In-Person Clinic Visits After Laparoscopic Cholecystectomy: Lessons Learned From COVID-19 Pandemic.

INTRODUCTION: The utility of routine in-person clinic appointments after laparoscopic cholecystectomy (LC) is uncertain, especially after the increase of telehealth visits during the COVID-19 pandemic. The purpose of this study was to evaluate the utility of routine in-person follow-up for patients undergoing LC prior to changes implemented during the pandemic and to determine whether a return to routine in-person follow-up is warranted. METHODS: We retrospectively reviewed follow-up encounters for all patients undergoing LC from April 2018 to February 2020. All patients were routinely scheduled for in-person postoperative clinic follow-up 2-4 wk after discharge. Follow-up was considered nonroutine if new studies or medications were ordered, the patient was referred to the emergency department or readmitted, or malignancy was identified on pathology review. RESULTS: Of 661 patients undergoing LC, 449 (68%) attended their scheduled in-person postoperative appointment and 212 (32%) did not. The postoperative appointment was nonroutine for 39 patients (9% of clinic attenders). Readmission occurred in 42 patients, with no differences between clinic attenders and nonattenders (P = 0.12). Furthermore, attending a postoperative clinic visit did not affect odds of readmission (odds ratio: 0.705, 95% confidence interval: 0.368, 1.351; P = 0.29). Readmission occurred on median day 9 after discharge in both groups. CONCLUSIONS: The incidence of nonroutine follow-up after LC is low, and attendance at follow-up clinic was not associated with reduced readmissions. A return to routinely scheduling in-person follow-up 2-4 wk after discharge may not be warranted. Telehealth visits within 1 wk of discharge after LC should be considered.

Integrating principles and tools of decision science into value-driven watershed planning for compensatory mitigation.

Several environmental policies strive to restore impaired ecosystems and could benefit from a consistent and transparent process-codeveloped with key stakeholders-to prioritize impaired ecosystems for restoration activities. The Clean Water Act, for example, establishes reallocation mechanisms to transfer ecosystem services from sites of disturbance to compensation sites to offset aquatic resource functions that are unavoidably lost through land development. However, planning for the prioritization of compensatory mitigation areas is often hampered by decision-making processes that fall into a myopic decision frame because they are not coproduced with stakeholders. In this study, we partnered with domain experts from the North Carolina Division of Mitigation Services to codevelop a real-world decision framework to prioritize catchments by potential for the development of mitigation projects following principles of a structured decision-making process and knowledge coproduction. Following an iterative decision analysis cycle, domain experts revised foundational components of the decision framework and progressively added complexity and realism as they gained additional insights or more information became available. Through the course of facilitated in-person and remote interactions, the codevelopment of a decision framework produced three main "breakthroughs" from the perspective of the stakeholder group: (a) recognition of the problem as a multiobjective decision driven by several values in addition to biogeophysical goals (e.g., functional uplift, restoring or enhancing lost functionality of ecosystems); (b) that the decision comprises a linked and sequential planning-to-implementation process; and (c) future risk associated with land-use and climate change must be considered. We also present an interactive tool for "on-the-fly" assessment of alternatives and tradeoff analysis, allowing domain experts to quickly test, react to, and revise prioritization strategies. The decision framework described in this study is not limited to the prioritization of compensatory mitigation activities across North Carolina but rather serves as a framework to prioritize a wide range of restoration, conservation, and resource allocation activities in similar environmental contexts across the nation.

Depression and Anxiety Are Common Among Patients With Cirrhosis.

