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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.

Background For emergent intrapartum cesarean delivery (CD), the literature does not support the use of any particular local anesthetic solution to extend epidural analgesia to cesarean anesthesia. We hypothesized that 3% chloroprocaine (CP) would be noninferior to a mixture of 2% lidocaine, 150 µg of epinephrine, 2 mL of 8.4% bicarbonate, and 100 µg of fentanyl (LEBF) in terms of onset time to surgical anesthesia. Methods In this single-center randomized noninferiority trial, adult healthy women undergoing CD were randomly assigned to epidural anesthesia with either CP or LEBF. Sensory blockade (pinprick) to T10 was established before operating room (OR) entry for elective CD. On arrival to the OR, participants received the epidural study medications in a standardized manner to simulate the conversion of "epidural labor analgesia to surgical anesthesia." The primary outcome was the time to loss of touch sensation at the T7 level. A noninferiority margin was set at 3 minutes. The secondary outcome was the need for intraoperative analgesia supplementation. Results In total, 70 women were enrolled in the study. The mean onset time to achieve a bilateral sensory block to touch at the T7 dermatome level was 655 (standard deviation [SD] = 258) seconds for group CP and 558 (269) seconds for group LEBF, a difference in means of 97 seconds (90% confidence interval [CI], SD = -10.6 to 204; P = .10 for noninferiority). The upper limit of the 90% CI for the mean difference exceeded the prespecified 3-minute noninferiority margin. There was no meaningful difference in the requirement for intraoperative analgesia between the 2 groups. Conclusion Both anesthetic solutions have a rapid onset of anesthesia when used to extend low-dose epidural sensory block to surgical anesthesia. Data from the current study provide insufficient evidence to confirm that CP is noninferior to LEBF for rapid epidural extension anesthesia for CD, and further research is required to determine noninferiority.

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.

OBJECTIVE: To investigate a possible link between breast and thyroid cancer. METHODS: A multi-center 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 their 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 estimate was 1.77 (95% CI: 0.50 – 5.18). CONCLUSION: There was no association between 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 a larger sample size. Additionally, further analysis of the significance of regional risk ratio differences may be enlightening. LEVEL OF EVIDENCE: 3

Purpose: This retrospective study compares point-of-care ocular ultrasound to MRI in order to establish preliminary data for and identify challenges to a multicenter study into the utility of ocular ultrasound for diagnosing optic neuritis. Methods: Our ultrasound archive was queried to identify subjects suspected of having optic neuritis who underwent ocular ultrasound and MRI of the brain or orbit. Blinded ultrasounds were reviewed by ultrasound faculty. The presence of optic disc elevation, optic nerve, or sheath dilation, and overall impression were recorded and compared to MRI results. Sensitivity and specificity of each ultrasound finding and the overall impression, as well as agreement between the raters, were calculated. Results: Sensitivity and specificity of ultrasound for MRI confirmed optic neuritis was 100 % (95 % CI 54.1-100) and 58.3 % (95 % CI 27.7-84.8). Optic nerve sheath diameter had nearly perfect agreement (κ = 0.8828), however agreement on optic disc elevation (κ = 0.5641), nerve diameter (κ = 0.2174), and overall agreement (κ = 0.1818) were moderate, fair, and poor, respectively. Conclusions: This preliminary study estimates test characteristics of ocular ultrasound for the diagnosis of optic neuritis for the purposes of power analysis and to identify potential pitfalls in preparation for a larger prospective investigation.

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) β 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 β 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.

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, The safety of acetaminophen (APAP) use in cirrhosis is highly controversial. In this study, we compared novel, sensitive biomarkers of liver injury and pharmacokinetics between non‐cirrhotic and cirrhotic subjects with repeated APAP use over 5 days. There was no APAP‐induced liver damage in either group, but there was evidence of greater APAP‐protein binding and reduced APAP‐protein adduct clearance in the cirrhosis group that warrants caution and further study.

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.

Objective To examine the prevalence, types and temporal trends of reported financial conflicts of interest (FCOIs) among authors of drug therapy randomized controlled trials (RCTs) for RA and their association with study outcomes. Methods We identified original, non–phase 1, parallel-group, drug therapy RA RCTs published in the years 2002–03, 2006–07, and 2010–11. Two investigators independently obtained trial characteristics data. Authors’ FCOIs were classified as honoraria/consultation fees receipt, employee status, research grant, and stock ownership. Multivariable logistic regression was performed to identify whether FCOIs were independently associated with study outcome. Results A total of 146 eligible RCTs were identified. Of these, 83 (58.4%) RCTs had at least one author with an FCOI [employee status: 63 (43.2%), honoraria/consultation fees receipt: 49 (33.6%), research grant: 30 (20.5%), and stock ownership: 28 (19.2%)]. A remarkable temporal increase in reporting of honoraria/consultation fees receipt, research grant, and stock ownership was seen. The reporting of any FCOI itself was not associated with positive outcome [50/73 (68.5%) with author FCOI vs 36/52 (69.2%) without author FCOI, P = 0.93]. However, honoraria/consulting fees receipt was independently associated with increased likelihood of a positive outcome [adjusted odds ratio (95% CI) of 3.24 (1.06–9.88)]. In general, trials with FCOIs were significantly more likely to be multicentre, have larger enrolment, use biologic or a small molecule as the experimental intervention, and have better reporting of some methodological quality measures. Conclusion FCOI reporting in RA drug RCT authors is common and temporally increasing. Receipt of honoraria/consulting fees was independently associated with a positive study outcome.

