NSAIDs was not associated with postoperative cardiovascular complications (estimated odds ratio (OR), 1.78; 95% confidence interval (CI), 0.97 to 3.25; P =  0.06), combined renal and gastrointestinal complications (estimated OR, 1.30; 95% CI, 0.53 to 3.20; P =  0.57), and length of postoperative hospital stay in days (incidence rate ratio, 1.06; 95% CI, 0.93 to 1.21; P =  0.39)., Conclusions: In older adult non-cardiac surgical patients, receipt of perioperative NSAIDs was not associated with increased incidences of postoperative cardiovascular complications, and renal and gastrointestinal complications within 30 days after surgery, or length of postoperative hospital stay., (© 2024. The Author(s).)

Intrinsically disordered regions (IDRs) are segments of proteins without stable three-dimensional structures. As this flexibility allows them to interact with diverse binding partners, IDRs play key roles in cell signaling and gene expression. Despite the prevalence and importance of IDRs in eukaryotic proteomes and various biological processes, associating them with specific molecular functions remains a significant challenge due to their high rates of sequence evolution. However, by comparing the observed values of various IDR-associated properties against those generated under a simulated model of evolution, a recent study found most IDRs across the entire yeast proteome contain conserved features. Furthermore, it showed clusters of IDRs with common "evolutionary signatures," i.e. patterns of conserved features, were associated with specific biological functions. To determine if similar patterns of conservation are found in the IDRs of other systems, in this work we applied a series of phylogenetic models to over 7,500 orthologous IDRs identified in the Drosophila genome to dissect the forces driving their evolution. By comparing models of constrained and unconstrained continuous trait evolution using the Brownian motion and Ornstein-Uhlenbeck models, respectively, we identified signals of widespread constraint, indicating conservation of distributed features is mechanism of IDR evolution common to multiple biological systems. In contrast to the previous study in yeast, however, we observed limited evidence of IDR clusters with specific biological functions, which suggests a more complex relationship between evolutionary constraints and function in the IDRs of multicellular organisms., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MBE is a founder and former member of the board of directors of PLOS., (Copyright: © 2024 Singleton, Eisen. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: We tested the hypothesis that patients who received methocarbamol postoperatively experience less severe pain and require smaller doses of opioids than those who did not receive methocarbamol., Materials and Methods: This is a retrospective cohort study of patients undergoing surgery involving the musculoskeletal system. Of 9089 patients, 704 received methocarbamol during 48 hours postoperatively, while 8385 did not receive methocarbamol. The patients who received methocarbamol postoperatively and the patients who did not receive methocarbamol were compared on the time-weighted average (TWA) pain score and opioid dose requirements in morphine milligram equivalents (MME) during the first 48 hours postoperatively, using propensity score-weighted regression models to adjusting for preoperative and intraoperative covariates., Results: Postoperative 48-hour TWA pain scores were 5.5±1.7 (mean±SD), and 4.3±2.1 for methocarbamol and non-methocarbamol patients. Postoperative 48-hour opioid dose requirements in MME were 276 [170-347] (median [interquartile range (IQR)]) mg, and 190 [60-248] mg for methocarbamol and non-methocarbamol patients. In propensity score-weighted regression models, receiving methocarbamol postoperatively was associated with 0.97-point higher postoperative TWA pain score (95% CI, 0.83-1.11; P <0.001), and 93.6-MME higher postoperative opioid dose requirements (95% CI, 79.9 to 107.4; P <0.001), compared with not receiving methocarbamol postoperatively., Discussion: Postoperative methocarbamol was associated with significantly higher acute postoperative pain burden and opioid dose requirements. Although the results of the study are influenced by residual confounding, they suggest a limited-if any-benefit of methocarbamol as an adjunct of postoperative pain management., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We tested the hypothesis that patients who continued buprenorphine postoperatively experience postoperative respiratory depression less frequently than those who discontinued buprenorphine., Methods: This is a retrospective cohort study of patients who were on buprenorphine preoperatively. The primary outcome was postoperative respiratory depression as defined by respiratory rate < 10/minute, oxygen saturation (SpO 2 ) < 90%, or requirement of naloxone for 48 h postoperatively. The secondary outcome was the composite of postoperative respiratory complications. The associations between postoperative buprenorphine continuation and respiratory depression and respiratory complications were estimated using separate multivariable logistic regression models, including demographic, intraoperative characteristics, and preoperative buprenorphine dose as covariates., Results: Postoperative buprenorphine continuation was not associated with postoperative respiratory depression (adjusted odds ratio (OR), 1.11, 95% confidence interval (CI), 0.61 to 1.99, P=0.72). In subanalysis stratified by the preoperative buprenorphine dose, buprenorphine continuation was not associated with postoperative respiratory depression either when preoperative buprenorphine dose was high (≥16 mg daily) or low (<16 mg daily). Postoperative buprenorphine continuation was associated with lower incidence of postoperative respiratory complications (adjusted OR, 0.43, 95% CI, 0.21 to 0.86, P=0.02)., Conclusions: Continuing buprenorphine was not associated with respiratory depression, but it was associated with a lower incidence of respiratory complications., (© 2022. The Author(s).)