BACKGROUND & AIMS: Depression and anxiety can have negative effects on patients and are important to treat. There have been few studies of their prevalence among patients with cirrhosis. We aimed to characterize the prevalence and risk factors for depression and anxiety in a large multi-center cohort of patients with cirrhosis. METHODS: We conducted a telephone-based survey of patients with cirrhosis at 3 health systems in the United States (a tertiary-care referral center, a safety net system, and a Veterans hospital) from April through December 2018. Of 2871 patients approached, 1021 (35.6%) completed the survey. Depression and anxiety were assessed using the PHQ-9 (range 0-25) and STAI (range 20-80) instruments, with clinically significant values defined as PHQ-9 ≥15 and STAI ≥40. We performed multivariate logistic regression analysis to identify factors associated with significant depression and anxiety. RESULTS: The median PHQ-9 score was 7 (25th percentile-75th percentile, 3-12) and the median STAI score was 33 (25th percentile-75th percentile, 23-47); 15.6% of patients had moderately severe to severe depression and 42.6% of patients had high anxiety. In multivariable analyses, self-reported poor health (odds ratio [OR], 4.08; 95% CI, 1.79-9.28), being widowed (OR, 2.08; 95% CI, 1.07-4.05), fear of hepatocellular carcinoma (OR, 1.89; 95% CI, 1.04-3.42), higher household income (OR, 0.30; 95% CI, 0.10-0.95), and Hispanic ethnicity (OR, 0.57; 95% CI, 0.33-0.97) were associated with moderately severe to severe depression. Male sex (OR, 0.71; 95% CI, 0.51-0.98), self-reported poor health (OR, 2.73; 95% CI, 1.73-4.32), and fear of hepatocellular carcinoma (OR, 2.24; 95% CI, 1.33-3.78) were associated with high anxiety. CONCLUSIONS: Nearly 1 in 6 patients with cirrhosis have moderately severe to severe depression and nearly half have moderate-severe anxiety. Patients with cirrhosis should be evaluated for both of these disorders.

Proton Resonance Frequency Shift Thermometry: A Review of Modern Clinical Practices.

Magnetic resonance imaging (MRI) has become a popular modality in guiding minimally invasive thermal therapies, due to its advanced, nonionizing, imaging capabilities and its ability to record changes in temperature. A variety of MR thermometry techniques have been developed over the years, and proton resonance frequency (PRF) shift thermometry is the current clinical gold standard to treat a variety of cancers. It is used extensively to guide hyperthermic thermal ablation techniques such as high-intensity focused ultrasound (HIFU) and laser-induced thermal therapy (LITT). Essential attributes of PRF shift thermometry include excellent linearity with temperature, good sensitivity, and independence from tissue type. This noninvasive temperature mapping method gives accurate quantitative measures of the temperature evolution inside biological tissues. In this review, the current status and new developments in the fields of MR-guided HIFU and LITT are presented with an emphasis on breast, prostate, bone, uterine, and brain treatments. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY STAGE: 3.

Provider Perception of Time During Trauma Resuscitation: A Prospective Quantitative Trauma Video Review Analysis.

INTRODUCTION: Delays in transition to the next phase of care result in increased mortality. Prehospital literature suggests emergency medical service technicians underestimate transport times by as much as 20%. What remains unknown is clinician perception of time during the trauma resuscitation. We sought to determine if clinicians have an altered perception of time. We hypothesized that clinicians underestimate time, resulting in delay of care. METHODS: Clinicians at a large level 1 trauma center completed a post-trauma activation survey on the perceived elapsed time to complete three specific resuscitation endpoints. The primary study endpoint was the time to the next phase of care, defined as leaving the trauma bay to go to the operating room, interventional radiology, computerized tomography or time of death. The data from the surveys were linked and compared with recorded videos of the resuscitations. The difference in perceived versus actual time, along with confounding variables, was used to assess the impact of perception of time on the time to the next phase of care using a stepwise multivariate linear model. RESULTS: There were 284 complete surveys and videos, culminating in 543 time points. The median perceived versus actual time (minutes [interquartile range]) to the next phase of care was 20 [10-25] versus 26 [19-40] (P < 0.001). Overall, clinicians underestimated time by 28%, such that if the resuscitation lasted 20 min, the clinician's perception was that 14.4 min elapsed. Differences in the perceived versus actual time in the procedure group impacted time to the next phase of care (P = 0.01). CONCLUSIONS: Clinicians have significant gaps in the perception of time during trauma resuscitations. This misperception occurs during procedures and correlates with an increase in the length of time to the next phase of care.

Blood-based biomarkers of human papillomavirus-associated cancers: A systematic review and meta-analysis.