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.

Variants of primary hyperparathyroidism (pHPT), described as normocalcemic (NC) and normohormonal (NH), can confuse the diagnosis of classic pHPT.A MEDLINE search was performed for variants of pHPT using the PubMed database (last queried October 2019).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.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).This information may serve to inform clinicians of the laboratory subtleties of these variants that are being seen with greater frequency in contemporary practice.

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.

Human papillomavirus (HPV) infection is associated with the vast majority of cervical cancer cases as well as with other anogenital cancers. PepCan is an investigational HPV therapeutic vaccine for treating cervical high-grade squamous intraepithelial lesions. The present study was performed to test whether the cervical microbiome influences vaccine responses and to explore host factors as determinants of the cervical microbiome composition in women with biopsy-proven high-grade squamous intraepithelial lesions. In a recently completed Phase I clinical trial of PepCan, histological response rate of 45% (14 of 31 patients), a significant increase in circulating T-helper type 1 cells, and a significant decrease in HPV 16 viral load were reported. DNA, extracted from liquid cytology specimens collected before and after vaccinations, were amplified and then hybridized to a G4 PhyloChip assay to characterize the microbiome. We describe trends that certain bacterial taxa in the cervix may be enriched in non-responders in comparison to responders ( Padj = .052 for phylum Caldithrix and Padj = .059 for phylum Nitrospirae). There was no difference in bacterial diversity between the 2 groups. A permutational analysis of variance performed for various demographic and immune parameters showed significant clustering with microbiome beta diversity for race, HPV 16 status, peripheral T-helper type 1 cells, and HLA-B40 ( P = .001, .014, .037, and .024, respectively). Further analyses showed significant differences at the empirical Operational Taxonomic Unit level for race and HPV 16 status. As these results are from a small Phase I study, further studies are needed to examine the role of cervical microbiome in response to HPV therapeutic vaccines.

Summary 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.

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.

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.

Factors contributing to aggressive behavior in vulvar squamous cell carcinoma (vSCC) are poorly defined; however, a recent study has shown that vSCCs with an infiltrative pattern of invasion and fibromyxoid stroma are associated with worse outcomes than tumors with a pushing or nested pattern of invasion and lymphoplasmacytic stroma. Epithelial-mesenchymal transition (EMT) has been associated with tumor progression in a number of malignancies, and this study proposes that EMT contributes to tumor aggressiveness in this subset of vSCC. Immunohistochemistry was used to detect nuclear localization of β-catenin, loss of E-cadherin, and presence of vimentin in 58 cases of vSCC. The association of these phenotypic changes with pathologic features and clinical outcomes was tested using Fisher’s exact and χ2 analyses (significance at p ≤0.05). EMT-associated features were identified in 45 of 58 cases (78%) with 28 cases exhibiting more than one feature. Nuclear β-catenin and presence of vimentin were significantly more likely to occur in tumors with an infiltrative pattern of invasion or a fibromyxoid stromal response. Loss of E-cadherin was significantly associated with an infiltrative pattern, but not a fibromyxoid stroma. Risk for tumor recurrence was significantly increased in tumors with nuclear localization of β-catenin alone or in tumors displaying multiple EMT-associated features. These results suggest that the development of an EMT may be a mechanism by which infiltrative vulvar tumors with a fibromyxoid stromal response behave more aggressively and convey worse outcomes than tumors that do not exhibit these pathologic features.

Major trunk trauma is common and costly, but comparisons of costs between trauma centers (TCs) are rare. Understanding cost is essential to improve quality, manage trauma service lines, and to facilitate institutional commitment for trauma. We have used results of a statewide trauma financial survey of Levels I to IV TC to develop a useful grouping method for costs and clinical characteristics of major trunk trauma. The trauma financial survey collected billing and clinical data on 75 per cent of the state trauma registry patients for fiscal year 2012. Cost was calculated by separately accounting for embedded costs of trauma response and verification, and then adjusting reasonable costs from the Medicare cost report for each TC. The cost-to-charge ratios were then recalculated and used to determine uniform cost estimates for each patient. From the 13,215 patients submitted for the survey, we selected 1,094 patients with major trunk trauma: lengths of stay ≥ 48 hours and a maximum injury of AIS ≥3 for either thorax or abdominal trauma. These patients were then divided into three Injury Severity Score (ISS) groups of 9 to 15, 16 to 24, or 25+ to stratify patients into similar injury groups for analysis of cost and cost drivers. For abdominal injury, average total cost for patients with ISS 9 to 15 was $17,429. Total cost and cost per day increased with severity of injury, with $51,585 being the total cost for those with ISS 25. Similar trends existed for thoracic injury. Use of the Medicare cost report and cost-to-charge ratios to compute uniform costs with an innovative grouping method applied to data collected across a statewide trauma system provides unique information regarding cost and outcomes, which affects quality improvement, trauma service line management, and decisions on TC participation.

We previously determined the extent to which mutations of different Staphylococcus aureus regulatory loci impact biofilm formation as assessed under in vitro conditions. Here we extend these studies to determine the extent to which those regulatory loci that had the greatest effect on biofilm formation also impact antibiotic susceptibility. The experiments were done under in vitro and in vivo conditions using two clinical isolates of S. aureus (LAC and UAMS-1) and two functionally diverse antibiotics (daptomycin and ceftaroline). Mutation of the staphylococcal accessory regulator ( sarA ) or sigB was found to significantly increase susceptibilities to both antibiotics and in both strains in a manner that could not be explained by changes in the MICs. The impact of a mutation in sarA was comparable to that of a mutation in sigB and greater than the impact observed with any other mutant. These results suggest that therapeutic strategies targeting sarA and/or sigB have the greatest potential to facilitate the ability to overcome the intrinsic antibiotic resistance that defines S. aureus biofilm-associated infections.