Objective: Traditional public health surveillance of nonfatal opioid overdose relies on emergency department (ED) billing data, which can be delayed substantially. We compared the timeliness of 2 new data sources for rapid drug overdose surveillance-emergency medical services (EMS) and syndromic surveillance-with ED billing data., Methods: We used data on nonfatal opioid overdoses in Kentucky captured in EMS, syndromic surveillance, and ED billing systems during 2018-2019. We evaluated the time-series relationships between EMS and ED billing data and syndromic surveillance and ED billing data by calculating cross-correlation functions, controlling for influences of autocorrelations. A case example demonstrates the usefulness of EMS and syndromic surveillance data to monitor rapid changes in opioid overdose encounters in Kentucky during the COVID-19 epidemic., Results: EMS and syndromic surveillance data showed moderate-to-strong correlation with ED billing data on a lag of 0 ( r = 0.694; 95% CI, 0.579-0.782; t = 9.73; df = 101; P < .001; and r = 0.656; 95% CI, 0.530-0.754; t = 8.73; df = 101; P < .001; respectively) at the week-aggregated level. After the COVID-19 emergency declaration, EMS and syndromic surveillance time series had steep increases in April and May 2020, followed by declines from June through September 2020. The ED billing data were available for analysis 3 months after the end of a calendar quarter but closely followed the trends identified by the EMS and syndromic surveillance data., Conclusion: Data from EMS and syndromic surveillance systems can be reliably used to monitor nonfatal opioid overdose trends in Kentucky in near-real time to inform timely public health response.

Purpose: Metarrestin is a first-in-class pyrrolo-pyrimidine-derived small molecule targeting a marker of genome organization associated with metastasis and is currently in preclinical development as an anti-cancer agent. Here, we report the in vitro ADME characteristics and in vivo pharmacokinetic behavior of metarrestin., Methods: Solubility, permeability, and efflux ratio as well as in vitro metabolism of metarrestin in hepatocytes, liver microsomes and S9 fractions, recombinant cytochrome P450 (CYP) enzymes, and potential for CYP inhibition were evaluated. Single dose pharmacokinetic profiles after intravenous and oral administration in mice, rat, dog, monkey, and mini-pig were obtained. Simple allometric scaling was applied to predict human pharmacokinetics., Results: Metarrestin had an aqueous solubility of 150 µM at pH 7.4, high permeability in PAMPA and moderate efflux ratio in Caco-2 assays. The compound was metabolically stable in liver microsomes, S9 fractions, and hepatocytes from six species, including human. Metarrestin is a CYP3A4 substrate and, in mini-pigs, is also directly glucuronidated. Metarrestin did not show cytochrome P450 inhibitory activity. Plasma concentration-time profiles showed low to moderate clearance, ranging from 0.6 mL/min/kg in monkeys to 48 mL/min/kg in mice and moderate to high volume of distribution, ranging from 1.5 L/kg in monkeys to 17 L/kg in mice. Metarrestin has greater than 80% oral bioavailability in all species tested. The excretion of unchanged parent drug in urine was < 5% in dogs and < 1% in monkeys over collection periods of ≥ 144 h; in bile-duct cannulated rats, the excretion of unchanged drug was < 1% in urine and < 2% in bile over a collection period of 48 h., Conclusions: Metarrestin is a low clearance compound which has good bioavailability and large biodistribution after oral administration. Biotransformation appears to be the major elimination process for the parent drug. In vitro data suggest a low drug-drug interaction potential on CYP-mediated metabolism. Overall favorable ADME and PK properties support metarrestin's progression to clinical investigation.

