Feasibility of regional center telehealth visits utilizing a rural research network in people with Parkinson's disease.

Background: Impaired motor and cognitive function can make travel cumbersome for People with Parkinson's disease (PwPD). Over 50% of PwPD cared for at the University of Arkansas for Medical Sciences (UAMS) Movement Disorders Clinic reside over 30 miles from Little Rock. Improving access to clinical care for PwPD is needed. Objective: To explore the feasibility of remote clinic-to-clinic telehealth research visits for evaluation of multi-modal function in PwPD. Methods: PwPD residing within 30 miles of a UAMS Regional health center were enrolled and clinic-to-clinic telehealth visits were performed. Motor and non-motor disease assessments were administered and quantified. Results were compared to participants who performed at-home telehealth visits using the same protocols during the height of the COVID pandemic. Results: Compared to the at-home telehealth visit group (n = 50), the participants from regional centers (n = 13) had similar age and disease duration, but greater disease severity with higher total Unified Parkinson's disease rating scale scores (Z = -2.218, p = 0.027) and lower Montreal Cognitive Assessment scores (Z = -3.350, p < 0.001). Regional center participants had lower incomes (Pearson's chi = 21.3, p < 0.001), higher costs to attend visits (Pearson's chi = 16.1, p = 0.003), and lived in more socioeconomically disadvantaged neighborhoods (Z = -3.120, p = 0.002). Prior research participation was lower in the regional center group (Pearson's chi = 4.5, p = 0.034) but both groups indicated interest in future research participation. Conclusions: Regional center research visits in PwPD in medically underserved areas are feasible and could help improve access to care and research participation in these traditionally underrepresented populations.

Comparative evaluation of small molecules reported to be inhibitors of Staphylococcus aureus biofilm formation.

IMPORTANCE: Because biofilm formation is such a problematic feature of Staphylococcus aureus infections, much effort has been put into identifying biofilm inhibitors. However, the results observed with these compounds are often reported in isolation, and the methods used to assess biofilm formation vary between labs, making it impossible to assess relative efficacy and prioritize among these putative inhibitors for further study. The studies we report address this issue by directly comparing putative biofilm inhibitors using a consistent in vitro assay. This assay was previously shown to maximize biofilm formation, and the results observed with this assay have been proven to be relevant in vivo. Of the 19 compounds compared using this method, many had no impact on biofilm formation under these conditions. Indeed, only one proved effective at limiting biofilm formation without also inhibiting growth.

Opioid Use in Patients With Cervical Cancer at a Tertiary Academic Medical Center.

BACKGROUND/AIM: Opioids are a common treatment for cancer-related pain and information is limited on the rates of opioid use for cervical cancer patients. This study aimed to analyze outpatient opioid use and various predictors among patients with cervical cancer at a tertiary academic medical center. PATIENTS AND METHODS: Data from patients with cervical cancer receiving treatment at a single institution, from August 2019 to July 2022, were retrospectively collected. Women with unrelated chronic opioid use or opioid use associated with acute inpatient stays were excluded. Charts were reviewed for patient demographics, disease characteristics, treatment characteristics, disease outcomes, and opioid prescriptions. The primary endpoint was duration of opioid use ≥6 months. Pearson's chi-squared testing, Welch's two-sample t-testing and Fisher's exact testing were used to determine predictors of opioid use ≥6 months. RESULTS: In total, 108 patients with cervical cancer (76.1%) of the 142 that received treatment were prescribed opioids. In women who were prescribed outpatient opioids, the median duration of opioid use was 69 days (interquartile range=5-359 days). In total, 40 (37.0%) had prescriptions for ≥180 days and 27 (25.0%) had prescriptions ≥365 days. On bivariate analysis, lower stage and receipt of surgery were associated with opioid use duration <6 months. Age, race, histology, substance/tobacco/alcohol use, depression/anxiety, and the receipt of brachytherapy/radiation were not associated with length of opioid prescriptions. CONCLUSION: This study demonstrated that 37% of patients with cervical cancer were using opioids for cancer-related pain longer than 6 months. Higher stage was associated with opioid use duration ≥6 months.