Introduction- High dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) remains the standard treatment for multiple myeloma (MM) for eligible patients. While ASCT in most centers is performed on an inpatient basis, we and others have shown its feasibility in an outpatient setting. Due to improved supportive care, enhanced patient and caregiver education and preference, the majority of MM patients at our center will initiate outpatient ASCT. However, a part of these patients will require hospital admission pre-emptively due to co-morbid conditions or related to therapy-associated toxicity. To elucidate clinical characteristics and markers predicting for hospital admission in an ambulatory setting, we investigated a total of 1446 MM patients receiving ASCT at UAMS from 2015-2019. Methods- Of the 1446 MM patients, 550 initiated their ASCT as inpatients, 280 started as outpatients but required subsequent hospital admission and 616 completed ASCT in an ambulatory setting. The decision to initiate ASCT as in- or outpatient was based on clinical and social factors. In most cases, Pptients received high dose Melphalan conditioning (74%) followed by dose-reduced Melphalan in combination with Cisplatin, Adriamycin, Cyclophosphamide and Etoposide (PACE, 15%) and BEAM conditioning (9.2%). For comparison between the transplant groups, we used analysis of variance (for continuous-like variables) and Pearson's chi-squared test (for categorical variables). Multivariable logistic regression model was used to examine the combined effects of various clinical variables on the probability of hospitalization after receiving an outpatient autologous transplant. Results- 62% (896/1446) of all patients initiated ASCT on an outpatient basis. Of those, 31% (280/896) required hospital admission within 15 days post-transplant. Main reasons for hospital admission were neutropenic fever (45%), intractable nausea/diarrhea/poor oral intake (29%, n=81/280) followed by more uncommon events such as cardiac problems (6%) and MM related pain (4%, n=12/280) and 16% other reasons (45/280). Median day of admission was D+7 after ASCT (range: D+1 to D+15) with a median length of stay of 8 days (range: 2-49 days). Median age of patients who completed outpatient ASCT (60.4 years) was significantly lower (p Conclusion- Outpatient stem cell transplantation can be safely performed in the large majority of patients with good performance status and organ function. Advanced age and reduced albumin levels predict for a significantly higher likelihood of inpatient admission. These factors could help guiding physicians to better identify patients at high risk for admission during outpatient ASCT. Disclosures van Rhee: Takeda: Consultancy; Adaptive Biotech: Consultancy; CDCN: Consultancy; EUSA: Consultancy; Karyopharm: Consultancy.

Objectives: Our group developed the use of the Candida skin test reagent as an adjuvant of cell-mediated immunity in designing a human papillomavirus therapeutic vaccine. Here, this technology is being applied for designing a prostate cancer immunotherapy. Methods: Peptides based on the prostate-specific antigen amino acid sequences were selected, synthesized, and evaluated in terms of their (1) solubility, (2) maturation effects on Langerhans cells by fluorescence-activated cell sorter analysis, and (3) recognition by peripheral immune cells from prostate cancer patients using interferon-γ enzyme-linked immunospot assay. Results: The peptides were soluble in 10 mM succinate at pH of 5 with 5% glycine, and they demonstrated no maturation effects on Langerhans cells from healthy donors. On the other hand, peripheral immune cells from 4 of 10 prostate cancer patients examined had positive responses in enzyme-linked immunospot assay to one or more prostate-specific antigen peptides. Conclusion: In summary, a design and a formulation of a novel prostate cancer immunotherapy are described. The immunogenicity of prostate-specific antigen peptides in some prostate cancer patients supports further development of this immunotherapy.

Patterns of invasion and stromal response are understudied in vulvar squamous cell carcinoma. The aim of this study was to explore whether histologic features such as an infiltrative pattern of invasion and fibromyxoid stromal response (FMX-SR) are meaningful prognostic factors. We reviewed 143 vulvar squamous cell carcinoma resections and correlated patterns of invasion and stromal response with patient age, ethnicity, depth of invasion, tumor size, perineural invasion (S100/AE1/3 stain), lymph node involvement (LNI), extranodal extension, margin status, pathologic stage, and recurrence. Univariate analyses of continuous variables were performed using t tests, whereas Pearson χ tests were used for categorical variables. Logistic regression analyses examined the relationship between histopathologic characteristics and clinical outcomes. There was a statistically significant association between infiltrative tumors and an FMX-SR in comparison with noninfiltrative tumors (P

The objective of this study was to describe national trends in robotic thyroid surgery from 2009 through 2013.The University HealthSystem Consortium (UHC) database was searched for patients undergoing robotic thyroidectomy (RT) from 2009 through 2013. Another U.S. institution's RT data, not included in the UHC database, were also evaluated. Patient demographics, institutional volume, comorbid conditions, complications, and cost information were analyzed.Sixty-one institutions performed 484 RT during the study period. From 2009 through 2011, U.S. annual RT volume increased from 39 cases to 140. Annual volume dropped to 69 cases in 2012 and 93 cases in 2013. Higher-volume centers reported lower complication rates (p0.02). Hematoma formation (3.7%) was the most common complication, and there was one death. More than 10% of patients were obese. Brachial plexus injury and axillary skin flap perforations were reported in1% of cases. Mean cost for a total RT was $13,287 ($5,125-42,444).From 2009 through early 2011, there was a steady increase in RT volume, especially among high-volume institutions. In mid-to-late 2011, there was a noticeable drop in RT volume, which significantly altered the projected trajectory of the procedure in this country. Despite higher complication rates, lower-volume centers perform the majority of RT and are also responsible for recent increases in RT utilization patterns in the United States.