BACKGROUND: Despite the significant societal burden of human papillomavirus (HPV)-associated cancers, clinical screening interventions for HPV-associated noncervical cancers are not available. Blood-based biomarkers may help close this gap in care. METHODS: Five databases were searched, 5687 articles were identified, and 3631 unique candidate titles and abstracts were independently reviewed by 2 authors; 702 articles underwent a full-text review. Eligibility criteria included the assessment of a blood-based biomarker within a cohort or case-control study. RESULTS: One hundred thirty-seven studies were included. Among all biomarkers assessed, HPV-16 E seropositivity and circulating HPV DNA were most significantly correlated with HPV-associated cancers in comparison with cancer-free controls. In most scenarios, HPV-16 E6 seropositivity varied nonsignificantly according to tumor type, specimen collection timing, and anatomic site (crude odds ratio [cOR] for p16+ or HPV+ oropharyngeal cancer [OPC], 133.10; 95% confidence interval [CI], 59.40-298.21; cOR for HPV-unspecified OPC, 25.41; 95% CI, 8.71-74.06; cOR for prediagnostic HPV-unspecified OPC, 59.00; 95% CI, 15.39-226.25; cOR for HPV-unspecified cervical cancer, 12.05; 95% CI, 3.23-44.97; cOR for HPV-unspecified anal cancer, 73.60; 95% CI, 19.68-275.33; cOR for HPV-unspecified penile cancer, 16.25; 95% CI, 2.83-93.48). Circulating HPV-16 DNA was a valid biomarker for cervical cancer (cOR, 15.72; 95% CI, 3.41-72.57). In 3 cervical cancer case-control studies, cases exhibited unique microRNA expression profiles in comparison with controls. Other assessed biomarker candidates were not valid. CONCLUSIONS: HPV-16 E6 antibodies and circulating HPV-16 DNA are the most robustly analyzed and most promising blood-based biomarkers for HPV-associated cancers to date. Comparative validity analyses are warranted. Variations in tumor type-specific, high-risk HPV DNA prevalence according to anatomic site and world region highlight the need for biomarkers targeting more high-risk HPV types. Further investigation of blood-based microRNA expression profiling appears indicated.

Patient-Reported Barriers Are Associated With Receipt of Hepatocellular Carcinoma Surveillance in a Multicenter Cohort of Patients With Cirrhosis.

BACKGROUND: More than 20% of patients with cirrhosis do not receive semi-annual hepatocellular carcinoma (HCC) surveillance as recommended. Few studies have evaluated the effects of patient-level factors on surveillance receipt. METHODS: We administered a telephone survey to a large cohort of patients with cirrhosis from 3 health systems (a tertiary care referral center, a safety-net health system, and Veterans Affairs) to characterize patient knowledge, attitudes, and perceived barriers of HCC surveillance. Multinomial logistic regression was performed to identify factors associated with HCC surveillance receipt (semi-annual and annual vs none) during the 12-month period preceding survey administration. RESULTS: Of 2871 patients approached, 1020 (35.5%) completed the survey. Patients had high levels of concern about developing HCC and high levels of knowledge about HCC. However, patients had knowledge deficits, including believing surveillance was unnecessary when physical examination and laboratory results were normal. Nearly half of patients reported barriers to surveillance, including costs (28.9%), difficulty scheduling (24.1%), and transportation (17.8%). In the year before the survey, 745 patients (73.1%) received 1 or more surveillance examination; 281 received on-schedule, semi-annual surveillance and 464 received annual surveillance. Semi-annual HCC surveillance (vs none) was significantly associated with receipt of hepatology subspecialty care (odds ratio, 30.1; 95% CI, 17.5-51.8) and inversely associated with patient-reported barriers (odds ratio, 0.62; 95% CI, 0.41-0.94). Patterns of associations comparing annual vs no surveillance were similar although the magnitude of effects were reduced. CONCLUSIONS: Patient-reported barriers such as knowledge deficits, costs, difficulty scheduling, and transportation are significantly associated with less frequent receipt of HCC surveillance, indicating a need for patient-centered interventions, such as patient navigation.

Randomized Clinical Trial of Inreach With or Without Mailed Outreach to Promote Hepatitis C Screening in a Difficult-to-Reach Patient Population.