Determinants for Thyroid Hormone Replacement Therapy in Subclinical Hypothyroidism: A Multicenter Electronic Health Records-Based Study.

Background: The frequency and factors associated with thyroid hormone replacement therapy among patients with subclinical hypothyroidism (SCH) remain uncertain. Methods: In this electronic health records-based observational cohort study, we included adults diagnosed with SCH from four academic centers (the United States and Mexico) from January 1, 2016, to December 31, 2018. We aimed to identify the determinants of thyroid hormone replacement therapy for SCH and the frequency of treated SCH. Results: A total of 796 patients (65.2% women) had SCH, and 165 (20.7%) were treated with thyroid hormone replacement therapy. The treated group was younger [51.0 (standard deviation {SD} 18.3) vs. 55.3 (SD 18.2) years, p = 0.008] and had a higher proportion of women (72.7% vs. 63.2%, p = 0.03) compared with the untreated group. Only 46.7% of patients in the treated group and 65.6% in the untreated group had confirmatory thyroid function tests (TFTs) before the decision to start thyroid hormone replacement therapy was made. There was no difference in the frequency of thyroid autoimmunity evaluation, but a positive thyroid autoimmunity test was more frequent in the treated group compared with the untreated group (48.2% vs. 20.3%, p < 0.001). In a multivariable logistic regression model, female sex (odds ratio [OR] = 1.71 [CI 1.13-2.59], p = 0.01) and index thyrotropin (TSH) level (OR = 1.97 [CI 1.56-2.49], p < 0.001 for every SD [2.75 mIU/L] change) were associated with higher odds of treatment. Conclusions: Among patients with SCH, female sex and index TSH level were associated with higher odds of treatment. Moreover, in our population, the decision to treat or not to treat SCH was often based on only one set of abnormal TFTs, and thyroid autoimmunity assessment was underused.

Feasibility of Reducing Animal Numbers in Radiation Countermeasure Experiments from Historic Levels when using Sample Size Calculations.

Historically, animal numbers have most often been in the hundreds for experiments designed to estimate the dose reduction factor (DRF) of a radiation countermeasure treatment compared to a control treatment. Before 2010, researchers had to rely on previous experience, both from others and their own, to determine the number of animals needed for a DRF experiment. In 2010, a formal sample size formula was developed by Kodell et al. This theoretical work showed that sample sizes for realistic, yet hypothetical, DRF experiments could be less than a hundred animals and still have sufficient power to detect clinically meaningful DRF values. However, researchers have been slow to use the formula for their DRF experiments, whether from ignorance to its existence or hesitancy to depart from "tried and true" sample sizes. Here, we adapt the sample size formula to better fit usual DRF experiments, and, importantly, we provide real experimental evidence from two independent DRF experiments that sample sizes smaller than what have typically been used can still statistically detect clinically meaningful DRF values. In addition, we update a literature review of DRF experiments which can be used to inform future DRF experiments, provide answers to questions that researchers have asked when considering sample size calculations rather than solely relying on previous experience, whether their own or others', and, in the supplementary material, provide R code implementing the formula, along with several exercises to familiarize the user with the adapted formula.

The Revised PENIS Score and proposal of the PACKAGE Checklist: a meta-epidemiologic study on penile amputation and replantation.