Background: Historically, recruitment and retention of young women in intervention-based clinical trials have been challenging. In August 2012, enrollment for a clinical trial testing of an investigational human papillomavirus therapeutic vaccine called PepCan was opened at our institution. This study was an open-label, single-arm, single-institution, dose-escalation Phase I clinical trial. Women with recent Papanicolaou smear results showing high-grade squamous intraepithelial lesions or results that could not rule out high-grade squamous intraepithelial lesion were eligible to enroll. Patients with biopsy-confirmed high-grade squamous intraepithelial lesion were also eligible. Colposcopy was performed at the screening visit, and participants became eligible for vaccination when the diagnosis of high-grade squamous intraepithelial lesion was confirmed with biopsy and other inclusion criteria were met. The aim of this study was to identify strategies and factors effective in recruitment and retention of study participants. Methods: Potential vaccine candidates were recruited through direct advertisement as well as referrals, including referrals through the Arkansas telecolposcopy network. The network is a federally funded program, administered by physicians and advanced practice nurses. The network telemedically links rural health sites and allows physician-guided colposcopy and biopsies to be conducted by advanced practice nurses. A variety of strategies were employed to assure good retention, including face-to-face contact with the study coordinator at the time of consent and most of study visits; frequent contact using text messaging, phone calls, and e-mails; and creation of a private Facebook page to improve communication among research staff and study participants. A questionnaire, inquiring about motivation for joining the study, occupation, education, household income, number of children, and number of sexual partners, was administered at the screening visit with the intent of identifying factor(s) associated with recruitment and retention. Results: A total of 37 participants were enrolled between September 2012 and March 2014. The largest proportion of participants (46%) was enrolled from the telecolposcopy network. Others were enrolled through outside institutions (43%), in-house referrals (8%), or direct advertisement (3%). Most participants were motivated to join the study to take care of their health issues. Only two participants joined the Facebook private page. Of the 24 participants who qualified for vaccination, only 1 terminated early due to an unanticipated move. Conclusion: The availability of a large number of potential participants from the telecolposcopy network increased recruitment to this clinical trial by 85% over other traditional means of recruitment. The telecolposcopy network is not only a means of providing a gynecological service to women who otherwise would forego care but also a novel and valuable resource in recruiting participants for a clinical trial.

To examine whole body protein turnover and muscle protein fractional synthesis rate (MPS) following ingestions of protein in mixed meals at two doses of protein and two intake patterns, 20 healthy older adult subjects (52–75 yr) participated in one of four groups in a randomized clinical trial: a level of protein intake of 0.8 g (1RDA) or 1.5 g·kg−1·day−1 (∼2RDA) with uneven (U: 15/20/65%) or even distribution (E: 33/33/33%) patterns of intake for breakfast, lunch, and dinner over the day (1RDA-U, 1RDA-E, 2RDA-U, or 2RDA-E). Subjects were studied with primed continuous infusions of l-[2H5]phenylalanine and l-[2H2]tyrosine on day 4 following 3 days of diet habituation. Whole body protein kinetics [protein synthesis (PS), breakdown, and net balance (NB)] were expressed as changes from the fasted to the fed states. Positive NB was achieved at both protein levels, but NB was greater in 2RDA vs. 1RDA (94.8 ± 6.0 vs. 58.9 ± 4.9 g protein/750 min; P = 0.0001), without effects of distribution on NB. The greater NB was due to the higher PS with 2RDA vs. 1RDA (15.4 ± 4.8 vs. −18.0 ± 8.4 g protein/750 min; P = 0.0018). Consistent with PS, MPS was greater with 2RDA vs. 1RDA, regardless of distribution patterns. In conclusion, whole body net protein balance was greater with protein intake above recommended dietary allowance (0.8 g protein·kg−1·day−1) in the context of mixed meals, without demonstrated effects of protein intake pattern, primarily through higher rates of protein synthesis at whole body and muscle levels.

Purpose To determine whether unilateral strabismus surgery creates lateral incomitance in patients with exotropia. Methods Patients >7 years of age with intermittent or constant exotropia who underwent unilateral horizontal rectus muscle surgery between December 2009 and January 2012 were prospectively evaluated. Prism and alternate cover testing was performed with distance fixation in primary position, right gaze, and left gaze after 1 hour of monocular occlusion. Measurements were obtained within 1 month prior to surgery, within 1 week after surgery, and >3 months after surgery. The surgical procedure varied according to the surgeon's discretion. The change in deviation induced by strabismus surgery in lateral gaze was expressed as a percentage of the change in deviation induced in primary position. Results A total of 12 patients met inclusion criteria. Of the 11 patients with postoperative examinations within 1 week after surgery, 10 (91%) had greater surgical effect with gaze toward the operated eye ( P = 0.007). All 9 patients with >3 months' follow-up had greater surgical effect with gaze toward the operated eye ( P = 0.003). On average, the surgical effect in gaze toward the operated eye was 120% of that achieved in primary position; in gaze away from the operated eye, 75% ( P 6 months after surgery. Conclusions Unilateral strabismus surgery induces lateral incomitance that may cause diplopia >6 months after surgery in patients with exotropia. This should be considered when planning strabismus surgery and counseling patients.