INTRODUCTION: Hepatitis C virus (HCV) treatment can significantly reduce the risk of liver-related mortality; however, many patients remain unaware of their infection in clinical practice. The aim of this study is to compare the effectiveness of inreach, with and without mailed outreach, to increase HCV screening and follow-up in a large, difficult-to-reach patient population. METHODS: We conducted a pragmatic randomized clinical trial from August 2018 to May 2019 in a large safety-net health system. Patients born between 1945 and 1965 were randomly assigned (1:1) to inreach with an electronic health record reminder to providers (n = 6,195) or inreach plus mailed HCV screening outreach (n = 6,191) to complete HCV antibody screening. Outreach also included processes to promote HCV RNA testing among those with a positive HCV antibody and linkage to care among those with positive HCV RNA. The primary outcome was completion of HCV antibody testing within 3 months of randomization (ClinicalTrials.gov NCT03706742). RESULTS: We included 12,386 eligible patients (median age 60 years; 46.5% Hispanic, 33.0% Black, and 16.0% White). In intent-to-treat analyses, HCV screening completion was significantly higher among inreach-plus-outreach patients than inreach-alone patients at 3 months (14.6% vs 7.4%, P < 0.001) and 6 months (17.4% vs 9.8%, P < 0.001) after randomization. Among those who completed HCV screening within 6 months, a higher proportion of inreach-plus-outreach patients with positive antibody results completed RNA testing within 3 months than inreach-alone patients (81.1% vs 57.1%, respectively, P = 0.02); however, linkage to care within 3 months of HCV infection confirmation did not significantly differ between the 2 groups (48.1% vs 75.0%, respectively, P = 0.24). DISCUSSION: Among difficult-to-reach patients, a combination of inreach and mailed outreach significantly increased HCV screening compared with inreach alone. However, HCV screening completion in both arms remained low, highlighting a need for more intensive interventions.

Redefining High-Volume Gastric Cancer Centers: The Impact of Operative Volume on Surgical Outcomes.

BACKGROUND: Performance of technically complex surgery at high-volume (HV) centers is associated with improved outcomes. OBJECTIVE: The aim of this study was to assess whether hospital gastrectomy volume is associated with surgical outcomes, and what threshold of case volume meaningfully impacts surgical outcomes. METHODS: We conducted a retrospective review of adult NCDB patients with gastric adenocarcinoma undergoing gastrectomy between 2004 and 2015. A multivariable Cox proportional hazards model with restricted cubic splines was used to examine the association of annual hospital gastrectomy volume and overall survival. Bootstrap simulation was used to estimate the cut-point corresponding to maximum change in log hazard ratio. Hospitals were divided into HV (≥ 17 cases/year) and low-volume (LV; < 17 cases/year) groups. We examined the relationship between volume groups and adequate nodal examination, R0 resection, unplanned readmission, and 30- and 90-day mortality. RESULTS: Our cohort consisted of 29,559 patients (7.8% treated at an HV center). Treatment at an HV center was associated with an increased likelihood of adequate nodal examination [odds ratio (OR) 2.12, 95% confidence interval (CI) 1.94-2.32] and R0 resection among patients with cardia tumors (OR 1.42, 95% CI 1.07-1.88). Patients treated at HV centers had decreased 30- and 90-day postoperative mortality, which was more pronounced in those undergoing total gastrectomy. CONCLUSIONS: Treatment at an HV gastrectomy center is associated with improved surgical outcomes. Our study identified 17 cases/year as a clinically meaningful distinction between HV and LV centers. This definition of an HV center should be considered when evaluating regionalization of gastric cancer care to improve patient outcomes.

Inaccurate Clinical Stage Is Common for Gastric Adenocarcinoma and Is Associated with Undertreatment and Worse Outcomes.