INTRODUCTION: Penile amputation causes severe physical and psychosocial distress. Microsurgical implementation in penile replantation is presumed to be superior to surgical repair. This assumption has been difficult to verify. OBJECTIVES: The purpose of this study was threefold: (1) to produce an updated review of penile replantation, substantiated by the largest sample size to date; (2) to appraise the comparative value of the novel PENIS Score and propose the PACKAGE Checklist, a guide for standardization of future case reports and reviews; and (3) to improve confusing terminology and recommend the standardization of vocabulary. METHODS: A literature review assessed 432 full-text case reports in 20 languages and identified 123 microsurgical and 40 surgical cases of penile replantation. The novel PENIS Score stratified penile amputations based on 5 criteria: position along the shaft, extension through the penis, neurovascular repair, ischemia time and type, and severed edge condition and contamination. For the outcome measurements, a Kendall tau coefficient evaluated the association between each PENIS criterion for short-term postoperative complications and 3 outcome measures: erection, urination, and sensation. RESULTS: Less than half of surgical reports on penile replantation are sufficiently detailed to complete all PENIS Score criteria. The viability of microsurgical and surgical replantation was equivalent at 92% and 94%, respectively. A statistically significant correlation was found between microsurgical repair and the return of sensation but not with nerve repair. Return of sensation with nerve repair was 51%, and microsurgical replantation without nerve repair was 42%; both were significantly higher than the 14% for surgical replantation. Preservation of a skin bridge was associated with a 40% reduction in severe postoperative complications. CONCLUSION: Microsurgical replantation is superior in return of sensation, with or without nerve repair. Implementing the PACKAGE Checklist and PENIS Score will help inform case reports and reviews.

Treatment of COVID-19 Patients with Two Units of Convalescent Plasma in a Resource-Constrained State.

IMPORTANCE: Many therapies are used to treat COVID-19, the disease caused by the virus SARS-CoV-2, including convalescent plasma. The clinical utility of using 2 units of convalescent plasma for COVID-19 hospitalized patients is not fully understood. OBJECTIVE: Many therapies are used to treat COVID-19, the disease caused by the virus SARS-CoV-2, including convalescent plasma. The clinical utility of using 2 units of convalescent plasma for COVID-19 hospitalized patients is not fully understood. Our study aims to determine the safety and efficacy of treating hospitalized COVID-19 patients with 2 units of COVID-19 convalescent plasma (CCP). METHOD: This was a retrospective study of Arkansas patients treated with CCP using the (US) Food and Drug Administration (FDA) emergency Investigational New Drug (eIND) mechanism from April 9, 2020, through August 9, 2020. It was a multicenter, statewide study in a low-resource setting, which are areas that lack funding for health care cost coverage on various levels including individual, family, or social. Adult patients (n = 165, volunteer sample) in Arkansas who were hospitalized with severe or life-threatening acute COVID-19 disease as defined by the FDA criteria were transfused with 2 units of CCP (250 mL/unit) using the FDA eIND mechanism. The primary outcome was 7- and 30-day mortality after the second unit of CCP. RESULTS: Unadjusted mortality was 12.1% at 7 days and 23.0% at 30 days. The unadjusted mortality was reduced to 7.7% if the first CCP unit was transfused on the date of diagnosis, 8.7% if transfused within 3 days of diagnosis, and 32.0% if transfused at or after 4 or more days of diagnosis. The risk of death was higher in patients that received low, negative, or missing titer CCP units in comparison to those that received higher titer units. CONCLUSION: The provision of 2 units of CCP was associated with a reduction in mortality in patients treated with high titer units within 3 days of COVID-19 diagnosis. Given the results, CCP is a viable, low-cost therapy in resource-constrained states and countries.

Breast and thyroid cancer: A multicenter study with Accrual to Clinical Trials Network.

OBJECTIVE: To investigate a possible link between breast and thyroid cancer. METHODS: A multicenter retrospective review of patients in the electronic medical records of six Accrual to Clinical Trial (ACT) institutions with both breast cancer and thyroid carcinoma. Each center queried its data using a predefined data dictionary. Information on thyroid and breast cancer included dates of diagnosis, histology, and patient demographics. RESULTS: A random-effects model was used. There were 4.24 million women's records screened, 44 605 with breast cancer and 11 846 with thyroid cancer. The relative risks observed at each institution ranged from 0.49 to 13.47. The combined risk ratio (RR) estimate was 1.77 (95% confidence interval: 0.50-5.18). CONCLUSION: There was no association between the risk of developing thyroid cancer and being a breast cancer survivor compared to no history of breast cancer, but the range of relative risks among the participating institutions was wide. Our findings warrant further study of more institutions with larger sample size. Additionally, further analysis of the significance of regional RR differences may be enlightening.