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.

To determine if preoperative Goldmann Visual Field (GVF) testing in patients with functional dermatochalasis accurately depicts the postoperative superior visual field (SVF) outcome.A prospective cohort study was done to compare preoperative and postoperative GVF field tests in patients undergoing upper eyelid blepharoplasty for treatment of dermatochalasis. This study was conducted in accordance with the Declaration of Helsinki and approved by the University of Arkansas for Medical Sciences institutional review board. A preoperative GVF was obtained with the eyelids in the natural position (untaped) and then again with excess skin elevated (taped). One month post-blepharoplasty, another GVF was conducted with eyelids untaped. The pre- and post GVF tests were analyzed to determine if preoperative testing accurately predicts the SVF improvement post-blepharoplasty.Forty-six eyelids (23 patients) who underwent blepharoplasty for dermatochalasis were included. The preoperative testing underestimated 76% (35/46) of cases by a mean of 61%; and overestimated the final outcome in 24% (11/46) of cases by mean of 23%. Overall, the preoperative GVF testing underestimated the postoperative outcome by a mean of 35%.Improvement of the SVF after a blepharoplasty is typically greater than the preoperative GVF testing predicts.

The Lyme disease spirochete, Borrelia burgdorferi , occupies both a tick vector and mammalian host in nature. Considering the unique enzootic life cycle of B. burgdorferi , it is not surprising that a large proportion of its genome is composed of hypothetical proteins not found in other bacterial pathogens. bb0238 encodes a conserved hypothetical protein of unknown function that is predicted to contain a tetratricopeptide repeat (TPR) domain, a structural motif responsible for mediating protein-protein interactions. To evaluate the role of bb0238 during mammalian infection, a bb0238 -deficient mutant was constructed. The bb0238 mutant was attenuated in mice infected via needle inoculation, and complementation of bb0238 expression restored infectivity to wild-type levels. bb0238 expression does not change in response to varying culture conditions, and thus, it appears to be constitutively expressed under in vitro conditions. bb0238 is expressed in murine tissues during infection, though there was no significant change in expression levels among different tissue types. Localization studies indicate that BB0238 is associated with the inner membrane of the spirochete and is therefore unlikely to promote interaction with host ligands during infection. B. burgdorferi clones containing point mutations in conserved residues of the putative TPR motif of BB0238 demonstrated attenuation in mice that was comparable to that in the bb0238 deletion mutant, suggesting that BB0238 may contain a functional TPR domain.

Objective To examine characteristics associated with the publication and timeliness of publication of randomized controlled trials (RCTs) of treatment of rheumatoid arthritis (RA). Methods RA RCTs (phases II–IV) registered at ClinicalTrials.gov and completed by December 31, 2009 were identified. A standardized strategy was used to determine publication status and outcome assessment. The association of RCT characteristics recorded at ClinicalTrials.gov and study outcome with publication and time to publication were assessed. Results A search conducted at least 30 months after trial completion revealed that among 143 eligible RCTs, 95 (64.4%) were published. The 48 unpublished RCTs had enrolled >10,000 patients. Efficacy outcomes could be ascertained for 127 of the RCTs. RCT publication was associated with positive outcome, with an adjusted odds ratio [OR] of 4.3 (95% confidence interval [95% CI] 1.8–10.2) (P = 0.001), and marginally with RCT registration before completion (adjusted OR 0.4 [95% CI 0.1–1.0], P = 0.06). The estimated median time to publication was 38 months. Positive outcome was associated with earlier publication (adjusted hazard ratio 1.9 [95% CI 1.2–2.9], P = 0.006). RCTs completed in 2006–2007 or 2008–2009 were likely to be published sooner than RCTs completed in or before 2005. Sensitivity analyses to assess the impact of 16 RCTs with unknown outcome did not alter these findings, except in the highly implausible scenario of all such trials being positive. Conclusion Positive study outcome was associated with publication and timeliness of publication despite registration in a publicly available registry. A substantial minority of RA RCTs remained unpublished. Efforts to improve transparency in reporting of clinical trials need to continue.

Object Many patients with myelomeningocele (MMC) develop hydrocephalus, and most will undergo CSF diversion. The goal of this retrospective study was to determine whether there was a change in the shunt rate over the 7 consecutive years of the study. The authors will also identify the criteria used to determine the need for shunt placement. Methods During a 7-year period, 73 patients underwent MMC closure at Arkansas Children's Hospital. The shunt rate for each year was calculated. Clinical characteristics were evaluated, including apneic and bradycardic spells, CSF leak, level of the MMC, head circumference, and rate of head growth. In addition, radiological images were reviewed, and the frontooccipital horn ratio (FOHR), ventricular index (VI), and thalamooccipital distance (TOD) were calculated. Comparisons were made between those patients who underwent shunt placement and those who did not. Results One patient was excluded due to death in the perinatal period. Of the 72 remaining patients, 54 (75%) underwent placement of a ventriculoperitoneal shunt. This rate did not change significantly over time. Between the cohorts with and without a shunt there was no significant difference in age, sex, or race. There was no significant difference in apneic episodes or bradycardic episodes. There was a statistically significant difference in fontanelle characteristics, head circumference at birth, and rate of head growth. Patients who required CSF diversion had a mean head growth of 0.32 cm/day compared with those who did not receive a shunt (0.13 cm/day; p < 0.05). All radiological parameters were found to be statistically significant. Conclusions In this study, several classic indicators of hydrocephalus in the neonate were not found to be significantly associated with the need for CSF diversion. Fontanelle characteristics, head circumference at birth, and head growth velocity were associated with the need for shunt placement. Imaging information including the VI, TOD, and FOHR are statistically significant measures to evaluate prior to placement of a ventriculoperitoneal shunt. The optimal patient with MMC for CSF diversion will have full to tense fontanelle, increasing head circumference of more than 3 mm/day, and radiological evidence of an elevated VI, TOD, and/or FOHR.