Background: Surveillance of youth suicide attempts presents many challenges. To assess common data sources that capture information about youth suicidal behavior, we compared counts of high school students who reported (a) a suicide attempt and (b) an injurious suicide attempt, requiring medical treatment in the previous twelve months, with counts of suicide deaths and intentional self-injuries obtained from administrative data sources., Method: Youth Risk Behavior Surveillance System (YRBSS), high school enrollments, and vital statistics were used to estimate the ratio of suicide attempts to suicide deaths among Kentucky high school students. YRBSS and enrollment data were used to estimate the number of Kentucky high school students who received medical treatment following a suicide attempt, which was compared with hospital and emergency department (ED) discharges for intentional self-injury from administrative claim records., Results: We estimated 943 students reporting a suicide attempt for every suicide death, a result that is higher than previous estimates for youth. Self-reported suicide attempts resulting in medical treatment were 7.5 times higher than self-injuries reported in claims records., Conclusion: Future research should address concerns about undocumented cases of intentional self-injury in administrative claims systems; patient encounters in nonhospital settings for injuries resulting from a suicide attempt; and validity of Youth Risk Behavior Survey questions on suicidal behavior., (© 2019 The American Association of Suicidology.)

Introduction: Co-morbid post-traumatic stress disorder (PTSD) and low back pain (LBP) are common reasons for increased disability in the Veteran communities. Medical discharge from the military represents a considerable financial cost to society. Little is currently known about the impact of LBP and PTSD as longitudinal risk factors for medical discharge from Active Duty military service., Materials and Methods: A retrospective analysis of US Army Active Duty Soldiers from 2002 to 2012 was performed to determine the risk for medical discharge. Four levels of exposure for were identified as independent variables: no chronic LBP or PTSD, chronic LBP only, PTSD only, and co-morbid PTSD present with chronic LBP. Statistical analysis utilized modified Poisson regression controlling for sex, age, rank, time in service, deployment, mental health, sleep disorders, alcohol use, tobacco use, obesity, and military occupation. This study was approved by a Department of Defense Institutional Review Board., Results: After controlling for potential confounding variables, the RR for chronic LBP and PTSD independently was 3.65 (95% CI: 3.59-3.72) and 3.64 (95% CI: 3.53-3.75), respectively, and 5.17 (95% CI: 5.01-5.33) when both were present., Conclusions: This is the first study to identify a history of both chronic LBP and PTSD as substantial risk factors for medical discharge from the US Army. PTSD and chronic LBP may mutually reinforce one another and deplete active coping strategies, making Soldiers less likely to be able to continue military service. Future research should target therapies for co-morbid PTSD and chronic LBP as these conditions contribute a substantial increase in risk of medical discharge from the US Army., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2019.)

Purpose: Metarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers., Methods: PK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC-MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice., Results: Metarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC 0-∞ of 14400 ng h/mL, C max of 810 ng/mL and half-life (t 1/2 ) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 µg/g tissue (or 13 µM), well above the cell-based IC 50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC 0-24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC 0-24h and C 24h . AUC 0-24h MD to AUC 0-24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors., Conclusions: Metarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery.