Short-Term Safety of Repeated Acetaminophen Use in Patients With Compensated Cirrhosis.

Current guidelines recommend restricting acetaminophen (APAP) use in patients with cirrhosis, but evidence to support that recommendation is lacking. Prior studies focused on pharmacokinetics (PK) of APAP in cirrhosis but did not rigorously examine clinical outcomes, sensitive biomarkers of liver damage, or serum APAP-protein adducts, which are a specific marker of toxic bioactivation. Hence, the goal of this pilot study was to test the effects of regularly scheduled APAP dosing in a well-defined compensated cirrhosis group compared to control subjects without cirrhosis, using the abovementioned outcomes. After a 2-week washout, 12 subjects with and 12 subjects without cirrhosis received 650 mg APAP twice per day (1.3 g/day) for 4 days, followed by 650 mg on the morning of day 5. Patients were assessed in-person at study initiation (day 1) and on days 3 and 5. APAP-protein adducts and both conventional (alanine aminotransferase) and sensitive (glutamate dehydrogenase [GLDH], full-length keratin 18 [K18], and total high-mobility group box 1 protein) biomarkers of liver injury were measured in serum on the mornings of days 1, 3, and 5, with detailed PK analysis of APAP, metabolites, and APAP-protein adducts throughout day 5. No subject experienced adverse clinical outcomes. GLDH and K18 were significantly different at baseline but did not change in either group during APAP administration. In contrast, clearance of APAP-protein adducts was dramatically delayed in the cirrhosis group. Minor differences for other APAP metabolites were also detected. Conclusion: Short-term administration of low-dose APAP (650 mg twice per day, <1 week) is likely safe in patients with compensated cirrhosis. These data provide a foundation for future studies to test higher doses, longer treatment, and subjects who are decompensated, especially in light of the remarkably delayed adduct clearance in subjects with cirrhosis.

Expansion of Human Papillomavirus-Specific T Cells in Periphery and Cervix in a Therapeutic Vaccine Recipient Whose Cervical High-Grade Squamous Intraepithelial Lesion Regressed.

Advances in high-throughput sequencing have revolutionized the manner with which we can study T cell responses. We describe a woman who received a human papillomavirus (HPV) therapeutic vaccine called PepCan, and experienced complete resolution of her cervical high-grade squamous intraepithelial lesion. By performing bulk T cell receptor (TCR) ß deep sequencing of peripheral blood mononuclear cells before and after 4 vaccinations, 70 putatively vaccine-specific clonotypes were identified for being significantly increased using a beta-binomial model. In order to verify the vaccine-specificity of these clonotypes, T cells with specificity to a region, HPV 16 E6 91-115, previously identified to be vaccine-induced using an interferon-γ enzyme-linked immunospot assay, were sorted and analyzed using single-cell RNA-seq and TCR sequencing. HPV specificity in 60 of the 70 clonotypes identified to be vaccine-specific was demonstrated. TCR ß bulk sequencing of the cervical liquid-based cytology samples and cervical formalin-fixed paraffin-embedded samples before and after 4 vaccinations demonstrated the presence of these HPV-specific T cells in the cervix. Combining traditional and cutting-edge immunomonitoring techniques enabled us to demonstrate expansion of HPV-antigen specific T cells not only in the periphery but also in the cervix. Such an approach should be useful as a novel approach to assess vaccine-specific responses in various anatomical areas.

The Increased Accumulation of Staphylococcus aureus Virulence Factors Is Maximized in a purR Mutant by the Increased Production of SarA and Decreased Production of Extracellular Proteases.