We demonstrate that coating calcium sulfate with deacetylated chitosan enhances the elution profile of daptomycin by prolonging the period during which high concentrations of antibiotic are released. Coatings reduced initial bolus release of daptomycin by a factor of 10 to approximately 1000 µg/ml, and levels remained above 100 µg/ml for up to 10 days. Chitosan-coated and uncoated calcium sulfate implants with and without 15% daptomycin were evaluated in an experimental model of staphylococcal osteomyelitis through bacteriology scores, radiology, histopathology, and Gram staining. Significant reduction in bacteriology scores was observed for implants containing daptomycin and coated with chitosan compared with all the other groups. We confirm that the use of chitosan-coated calcium sulfate beads for local antibiotic delivery can be correlated with an improved therapeutic outcome following surgical debridement in the treatment of chronic osteomyelitis.

We investigated the in vivo relevance of the impact of sarA and saeRS on protease production using derivatives of the USA300 strain LAC. The results confirmed that mutation of saeRS or sarA reduces virulence in a bacteremia model to a comparable degree. However, while eliminating protease production restored virulence in the sarA mutant, it had little impact in the saeRS mutant. Additionally, constitutive activation of saeRS (saeRS(C)) enhanced the virulence of LAC and largely restored virulence in the isogenic sarA mutant. Based on these results, together with our analysis of the representative virulence factors alpha toxin, protein A (Spa), and extracellular nucleases, we propose a model in which the attenuation of saeRS mutants is defined primarily by decreased production of such factors, while constitutive activation of saeRS increases virulence, and reverses the attenuation of sarA mutants, because it results in both increased production and decreased protease-mediated degradation of these same factors. This regulatory balance was also apparent in a murine model of catheter-associated infection, with the results suggesting that the impact of saeRS on nuclease production plays an important role during the early stages of these infections that is partially offset by increased protease production in sarA mutants.

The University HealthSystem Consortium (UHC) database collects discharge information on patients treated at academic health centers throughout the United States. We sought to use this database to identify outcome predictors for patients undergoing total laryngectomy. A secondary end point was to assess the validity of the UHC's predictive risk mortality model in this cohort of patients.Retrospective review.Academic medical centers (tertiary referral centers) and their affiliate hospitals in the United States.Using the UHC discharge database, we retrieved and analyzed data for 4648 patients undergoing total laryngectomy who were discharged between October 2007 and January 2011 from all of the member institutions. Demographics, comorbidities, institutional data, and outcomes were retrieved.The length of stay and overall costs were significantly higher among female patients (P.0001), while age was a predictor of intensive care unit stay (P = .014). The overall complication rate was higher among Asians (P = .019) and in patients with anemia and diabetes compared with other comorbidities. The average institutional case load was 1.92 cases/mo; we found an inverse correlation (R = -0.47) between the institutional case load and length of stay (P.0001). The UHC admit mortality risk estimator was found to be an accurate predictor not only of mortality (P.0002) but also of intensive care unit admission and complication rate (P.0001).This study provides an overview of laryngectomy outcomes in a contemporary cohort of patients treated at academic health centers. UHC admit mortality risk is an excellent outcome predictor and a valuable tool for risk stratification in these patients.

To compare the cost of same-day vs 23-hour observation outpatient thyroidectomy at US academic medical centers.Cross-sectional analysis of a national database.The University HealthSystem Consortium (UHC) data collected from discharge summaries.Discharge data were collected from the first quarter of 2009 through the second quarter of 2013. The UHC database, compiled from more than 200 affiliated hospitals, was searched based on diagnosis codes for outpatient thyroid procedures. Cost data, calculated based on reported charges, were collected in addition to demographics. Comparisons were made between same-day vs 23-hour observation based on cost. Additional stratification was performed based on the extent of thyroidectomy.During the study period, 49,936 outpatient thyroidectomies were performed. Overnight observation (63%) was more common than same-day discharge (37%). The overall mean cost of outpatient thyroidectomy was $5617, with a mean cost of same-day surgery of $4642 compared with $6101 for overnight observation (P.0001). When stratifying by extent of thyroidectomy, the cost of same-day surgery was consistently lower than that for overnight observation.Outpatient thyroidectomy is commonly performed in the United States. It is most commonly performed on a 23-hour overnight observation basis. Overnight stay and complications were chief among other factors associated with higher cost, independent of the type of thyroid procedure performed. In appropriately selected patients, same-day thyroidectomy is a safe and cost-effective alternative to overnight observation or inpatient thyroid procedures.

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.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.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.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.