Background: According to the National Center for Health Statistics, Kentucky had the third highest drug overdose fatality rate in the nation in 2015 at 29.9 drug overdose fatalities per 100 000 population., Objective: The elevated drug overdose fatality rate necessitated the development and implementation of a comprehensive multisource drug overdose fatality surveillance system (DOFSS)., Methods: DOFSS stakeholder work group members and data sources were identified, and memorandums of understanding were established. The following data sources were used to establish DOFSS: (1) death certificates; (2) autopsy reports; (3) toxicology result reports; (4) coroner reports; and (5) Kentucky All Schedule Prescription Electronic Reporting (KASPER) (prescription drug monitoring programme) data. Drug overdose poisonings were defined using Injury Surveillance Workgroup 7 definitions. Analyses were performed to investigate possible drug overdose-related health disparities for disabled drug overdose decedents and to characterise gabapentin in drug overdose deaths., Results: DOFSS identified 2106 drug overdose poisoning fatalities in Kentucky for 2013-2014. Identification of specific drugs involved in drug overdose deaths increased from 75.8% using a single data source to 97.5% using multiple data sources. Disabled drug overdose decedents were significantly more likely to have an active prescription for drugs identified in their system compared with the non-disabled drug overdose decedents. Toxicology data showed increased gabapentin involvement in drug overdose deaths from 2.9% in 2013 to 17% in 2014. Alprazolam was found most often in combination with gabapentin (41%), along with various other benzodiazepines and prescription opioids., Conclusions: A comprehensive multisource DOFSS improved drug overdose fatality surveillance by increasing completeness of data and data quality. DOFSS is a model that can be considered by other states to enhance their efforts in tracking drug overdose fatalities, identifying new and emerging trends, and informing policies and best practices, to address and reduce drug overdoses., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Although numerous observational studies have demonstrated a protective effect of motorcycle helmets against head injury, the degree of protection against specific head injury types remains unclear. Experimental biomechanics studies involving cadavers, animals, and computer models have established that head injuries have varying etiologies. This retrospective cross-sectional study compared helmet protection against skull fracture, cerebral contusion, intracranial hemorrhage, and cerebral concussion in a consecutive series of motorcycle operators involved in recent traffic crashes in Kentucky., Methods: Police collision reports linked to hospital inpatient and emergency department (ED) claims were analyzed for the period 2008 to 2012. Motorcycle operators with known helmet use who were not killed at the crash scene were included in the study. Helmet use was ascertained from the police report. Skull fracture, cerebral contusion, intracranial hemorrhage, and cerebral concussion were identified from International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes on the claims records. The relative risks of each type of head injury for helmeted versus unprotected operators were estimated using generalized estimating equations., Results: Helmets offer substantial protection against skull fracture (relative risk [RR] = 0.31, 95% confidence interval [CI], 0.23, 0.34), cerebral contusion (RR = 0.29, 95% CI, 0.16, 0.53), and intracranial hemorrhage (RR = 0.47, 95% CI, 0.35, 0.63). The findings pertaining to uncomplicated concussion (RR = 0.80, 95% CI, 0.64, 1.01) were inconclusive. A modest protective effect (20% risk reduction) was suggested by the relative risk estimate, but the 95% confidence interval included the null value., Conclusions: Motorcycle helmets were associated with a 69% reduction in skull fractures, 71% reduction in cerebral contusion, and 53% reduction in intracranial hemorrhage. This study finds that current motorcycle helmets do not protect equally against all types of head injury. Efforts to improve rotational acceleration management in motorcycle helmets should be considered.

Background: Young children with suspected abusive head trauma often receive skull radiographs to evaluate for fractures as well as computed tomography (CT) of the head to assess for intracranial injury. Using a CT as the primary modality to evaluate both fracture and intracranial injury could reduce exposure to radiation without sacrificing performance., Objective: To evaluate the sensitivity of CT head with (3-D) reconstruction compared to skull radiographs to identify skull fractures in children with suspected abusive head trauma., Materials and Methods: This was a retrospective (2013-2014) cross-sectional study of infants evaluated for abusive head trauma via both skull radiographs and CT with 3-D reconstruction. The reference standard was skull radiography. All studies were read by pediatric radiologists and neuroradiologists, with ten percent read by a second radiologist to evaluate for interobserver reliability., Results: One hundred seventy-seven children (47% female; mean/median age: 5 months) were included. Sixty-two (35%) had skull fractures by radiography. CT with 3-D reconstruction was 97% sensitive (95% confidence interval [CI]: 89-100%) and 94% specific (CI: 87-97%) for skull fracture. There was no significant difference between plain radiographs and 3-D CT scan results (P-value = 0.18). Kappa was 1 (P-value <0.001) between radiologist readings of CTs and 0.77 (P = 0.001) for skull radiographs., Conclusion: CT with 3-D reconstruction is equivalent to skull radiographs in identifying skull fractures. When a head CT is indicated, skull radiographs add little diagnostic value.