Mutation of purR was previously shown to enhance the virulence of Staphylococcus aureus in a murine sepsis model, and this cannot be fully explained by increased expression of genes within the purine biosynthesis pathway. Rather, the increased production of specific S. aureus virulence factors, including alpha toxin and the fibronectin-binding proteins, was shown to play an important role. Mutation of purR was also shown previously to result in increased abundance of SarA. Here, we demonstrate by transposon sequencing that mutation of purR in the USA300 strain LAC increases fitness in a biofilm while mutation of sarA has the opposite effect. Therefore, we assessed the impact of sarA on reported purR-associated phenotypes by characterizing isogenic purR, sarA, and sarA/purR mutants. The results confirmed that mutation of purR results in increased abundance of alpha toxin, protein A, the fibronectin-binding proteins, and SarA, decreased production of extracellular proteases, an increased capacity to form a biofilm, and increased virulence in an osteomyelitis model. Mutation of sarA had the opposite effects on all of these phenotypes and, other than bacterial burdens in the bone, all of the phenotypes of sarA/purR mutants were comparable to those of sarA mutants. Limiting the production of extracellular proteases reversed all of the phenotypes of sarA mutants and most of those of sarA/purR mutants. We conclude that a critical component defining the virulence of a purR mutant is the enhanced production of SarA, which limits protease production to an extent that promotes the accumulation of critical S. aureus virulence factors.

Normocalcemic and Normohormonal Primary Hyperparathyroidism: Laboratory Values and End-Organ Effects.

OBJECTIVE: Variants of primary hyperparathyroidism (pHPT), described as normocalcemic (NC) and normohormonal (NH), can confuse the diagnosis of classic pHPT. DATA SOURCES: A MEDLINE search was performed for variants of pHPT using the PubMed database (last queried October 2019). REVIEW METHODS: The search was restricted to articles published after 1960 that were specific to humans. Studies were included in our analysis if laboratory values and incidence of end-organ involvement were reported for NCpHPT and NHpHPT variants. The search returned 189 articles; 27 additional studies were identified and included for a total of 216. Non-English-language studies were excluded. Abstracts were screened, full-text articles were then assessed, and 82 articles were excluded. Data were pooled using a random-effects model in studies that compared NC or NH pHPT to classic pHPT. Comparative laboratory values are presented. CONCLUSION: This analysis compares NCpHPT and NHpHPT to classic pHPT. Nephrolithiasis was 21.7% (NCpHPT), 15.9% (classic pHPT), and 25.4% (NHpHPT). Decreased bone mineral density was 49.7% (NCpHPT), 39.7% (classic pHPT), and 40.3% (NHpHPT). Fractures in the NCpHPT group were not significantly different from the classic pHPT. Hypertension in the NCpHPT group was significantly less than classic pHPT (odds ratio, 0.59; 95% CI, 0.40-0.88). IMPLICATIONS FOR CLINICAL PRACTICE: This information may serve to inform clinicians of the laboratory subtleties of these variants that are being seen with greater frequency in contemporary practice.

The Effect of Horizontal Rectus Muscle Surgery on Distance-Near Incomitance.

PURPOSE: To determine the effect of horizontal rectus muscle surgery on distance-near incomitance. DESIGN: Prospective, comparative, interventional case series. METHODS: Prospective evaluation of patients >7 years old who had medial or lateral rectus muscle surgery at the University of Arkansas Medical Center or Arkansas Children's Hospital between December 2009 and January 2012. Prism and alternate cover testing was performed at distance (6 m) and near (0.3 m) fixation after >1 hour of monocular occlusion at preoperative and postoperative examinations within 1 week, and closest to 1 year after surgery. The change in distance-near incomitance was calculated. Patients with extraocular muscle fibrosis or paralysis were excluded. RESULTS: Forty-five patients met inclusion criteria. Twenty-five patients had medial rectus muscle surgery, and 20 patients had lateral rectus muscle surgery. Postoperative examinations showed a change in distance-near incomitance ≤10 prism diopters (PD) in 42 of 44 patients evaluated within 1 week after surgery and in all 28 patients evaluated 6-24 months after surgery. Horizontal rectus muscle surgery did not induce a clinically significant change in distance-near incomitance (±2 PD equivalence, TOST confidence interval, -1.8 +1.6 PD, P value = 0.014). Contrary to traditional teaching, medial rectus muscle surgery was not more likely to induce a greater effect at near fixation (P = 0.80) and lateral rectus muscle surgery was not more likely to induce a greater effect at distance fixation (P > 0.99). CONCLUSION: Horizontal rectus muscle surgery does not induce a clinically significant effect on distance-near incomitance. Contrary to traditional teaching, medial rectus muscle surgery does not induce a greater effect on ocular alignment at near fixation and lateral rectus muscle surgery does not induce a greater effect on ocular alignment at distance fixation. It is not necessary to consider distance-near incomitance when choosing between medial rectus and lateral rectus muscle surgery.