A vaccine adjuvant that can effectively promote cell-mediated immunity is currently not available. Because of the ability of a Candida skin test reagent injection to induce common wart regression, our group is using it as a novel adjuvant in a clinical trial of a peptide-based human papillomavirus therapeutic vaccine. The goal of this current study was to investigate the mechanisms of how Candida enhances the vaccine immune responses. Maturation effects on Langerhans cells, capacity to proliferate T-cells, expression of cytokines and pattern recognition receptors by Langerhans cells, and ability to induce Th1, Th2, and Th17 responses were investigated in healthy subjects. The vaccine, human papillomavirus peptides with Candida, demonstrated partial maturation effects on Langerhans cells indicated by significantly up-regulated CD40 (p=0.00007) and CD80 (p

Objective To assess intercentre variability in the ACR core set measures, DAS28 based on three variables (DAS28v3) and Routine Assessment of Patient Index Data 3 in a multinational study. Methods Seven thousand and twenty-three patients were recruited (84 centres; 30 countries) using a standard protocol in the Quantitative Standard Monitoring of Patients with RA study. Analysis of variance (ANOVA) and mixed-effect analysis of covariance models were used to model the relationship between study centre and different patient-reported and physician-reported RA activity measures. These models were built to adjust for the remaining ACR core set measure (for each ACR core set measure or each composite index), socio-demographics and medical characteristics. ANOVA and analysis of covariance models yielded similar results, and ANOVA tables were used to present variance attributable to recruiting centre. Results The proportion of variances attributable to recruiting centre was lower for patient reported outcomes (PROs: pain, HAQ, patient global) compared with objective measures (joint counts, ESR, physician global) in all models. In the full model, variance in PROs attributable to recruiting centre ranged from 1.53% for patient global to 3.71% for HAQ compared with objective measures that ranged from 5.92% for physician global to 9.25% for ESR; and was lower for Routine Assessment of Patient Index Data 3 (2.6%) compared with DAS28v3 (11.75%). Conclusion Intercentre variability in PROs is lower than objective measures of RA activity demonstrating that PROs may be more comparable across centres, and the need for standardization of objective measures.

We used in vitro and in vivo models of catheter-associated biofilm formation to compare the relative activity of antibiotics effective against methicillin-resistant Staphylococcus aureus (MRSA) in the specific context of an established biofilm. The results demonstrated that, under in vitro conditions, daptomycin and ceftaroline exhibited comparable activity relative to each other and greater activity than vancomycin, telavancin, oritavancin, dalbavancin, or tigecycline. This was true when assessed using established biofilms formed by the USA300 methicillin-resistant strain LAC and the USA200 methicillin-sensitive strain UAMS-1. Oxacillin exhibited greater activity against UAMS-1 than LAC, as would be expected, since LAC is an MRSA strain. However, the activity of oxacillin was less than that of daptomycin and ceftaroline even against UAMS-1. Among the lipoglycopeptides, telavancin exhibited the greatest overall activity. Specifically, telavancin exhibited greater activity than oritavancin or dalbavancin when tested against biofilms formed by LAC and was the only lipoglycopeptide capable of reducing the number of viable bacteria below the limit of detection. With biofilms formed by UAMS-1, telavancin and dalbavancin exhibited comparable activity relative to each other and greater activity than oritavancin. Importantly, ceftaroline was the only antibiotic that exhibited greater activity than vancomycin when tested in vivo in a murine model of catheter-associated biofilm formation. These results emphasize the need to consider antibiotics other than vancomycin, most notably, ceftaroline, for the treatment of biofilm-associated S. aureus infections, including by the matrix-based antibiotic delivery methods often employed for local antibiotic delivery in the treatment of these infections.

Objective Aortic graft infection remains a formidable challenge for the vascular surgeon. Traditionally, reconstruction with a neoaortoiliac system (NAIS) involves removal of the entire synthetic graft with in situ reconstruction using femoral vein. Whereas the NAIS procedure is durable with excellent graft patency and a low reinfection rate, it can take up to 10 hours and result in a high perioperative complication rate with significant mortality. Not infrequently, the infection is limited to a single limb. In addition, the patient may be too frail to tolerate aortic clamping for a complete graft excision. Under such circumstances, complete excision of the aortofemoral bypass graft (AFBG) may not be indicated. It is hypothesized that local control of infection and limited reconstruction using femoral vein may be acceptable. The objective of this study was to examine the outcomes of all patients who underwent partial AFBG resection and in situ reconstruction with femoral vein. Methods A retrospective review of all AFBG infections from 2003 to 2015 treated at a tertiary care facility was undertaken. Patients who underwent unilateral partial graft excision with inline reconstruction using femoral vein at the distal (femoral) anastomosis were included. Complete excisions with bilateral revascularizations using any conduit or any extra-anatomic reconstructions were excluded. The primary end point was successful treatment of infection. Secondary end points were procedure-related mortality, graft patency, and perioperative complications. Results During a 12-year period, partial graft excision with bypass using the femoral vein was performed in 21 patients (24 limbs). Mean age was 61 ± 12 years. There were 13 men and 8 women. Mean follow-up was 53 ± 27 months. Successful treatment was achieved in 19 of 21 patients. The two treatment failures were due to persistent infection. One of these patients declined complete graft excision and is receiving lifelong suppressive antibiotic therapy. The other patient underwent complete graft excision and an NAIS reconstruction. There were no perioperative or procedure-related deaths. There were no major amputations, and primary graft patency was 92% at 72 months. The most common AFBG culture isolate was Staphylococcus species. Approximately one-third of cultures did not yield any growth. Patients underwent anywhere from 1 to 12 weeks of combined intravenous and oral antibiotic therapy. Conclusions This limited series demonstrates excellent graft patency with a low persistent infection rate. Thus, in patients with localized graft infection, partial excision with preservation of the proximal synthetic graft is an acceptable alternative when patient factors preclude complete graft excision.