In this paper, we propose a nonlinear hierarchical model (NLHM) for analyzing longitudinal experimental infection (EI) data. The NLHM offers several improvements over commonly used alternatives such as repeated measures analysis of variance (RM-ANOVA) and the linear mixed model (LMM). It enables comparison of relevant biological properties of the course of infection including peak intensity, duration and time to peak, rather than simply comparing mean responses at each observation time. We illustrate the practical benefits of this model and the insights it yields using data from experimental infection studies on equine arteritis virus. Finally, we demonstrate via simulation studies that the NLHM substantially reduces bias and improves the power to detect differences in relevant features of the infection response between two populations. For example, to detect a 20% difference in response duration between two groups (n=15) in which the peak time and peak intensity were identical, the RM-ANOVA test had a power of just 11%, and LMM a power of just 12%. By comparison, the nonlinear model we propose had a power of 58% in the same scenario, while controlling the Type I error rate better than the other two methods., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Microorganisms form biofilms containing differentiated cell populations. To determine factors driving differentiation, we herein visualize protein and metal distributions within Pseudomonas aeruginosa biofilms using imaging mass spectrometry. These in vitro experiments reveal correlations between differential protein distribution and metal abundance. Notably, zinc- and manganese-depleted portions of the biofilm repress the production of anti-staphylococcal molecules. Exposure to calprotectin (a host protein known to sequester metal ions at infectious foci) recapitulates responses occurring within metal-deplete portions of the biofilm and promotes interaction between P. aeruginosa and Staphylococcus aureus. Consistent with these results, the presence of calprotectin promotes co-colonization of the murine lung, and polymicrobial communities are found to co-exist in calprotectin-enriched airspaces of a cystic fibrosis lung explant. These findings, which demonstrate that metal fluctuations are a driving force of microbial community structure, have clinical implications because of the frequent occurrence of P. aeruginosa and S. aureus co-infections.

The purpose of this study was to further evaluate and validate two commercially available equine arteritis virus (EAV) competitive ELISAs (original and enhanced cELISAs) using archived equine sera from experimentally inoculated animals and field sera submitted for laboratory diagnosis. First, the original and subsequently enhanced cELISAs were compared with the virus neutralisation test (VNT) using a panel of archived serum samples from experimentally inoculated animals. Then, the enhanced cELISA was compared with the VNT using a large panel of archived serum samples. The total number of equine sera tested was 3255, which included sera against 25 different EAV strains. The study confirmed that the enhanced cELISA was more sensitive than the original cELISA. Based on testing sera from experimentally inoculated animals and field sera, the enhanced cELISA had an estimated sensitivity (98.9 percent and 99.6 percent, respectively) and specificity (98.3 percent and 98.7 percent, respectively). The currently marketed enhanced VMRD EAV antibody cELISA test kit (VMRD Inc., Pullman, Washington, USA) has high sensitivity and specificity relative to the VNT. Based on the findings of this study, the authors would propose that the enhanced cELISA should be considered as an alternative approved method to the VNT for the detection of antibodies to EAV., (British Veterinary Association.)

Background: Emergency departments (EDs) serve a wide range of patients who present at risk of impending suicide and homicide., Aims: Two statewide surveillance systems were probabilistically linked to understand who utilizes EDs and then dies violently within 6 weeks., Method: Each identified case was matched with four randomly selected controls on sex, race, date of birth, resident zip code, and date of ED visit vs. date of death. Matched-pair odds ratios were estimated by conditional logistic regression to assess differences between cases and controls on reported diagnoses and expected payment sources., Results: Of 1,599 suicides and 569 homicides in the 3-year study period, 10.7% of decedents who died by suicide (mean = 13.6 days) and 8.3% who died by homicide (mean = 16.3 days) were seen in a state ED within 6 weeks prior to death. ED attendees who died by suicide were more likely to have a diagnosis of injury/ poisoning diagnosis or mental disorder and more likely to have Medicare. Those who died by homicide were more likely to have a diagnosis of injury/poisoning and less likely to have commercial insurance., Conclusion: It is essential for research to further explore risk factors for imminent suicide and homicide in ED patients who present for psychiatric conditions and general injuries.

Reasons for Performing Study: Exercise-induced pulmonary haemorrhage (EIPH) is reported as a performance limiting condition in racehorses, yet few longitudinal studies characterising EIPH have been reported., Objectives: To characterise EIPH during training and racing in the absence of prophylactic medication with furosemide among horses imported to Hong Kong during 2007-2012., Study Design: Retrospective descriptive study of clinical endoscopy, EIPH status, and racing records., Methods: Thoroughbred geldings (n = 822) imported from New Zealand between 2007 and 2012 were retrospectively assigned to 4 groups: diagnosed with EIPH via endoscopy (EIPH+), graded using recognised criteria; observed with epistaxis (Epistaxis); free of EIPH on endoscopy (EIPH-); and those in which no endoscopy was performed., Results: The majority of horses (89%) were subjected to endoscopy once or more (median 15, interquartile range 3-18). Of those undergoing endoscopy, 55% of horses were diagnosed EIPH+ which varied in severity. Few (4%) experienced epistaxis. EIPH+ was diagnosed most frequently (63%) after racing. There was no significant difference in the proportion of EIPH+ and EIPH- horses that raced. Racing career longevity was longest for EIPH+ horses. The number of starts in Hong Kong for EIPH+ horses was not significantly different to EIPH- horses. [Correction added on 9 January 2015, after first online publication: The term 'lifetime starts' has been changed to 'starts in Hong Kong' in the preceding sentence.] Days to retirement were longer for EIPH+ horses. Horses with mild EIPH+ (grade <3) were more likely to be retired for other causes whereas severe grades (≥3) were more likely to be retired for EIPH., Conclusions: Exercise-induced pulmonary haemorrhage is common and varies in severity between individuals and between episodes in the same individual. There is no difference in racing career longevity between EIPH+ and EIPH- horses trained and raced without furosemide. See also correspondences by PS Morley and KW Hinchcliff; AD Richards; and S. Preston and C. M. Riggs., (© 2014 EVJ Ltd.)