Exploiting Correlations between Protein Abundance and the Functional Status of saeRS and sarA To Identify Virulence Factors of Potential Importance in the Pathogenesis of Staphylococcus aureus Osteomyelitis.

We used a murine model of postsurgical osteomyelitis (OM) to evaluate the relative virulence of the Staphylococcus aureus strain LAC and five isogenic variants that differ in the functional status of saeRS and sarA relative to each other. LAC and a variant in which saeRS activity is increased (saeC) were comparably virulent to each other, while ΔsaeRS, ΔsarA, ΔsaeRS/ΔsarA, and saeC/ΔsarA mutants were all attenuated to a comparable degree. Phenotypic comparisons including a mass-based proteomics approach that allowed us to assess the number and abundance of full-length proteins suggested that mutation of saeRS attenuates virulence in our OM model owing primarily to the decreased production of S. aureus virulence factors, while mutation of sarA does so owing to protease-mediated degradation of these same virulence factors. This was confirmed by demonstrating that eliminating protease production restored virulence to a greater extent in a LAC sarA mutant than in the isogenic saeRS mutant. Irrespective of the mechanism involved, mutation of saeRS or sarA was shown to result in reduced accumulation of virulence factors of potential importance. Thus, using our proteomics approach we correlated the abundance of specific proteins with virulence in these six strains and identified 14 proteins that were present in a significantly increased amount (log2 ≥ 5.0) in both virulent strains by comparison to all four attenuated strains. We examined biofilm formation and virulence in our OM model using a LAC mutant unable to produce one of these 14 proteins, specifically staphylocoagulase. The results confirmed that mutation of coa limits biofilm formation and, to a lesser extent, virulence in our OM model, although in both cases the limitation was reduced by comparison to the isogenic sarA mutant.

Chlamydia muridarum Genital and Gastrointestinal Infection Tropism Is Mediated by Distinct Chromosomal Factors.

Some members of the genus Chlamydia, including the human pathogen Chlamydia trachomatis, infect multiple tissues, including the genital and gastrointestinal (GI) tracts. However, it is unknown if bacterial targeting to these sites is mediated by multifunctional or distinct chlamydial factors. We previously showed that disruption of individual large clostridial toxin homologs encoded within the Chlamydia muridarum plasticity zone were not critical for murine genital tract infection. Here, we assessed whether cytotoxin genes contribute to C. muridarum GI tropism. Infectivity and shedding of wild-type (WT) C. muridarum and three mutants containing nonsense mutations in different cytotoxin genes, tc0437, tc0438, and tc0439, were compared in mouse genital and GI infection models. One mutant, which had a nonsense mutation in tc0439, was highly attenuated for GI infection and had a GI 50% infectious dose (ID50) that was 1,000 times greater than that of the WT. GI inoculation with this mutant failed to elicit anti-chlamydial antibodies or to protect against subsequent genital tract infection. Genome sequencing of the tc0439 mutant revealed additional chromosomal mutations, and phenotyping of additional mutants suggested that the GI attenuation might be linked to a nonsense mutation in tc0600 The molecular mechanism underlying this dramatic difference in tissue-tropic virulence is not fully understood. However, isolation of these mutants demonstrates that distinct chlamydial chromosomal factors mediate chlamydial tissue tropism and provides a basis for vaccine initiatives to isolate chlamydia strains that are attenuated for genital infection but retain the ability to colonize the GI tract and elicit protective immune responses.