BACKGROUND: Accurate clinical staging (CS) of gastric cancer is critical for appropriate treatment selection and prognostication, but CS remains highly imprecise. Our study evaluates factors associated with inaccurate CS, the impact of inaccurate CS on outcomes, and utilization of adjuvant therapy in patients who are understaged. METHODS: We conducted a retrospective review of NCDB patients diagnosed with clinical early stage gastric adenocarcinoma (cT1-2N0M0) between 2004 and 2016. Patients not undergoing upfront gastrectomy or with missing pathologic staging were excluded. Patients were classified as accurately staged, inaccurately staged with receipt of adjuvant therapy (IS+), and inaccurately staged with no receipt of adjuvant therapy (IS-). Logistic regression was utilized to assess the impact of factors on CS accuracy and receipt of adjuvant therapies. Kaplan-Meier and Cox proportional hazard methods were used for survival analysis. RESULTS: Approximately 40% of patients were inaccurately staged (IS). cT2, moderately/poorly differentiated, and site-overlapping tumors were associated with increased likelihood of being IS. Treatment at an academic facility was associated with decreased likelihood of understaging. Only 54% of patients who were IS received adjuvant therapy. CONCLUSION: Accurate CS of gastric cancer remains inadequate. Understaging is associated with detrimental effects on receiving guideline-concordant care and, possibly, patient outcomes. Targeted interventions reducing the proportion of understaged patients and ensuring receipt of appropriate therapy is needed to optimize outcomes. Patients with high-risk disease that are frequently understaged may benefit from selective neoadjuvant therapy. Centralization of gastric cancer care may also be a key strategy in improving receipt of guideline-concordant therapies.

Blood Conservation and Hemostasis in Cardiac Surgery: A Survey of Practice Variation and Adoption of Evidence-Based Guidelines.

BACKGROUND: Blood conservation and hemostasis are integral parts of reducing avoidable blood transfusions and the associated morbidity and mortality. Despite the publication of blood conservation guidelines for cardiac surgery, evidence suggests persistent variability in practice patterns. Members of the Society of Cardiovascular Anesthesiologists (SCA) created a survey to audit conformance to existing guidelines and use the results to help narrow the evidence-to-practice gap. METHODS: Members of the SCA and its Continuous Practice Improvement (CPI)- Blood Conservation Work Group developed a 48-item Blood Conservation and Hemostasis in Cardiac Surgery (BCHCS) survey. The questionnaire included the components of the Anesthesia Quality Institute's (AQI) composite measure AQI49. The survey was distributed to the entire SCA membership by e-mail via the Research Electronic Data Capture (REDCap) Consortium between the fall of 2017 and early 2018. RESULTS: Of 3152 SCA members, 536 returned surveys for a response rate of 17%. Most responders worked at academic institutions. The median transfusion trigger after cardiopulmonary bypass was hemoglobin (Hgb) 7.0 to 8.0 g/dL. There are 4 components to AQI49, and the composite conformance to all of them was low due to 1 specific component: the use of transfusion algorithms supplemented with point-of-care (POC) testing. There was good conformance to the other 3 components of AQI49: use of antifibrinolytics, minimization of hemodilution and use of red cell salvage. Overall, practices with a multidisciplinary patient blood management (PBM) team were the most successful in meeting all 4 AQI49 criteria. CONCLUSIONS: The survey demonstrated widespread adoption of several best practices, including the tolerance of lower hemoglobin transfusion triggers, use of antifibrinolytics, minimization of hemodilution, and use of red cell salvage. The survey also confirms that gaps remain in preoperative anemia management and the use of transfusion algorithms supplemented with POC hemostasis testing. Serial use of this survey can be used to identify barriers to implementation and audit the effectiveness of interventions described in this article. This instrument could also help harmonize local, regional, and national efforts and become an essential component of an implementation strategy for PBM in cardiac surgery.

Prophylactic antibiotics for penetrating abdominal trauma: duration of use and antibiotic choice.