Objective The aim of this study was to examine a series of clinically identified cervical polyps and determine the incidence of significant histologic and concurrent cytologic findings. Methods Consecutive cervical polyps from January 2000 through September 2012 were retrieved from the hospital laboratory information system. Histologic evaluation of these polyps was performed, followed by a chart review of clinical findings and correlation with the immediately prior or concurrently collected cervical Papanicolaou (Pap) test results, when available. Results A total of 369 cervical polyps were identified and reviewed. The patient ages ranged from 18 to 87 years (mean 46.5 years). Eight polyps demonstrated squamous dysplasia (6 Cervical Intraepithelial Neoplasia/CIN I, and 2 CIN II/III), while 6 had malignant or atypical/potentially malignant features (2 adenosarcoma, 2 atypical polyps concerning for Mullerian adenosarcoma, 1 endometrioid endometrial adenocarcinoma and 1 adenocarcinoma in-situ). An increased incidence of atypical squamous cells of undetermined significance (ASCUS) and atypical glandular cells not otherwise specified (AGC NOS) Pap diagnoses (12.7% and 6.1%, respectively) was found in women with benign polyps on biopsy. Discussion We demonstrated a higher rate of clinically significant histologic findings in cervical polyps (14 of 369 cases, 3.7%) compared to previously reported studies. The increase in ASCUS and AGC Pap results was most likely related to reactive and inflammatory changes present in benign polyps. Our results suggest that removal of all cervical polyps with subsequent histologic review is warranted.

Blunt aortic injuries (BAIs) are traditionally treated as surgical emergencies, with the majority of repairs performed in an urgent fashion within 24 hours, irrespective of the grade of aortic injury. These patients are often underresuscitated and often have multiple other trauma issues that need to be addressed. This study reviews a single center's experience comparing urgent (24 hours) thoracic endovascular aneurysm repair (TEVAR) versus delayed (24 hours) TEVAR for Grade III BAI.All patients undergoing TEVAR for BAI at a single institution between March 2004 and March 2014 were reviewed (n = 43). Patients with Grade I, II, or IV aortic injuries as well as those who were repaired with an open procedure or who lacked preoperative imaging were excluded from the analysis. Demographics, intraoperative data, postoperative survival, and complications were compared.During this period, there were 43 patients with blunt thoracic aortic injury. There were 29 patients with Grade III or higher aortic injuries. Of these 29 patients, 1 declined surgery, 2 were repaired with an open procedure, 10 underwent urgent TEVAR, and 16 had initial observation. Of these 16, 13 underwent TEVAR in a delayed fashion (median, 9 days; range, 2-91 days), and 3 died of non-aortic-related pathology. Comparing the immediate repair group versus the delayed repair group, there were no significant demographic differences. Trauma classification scores were similar, although patients in the delayed group had a higher number of nonaortic injuries. The 30-day survival was similar between the two groups (9 of 10 vs. 12 of 16), with no mortalities caused by aortic pathology in either group.Watchful waiting may be permissible in patients with Grade III BAI with other associated multisystem trauma. This allows for a repair in a more controlled environment.Therapeutic study, level V.

Mutation of staphylococcal accessory regulator (sarA) results in increased production of extracellular proteases in Staphylococcus aureus, which has been correlated with decreased biofilm formation and decreased accumulation of extracellular toxins. We used murine models of implant-associated biofilm infection and S. aureus bacteremia (SAB) to compare virulence of USA300 strain LAC, its isogenic sarA mutant, and derivatives of each of these strains with mutations in all 10 of the genes encoding recognized extracellular proteases. The sarA mutant was attenuated in both models, and this was reversed by eliminating production of extracellular proteases. To examine the mechanistic basis, we identified proteins impacted by sarA in a protease-dependent manner. We identified 253 proteins where accumulation was reduced in the sarA mutant compared to the parent strain, and was restored in the sarA/protease mutant. Additionally, in SAB, the LAC protease mutant exhibited a hypervirulent phenotype by comparison to the isogenic parent strain, demonstrating that sarA also positively regulates production of virulence factors, some of which are subject to protease-mediated degradation. We propose a model in which attenuation of sarA mutants is defined by their inability to produce critical factors and simultaneously repress production of extracellular proteases that would otherwise limit accumulation of virulence factors.

To better understand relationships of parathyroid hormone (PTH) production, adenoma gamma counts, and adenoma mass in patients undergoing minimally radioguided invasive parathyroidectomy for primary hyperparathyroidism from single-gland disease.A prospective review of 104 patients operated on by a single surgeon.University tertiary hospital.Adults who have primary hyperparathyroidism due to a single gland.There were 23 men and 81 women with an average age of 63 years. The mean (SD) adenoma mass was 0.78 (0.69) g (median, 0.57 g). The mean (SD) percent of background for the adenoma was 120.2 (90.5). Preoperative PTH and percent of background gamma count of the adenoma showed a likely correlation with a Spearman ρ value of 0.2039 and a P value of .037. There were significant correlations between both percent of background of the adenoma and adenoma mass (Spearman ρ = 0.4991 and P.0001). Preoperative PTH and adenoma mass also showed a significant positive correlation (Spearman ρ = 0.308 and P = .002).There exist correlations between gland mass, radioactivity, and PTH level. Adenoma radiation counts do not appear to be a proxy for changes in PTH levels measured during surgery as has been reported. Intraoperative PTH has been shown by others not to be necessary when doing radioguided parathyroid surgery if the Norman rule is observed. However, a radioguided technique and intraoperative PTH can provide complementary information in making an assessment of completion of parathyroid procedures.