Mynx Vascular Closure Device in Arterial Endovascular Procedures.

BACKGROUND: Vascular closure devices have been used to achieve hemostasis of percutaneous access sites following endovascular procedures, with reported decreased time for arterial control as well as decreased time to ambulation. We sought to determine rates and risk factors of postoperative bleeding complications and failures using these devices from a single institution experienced in the use of vascular closure devices. METHODS: All patients undergoing arterial endovascular procedures with percutaneous access between March 2010 and October 2015 at a single institution were identified and analyzed (n = 894). Patients undergoing endovascular aneurysm repair, open access, venous procedures, or upper extremity access were excluded. Comparison groups were formed between those using the Mynxgrip® (Mynx), Angio-Seal™, Perclose® vascular closure devices and manual pressure (MP). Patient demographics, intraoperative data, and postoperative complications were compared. RESULTS: A total of 615 (69%) patients received Mynx, 165 other vascular closure devices (VCD) ([14%] Perclose, 44 [4%] Angio-Seal), and 114 (13%) MP. MP patients were more likely to be diagnostic angiogram with smaller sheaths, while VCD patients were more likely to be interventions with larger sheaths. Univariate analysis identified age, atrial fibrillation, intervention (as opposed to diagnostic), and sheath size >5F associated with postoperative bleeding (P < 0.05), and in backward, logistic regression analysis, sheath size, age, and renal failure were independent predictors of the same. CONCLUSIONS: Use of vascular closure devices has a low rate of bleeding complication, device failure, and need for operative repair. Bleeding is associated with increased age, interventional procedure, and end-stage renal disease. Mynx, Perclose, and Angio-Seal have similar rates of complications. Use of these devices are a safe option for groin vessel closure.

Protein intake distribution pattern does not affect anabolic response, lean body mass, muscle strength or function over 8 weeks in older adults: A randomized-controlled trial.

BACKGROUND & AIMS: In our recent acute metabolic study, we found no differences in the anabolic response to differing patterns of dietary protein intake. To confirm this in a chronic study, we investigated the effects of protein distribution pattern on functional outcomes and protein kinetics in older adults over 8 weeks. METHODS: To determine chronic effects of protein intake pattern at 1.1 g protein/kg/day in mixed meals on lean body mass (LBM), functional outcomes, whole body protein kinetics and muscle protein fractional synthesis rate (MPS) over 8-week respective dietary intervention, fourteen older subjects were randomly divided into either EVEN or UNVEN group. The UNEVEN group (n = 7) consumed the majority of dietary protein with dinner (UNEVEN, 15/20/65%; breakfast, lunch, dinner), while the EVEN group (n = 7) consumed dietary protein evenly throughout the day (EVEN: 33/33/33%). RESULTS: We found no significant differences in LBM, muscle strength, and other functional outcomes between EVEN and UNEVEN before and after 8-week intervention. Consistent with these functional outcomes, we did not find significant differences in the 20-h integrated whole body protein kinetics [net protein balance (NB), protein synthesis (PS), and breakdown (PB)] above basal states and MPS between EVEN and UNEVEN intake patterns. CONCLUSIONS: We conclude that over an 8-week intervention period, the protein intake distribution pattern in mixed meals does not play an important role in determining anabolic response, muscle strength, or functional outcomes. This trial is registered at https://ClinicalTrials.gov as NCT02787889.

Impact of Staphylococcus aureus regulatory mutations that modulate biofilm formation in the USA300 strain LAC on virulence in a murine bacteremia model.