BACKGROUND: Penetrating abdominal trauma (PAT) is a common type of trauma leading to admission to hospital, which often progresses to septic complications. Antibiotics are commonly administered as prophylaxis prior to laparotomy for PAT. However, an earlier Cochrane Review intending to compare antibiotics with placebo identified no relevant randomised controlled trials (RCTs). Despite this, many RCTs have been carried out that compare different agents and durations of antibiotic therapy. To date, no systematic review of these trials has been performed. OBJECTIVES: To assess the effects of antibiotics in penetrating abdominal trauma, with respect to the type of agent administered and the duration of therapy. SEARCH METHODS: We searched the following electronic databases for relevant randomised controlled trials, from database inception to 23 July 2019; Cochrane Injuries Group's Specialised Register, CENTRAL, MEDLINE Ovid, MEDLINE Ovid In-Process & Other Non-Indexed Citations, MEDLINE Ovid Daily and Ovid OLDMEDLINE, Embase Classic + Embase Ovid, ISI Web of Science (SCI-EXPANDED, SSCI, CPCI-S & CPSI-SSH), and two clinical trials registers. We also searched reference lists from included studies. We applied no restrictions on language or date of publication. SELECTION CRITERIA: We included RCTs only. We included studies involving participants of all ages, which were conducted in secondary care hospitals only. We included studies of participants who had an isolated penetrating abdominal wound that breached the peritoneum, who were not already taking antibiotics. DATA COLLECTION AND ANALYSIS: Two study authors independently extracted data and assessed risk of bias. We used standard Cochrane methods. We aggregated study results using a random-effects model. We also conducted trial sequential analysis (TSA) to help reduce type I and II errors in our analyses. MAIN RESULTS: We included 29 RCTs, involving a total of 4458 participants. We deemed 23 trials to be at high risk of bias in at least one domain. We are uncertain of the effect of a long course of antibiotic prophylaxis (> 24 hours) compared to a short course (≤ 24 hours) on abdominal surgical site infection (RR 1.00, 95% CI 0.81 to 1.23; I² = 0%; 7 studies, 1261 participants; very low-quality evidence), mortality (Peto OR 1.67, 95% CI 0.73 to 3.82; I² = 8%; 7 studies, 1261 participants; very low-quality evidence), or intra-abdominal infection (RR 1.23, 95% CI 0.84 to 1.80; I² = 0%; 6 studies, 111 participants; very-low quality evidence). Based on very low-quality evidence from fifteen studies, involving 2020 participants, which compared different drug regimens with activity against three classes of gastrointestinal flora (gram positive, gram negative, anaerobic), we are uncertain whether there is a benefit of one regimen over another. TSA showed the majority of comparisons did not cross the alpha adjusted boundary for benefit or harm, or reached the required information size, indicating that further studies are required for these analyses. However, in the three analyses which crossed the boundary for futility, further studies are unlikely to show benefit or harm. AUTHORS' CONCLUSIONS: Very low-quality evidence means that we are uncertain about the effect of either the duration of antibiotic prophylaxis, or the superiority of one drug regimen over another for penetrating abdominal trauma on abdominal surgical site infection rates, mortality, or intra-abdominal infections. Future RCTs should be adequately powered, test currently used antibiotics, known to be effective against gut flora, use methodology to minimise the risk of bias, and adequately report the level of peritoneal contamination encountered at laparotomy.

Short-term pre-operative high-intensity interval training does not improve fitness of colorectal cancer patients.

BACKGROUND: Pre-operative cardiorespiratory fitness (CRF) in colorectal cancer (CRC) patients has been shown to affect post-operative outcomes. The aim of this study was to test the feasibility of high-intensity interval training (HIIT) for improving fitness in pre-operative CRC patients within the 31-day cancer waiting-time targets imposed in the UK. METHODS: Eighteen CRC patients (13 males, mean age: 67 years (range: 52-77 years) participated in supervised HIIT on cycle ergometers 3 or 4 times each week prior to surgery. Exercise intensity during 5 × 1-minute HIIT intervals (interspersed with 90-second recovery) was 100%-120% maximum wattage achieved at a baseline cardiopulmonary exercise test (CPET). CPET before and after HIIT was used to assess CRF. RESULTS: Patients completed a mean of eight HIIT sessions (range 6-14) over 19 days (SD 7). There was no significant increase in VO2 peak (23.9 ± 7.0 vs 24.2 ± 7.8 mL/kg/min (mean ± SD), P = 0.58) or anaerobic threshold (AT: 14.0 ± 3.4 vs 14.5 ± 4.5 mL/kg/min, P = 0.50) after HIIT. There was a significant reduction in resting systolic blood pressure (152 ± 19 vs 142 ± 19 mm Hg, P = 0.0005) and heart rate at submaximal exercise intensities after HIIT. CONCLUSIONS: Our pragmatic HIIT exercise protocol did not improve the pre-operative fitness of CRC patients within the 31-day window available in the UK to meet cancer surgical waiting-time targets.

Influence of beetroot juice supplementation on intermittent exercise performance.