Objective: Increases in asthma and obesity over the past three decades have led to speculation about a causal link between the two diseases. However, investigations of the relationship between body mass index (BMI) and fractional exhaled nitric oxide (FeNO) - a marker of eosinophilic airway inflammation - have produced mixed results. The purpose of this study was to evaluate the relationship between body mass index (BMI), asthma and FeNO in a sample of U.S. adults using data from the National Health and Nutrition Examination Surveys (NHANES) for 2007-2010., Methods: We assessed the relationship between FeNO and BMI in subjects with and without asthma using categorical and continuous models for BMI. All models controlled for age, gender, ethnicity, household income-to-poverty ratio, atopy and current smoking., Results: Adjusted asthma prevalence was positively associated with BMI, and subjects with asthma had higher adjusted FeNO levels than subjects without asthma. However, no association between FeNO and BMI was observed in either those with (β = 0.002, p = 0.74) or without (β = 0.0014, p = 0.51) asthma after adjusting for covariates., Conclusions: Our results suggest that in the U.S. adult population, BMI is not associated with eosinophilic airway inflammation.

Objectives: We investigated the incidence of hospital utilization for injuries and compared poisoning with other forms of injury. Previous studies have suggested poison control centers reduce health-care costs by decreasing hospital utilization., Methods: We conducted a one-year retrospective study involving patients treated for injuries at acute-care hospitals in Kentucky in 2008. We also compared inpatient discharges with discharges directly from the emergency department (ED) to determine hospitalization rates. The primary data sources were the Kentucky Hospital Billing database and the Kentucky Regional Poison Control Center (KRPCC) database., Results: In 2008, there were 377,642 hospital encounters for injuries in Kentucky. The most common mechanisms of injury were falls, struck by/against, motor vehicle traffic crashes, and overexertion. Three causes of injury were greater than one standard deviation above the mean in percentage of inpatient admissions: poisoning (41.3%), firearms (38.4%), and drowning (22.4%). During this same year, KRPCC reported 46,258 poisonings, with 76.5% of patients managed outside of a health-care facility, 11.4% of patients treated and released from the ED, 7.1% of patients admitted to inpatient care, 2.3% of patients admitted to psychiatric care, and 2.7% lost to follow-up., Conclusions: Three causes of injury had the greatest percentage of patients admitted for inpatient medical care--poisoning, firearms, and drowning--suggesting a high level of severity in these injuries presenting to the ED. We believe availability and use of a poison control center reduced hospital utilization for poisoning primarily by managing a large number of low-severity patients outside of the hospital system.

Objective: To determine the pharmacokinetics and relative bioavailability of para-aminosalicylic acid (PAS) granules., Design: Phase I pharmacokinetics study., Setting: University of Arizona School of Pharmacy., Participants: Sixteen healthy male and female volunteers aged 36 +/- 8 years., Interventions: Subjects received single doses of PAS granules (6 g) combined with cycloserine 500 mg, clofazimine 200 mg, ethionamide 500 mg, and pyridoxine 100 mg. Drugs were given on an empty stomach after an overnight fast (reference) with high-fat food, with orange juice, and with antacids., Measurements and Results: Four subjects did not complete all four treatments due to adverse events or personal reasons. Plasma and urine samples were collected for 48 hours and measured by a validated HPLC assay. Pharmacokinetic data analysis was performed with WinNonlin using noncompartmental methods and a one-compartmental model. Bioequivalence testing was performed using the mean ratios of the maximum concentrations (Cmax) and AUC(0-infinity) of PAS, with 90% confidence intervals. Compared with the fasted condition, food increased Cmax 1.5-fold and AUC(0-infinity) 1.7-fold, and it doubled the time to maximum concentration (tmax). The least-squares mean ratios (treatment/reference) for Cmax were 0.90 (58% to 139% CI), 1.16 (75% to 179% CI), and 0.82 (52% to 127% CI) with orange juice, food, or antacid treatment, respectively. Corresponding ratios for AUC(0-infinity) were 1.05 (71% to 155% CI), 1.52 (103% to 224% CI), and 0.84 (57% to 125% CI), respectively., Conclusions: Food significantly enhanced the absorption of PAS, while orange juice and antacids had minor effects.