Staphylococcus aureus causes acute and chronic forms of infection, the latter often associated with formation of a biofilm. It has previously been demonstrated that mutation of atl, codY, rot, sarA, and sigB limits biofilm formation in the USA300 strain LAC while mutation of agr, fur, and mgrA has the opposite effect. Here we used a murine sepsis model to assess the impact of these same loci in acute infection. Mutation of agr, atl, and fur had no impact on virulence, while mutation of mgrA and rot increased virulence. In contrast, mutation of codY, sarA, and sigB significantly attenuated virulence. Mutation of sigB resulted in reduced accumulation of AgrA and SarA, while mutation of sarA resulted in reduced accumulation of AgrA, but this cannot account for the reduced virulence of sarA or sigB mutants because the isogenic agr mutant was not attenuated. Indeed, as assessed by accumulation of alpha toxin and protein A, all of the mutants we examined exhibited unique phenotypes by comparison to an agr mutant and to each other. Attenuation of the sarA, sigB and codY mutants was correlated with increased production of extracellular proteases and global changes in extracellular protein profiles. These results suggest that the inability to repress the production of extracellular proteases plays a key role in attenuating the virulence of S. aureus in acute as well as chronic, biofilm-associated infections, thus opening up the possibility that strategies aimed at the de-repression of protease production could be used to broad therapeutic advantage. They also suggest that the impact of codY, sarA, and sigB on protease production occurs via an agr-independent mechanism.

Normal amniotic fluid volume across gestation: Comparison of statistical approaches in 1190 normal amniotic fluid volumes.

AIM: Ultrasound estimation and evaluation of amniotic fluid volume (AFV) is an important component of pregnancy surveillance and fetal well-being. The purpose of this study was to compare and contrast four statistical methods used to construct gestational age-specific reference intervals for the assessment of AFV. METHODS: A total of 1095 normal AFV derived from four studies that measured AFV using dye-dilution or direct measurement at the time of hysterotomy were used to construct reference intervals using polynomial regression, quantile regression, Royston and Wright mean and SD, and Cole's lambda mu sigma (LMS) methods. The 2.5th, 5th, 50th, 95th, and 97.5th centiles were derived for each statistical method. RESULTS: AFV increased curvilinearly from 15 gestational weeks and onward. Based on the 50th centile, the maximum value occurred at 30 weeks' gestation for the polynomial regression and mean and SD methods while the maximum was achieved at week 31 for the quantile regression and LMS methods. When data were sparse, the quantile regression method produced dramatically different estimates at the higher centile. CONCLUSION: The four statistical methods produced similar results at gestational ages in which AFV was high. The quantile regression approach, however, produces results that are more reflective of the data when the data are sparse. Given the flexibility and robustness of the quantile regression method, we recommend its use in constructing reference intervals when the interest lies in the tails of the reference distribution.

Does the Institution of a Statewide Trauma System Reduce Preventable Mortality and Yield a Positive Return on Investment for Taxpayers?

BACKGROUND: In July 2009, Arkansas began to annually fund $20 million for a statewide trauma system (TS). We studied injury deaths both pre-TS (2009) and post-TS (2013 to 2014), with attention to causes of preventive mortality, societal cost of those preventable mortality deaths, and benefit to tax payers of the lives saved. STUDY DESIGN: A multi-specialty trauma-expert panel met and reviewed records of 672 decedents (290 pre-TS and 382 post-TS) who met standardized inclusion criteria, were judged potentially salvageable, and were selected by a proportional sampling of the roughly 2,500 annual trauma deaths. Deaths were adjudicated into sub-categories of nonpreventable and preventable causes. The value of lives lost was calculated for those lives potentially saved in the post-TS period. RESULTS: Total preventable mortality was reduced from 30% of cases pre-TS to 16% of cases studied post-TS, a reduction of 14%. Extrapolating a 14% reduction of preventable mortality to the post-TS study period, using the same inclusion criteria of the post-TS, we calculate that 79 lives were saved in 2013 to 2014 due to the institution of a TS. Using a minimal standard estimate of $100,000 value for a life-year, a lifetime value of $2,365,000 per person was saved. This equates to an economic impact of the lives saved of almost $186 million annually, representing a 9-fold return on investment from the $20 million of annual state funding invested in the TS. CONCLUSIONS: The implementation of a TS in Arkansas during a 5-year period resulted in a reduction of the preventable death rate to 16% post-TS, and a 9-fold return on investment by the tax payer. Additional life-saving gains can be expected with ongoing financial support and additional system performance-improvement efforts.