The study objective was to determine the minimum frequency of dosing for standard 4-g doses of p-aminosalicylic acid (PAS) granules. Two sequential six-patient pharmacokinetic studies are described, followed by clinical data from 40 subsequent patients. All patients had multidrug-resistant tuberculosis (MDR-TB). Serum was collected at two to three time points after dosing, and assayed by a validated high performance liquid chromatography (HPLC) assay. Data were analyzed using noncompartmental methods. In six patients, twice-daily dosing produced median serum concentrations at 4, 8, and 12 h post-dose of 25.8, 23.2, and 16.4 microgram/ml. In six patients, once-daily dosing produced median serum concentrations at 6, 12, and 24 h post-dose of 23.4, 3.7, and 0 microgram/ml. In 40 patients, twice-daily dosing produced median serum concentrations at 4 to 8 and 9 to 12 h post-dose of 24.8 and 20.6 microgram/ml. Unlike once-daily dosing, twice-daily PAS maintained serum concentrations in excess of 1 microgram/ml, the typical minimal inhibitory concentration against Mycobacterium tuberculosis, for the entire dosing interval. We now use twice-daily PAS granules for our patients with MDR-TB.

Study Objectives: Determine the intrasubject and intersubject variability in, and the effects of food or antacids on, the pharmacokinetics of rifampin (RIF)., Design: Randomized, four-period crossover phase I study., Subjects: Fourteen healthy male and female volunteers., Interventions: Subjects ingested single doses of RIF, 600 mg, under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. They also received standard doses of isoniazid, pyrazinamide, and ethambutol., Measurements and Main Results: Serum was collected for 48 h and assayed by high-pressure liquid chromatography. Data were analyzed using noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: a mean RIF maximal serum concentration (Cmax) of 10.54+/-3.18 microg/mL, the time at which it occurred (Tmax) of 2.42+/-1.32 h, and the area under the curve from time zero to infinity (AUC0-infinity) of 57.15+/-13.41 microg x h/mL. These findings are similar to those reported previously. Antacids did not alter these parameters (Cmax of 10.89+/-5.22 microg/mL, Tmax of 2.36+/-1.28 h, and AUC0-infinity of 58.37+/-18.49 microg x h/mL). In contrast, the Food and Drug Administration high-fat meal reduced RIF Cmax by 36% (7.27+/-2.29 microg/mL), nearly doubled Tmax (4.43+/-1.09 h), but reduced AUC0-infinity by only 6% (55.20+/-14.48 microg x h/mL)., Conclusions: These changes in Cmax, Tmax, and AUC0-infinity can be avoided by giving RIF on an empty stomach whenever possible.

In the periphery alpha beta T lymphocytes recognize antigens in conjunction with major histocompatibility complex (MHC) molecules. In the thymus immature T cells are positively selected on MHC molecules in the apparent absence of cognate peptides. Thus, at different developmental stages a T cell responds to different epitopes, yet uses the identical alpha beta T cell antigen receptor (TcR). To explain this paradox it has been hypothesized that during positive selection immature T cells see peptides/ligands unique to the thymus, are selected by specific antagonists related to their cognate peptides, or are driven by lowered affinity thresholds of their TcR. Though different in detail, these theories rely on defined peptides uniquely matched to select certain TcR. However, we find that in a TcR-transgenic (TcR(trans +)) mouse severely limiting the diversity of peptides does not impair positive selection. We show that many unrelated peptides, including some naturally occurring on the cell surface, induce maturation of CD4-CD8+TcR(high) thymocytes. The same peptides when presented in conjunction with the selecting MHC molecule, are not recognized by peripheral T cells expressing the same TcR(trans). Therefore, these findings point to a promiscuous rather than discriminate recognition mode used by immature T cells.