PURPOSE: This study tested the hypothesis that nitrate (NO3-) supplementation would improve performance during high-intensity intermittent exercise featuring different work and recovery intervals. METHOD: Ten male team-sport players completed high-intensity intermittent cycling tests during separate 5-day supplementation periods with NO3 (-)-rich beetroot juice (BR; 8.2 mmol NO3- day(-1)) and NO3 (-)-depleted beetroot juice (PL; 0.08 mmol NO3- day(-1)). Subjects completed: twenty-four 6-s all-out sprints interspersed with 24 s of recovery (24 × 6-s); seven 30-s all-out sprints interspersed with 240 s of recovery (7 × 30-s); and six 60-s self-paced maximal efforts interspersed with 60 s of recovery (6 × 60-s); on days 3, 4, and 5 of supplementation, respectively. RESULT: Plasma [NO2-] was 237% greater in the BR trials. Mean power output was significantly greater with BR relative to PL in the 24 × 6-s protocol (568 ± 136 vs. 539 ± 136 W; P < 0.05), but not during the 7 × 30-s (558 ± 95 vs. 562 ± 94 W) or 6 × 60-s (374 ± 57 vs. 375 ± 59 W) protocols (P > 0.05). The increase in blood [lactate] across the 24 × 6-s and 7 × 30-s protocols was greater with BR (P < 0.05), but was not different in the 6 × 60-s protocol (P > 0.05). CONCLUSION: BR might be ergogenic during repeated bouts of short-duration maximal-intensity exercise interspersed with short recovery periods, but not necessarily during longer duration intervals or when a longer recovery duration is applied. These findings suggest that BR might have implications for performance enhancement during some types of intermittent exercise.

Proof of concept for a banding scheme to support risk assessments related to multi-product biologics manufacturing.

A banding scheme theory has been proposed to assess the potency/toxicity of biologics and assist with decisions regarding the introduction of new biologic products into existing manufacturing facilities. The current work was conducted to provide a practical example of how this scheme could be applied. Information was identified for representatives from the following four proposed bands: Band A (lethal toxins); Band B (toxins and apoptosis signals); Band C (cytokines and growth factors); and Band D (antibodies, antibody fragments, scaffold molecules, and insulins). The potency/toxicity of the representative substances was confirmed as follows: Band A, low nanogram quantities exert lethal effects; Band B, repeated administration of microgram quantities is tolerated in humans; Band C, endogenous substances and recombinant versions administered to patients in low (interferons), intermediate (growth factors), and high (interleukins) microgram doses, often on a chronic basis; and Band D, endogenous substances present or produced in the body in milligram quantities per day (insulin, collagen) or protein therapeutics administered in milligram quantities per dose (mAbs). This work confirms that substances in Bands A, B, C, and D represent very high, high, medium, and low concern with regard to risk of cross-contamination in manufacturing facilities, thus supporting the proposed banding scheme.

Harnessing entropic and enthalpic contributions to create a negative tone chemically amplified molecular resist for high-resolution lithography.

Here we present a new resist design concept. By adding dilute cross-linkers to a chemically amplified molecular resist, we synergize entropic and enthalpic contributions to dissolution by harnessing both changes to molecular weight and changes in intermolecular bonding to create a system that outperforms resists that emphasize one contribution over the other. We study patterning performance, resist modulus, solubility kinetics and material redistribution as a function of cross-linker concentration. Cross-linking varies from dilute oligomerization to creating a highly networked system. The addition of small amounts of cross-linker improves resist performance by reducing material diffusion and redistribution during development and stiffening the features to avoid pattern collapse. The new dilute cross-linking system achieves the highest resolution of a sensitive molecular glass resist at 20 nm half-pitch and line-edge roughness (LER) of 4.3 nm and can inform new resist design towards patterned feature control at the molecular level.

Intestinal spirochetosis: an enigmatic disease.

INTRODUCTION: Intestinal spirochetosis (IS) is a condition in which colonic and appendiceal epithelial cells are colonized by one of two anaerobic spirochetes, either the Brachyspira aalborgi or Brachyspira pilosicoli. There is much debate in the literature as to whether IS is a pathogen or a commensal inhabitant. A recent case of IS at our institution prompted a retrospective database search and review of the literature. METHODS: A pathology database search for IS was performed at Carolinas Medical Center from 2003 through 2007. After patient identification, a retrospective review of the endoscopic record and the pathology report was performed. Pathology slides were reviewed for accuracy and special silver stains and/or immunostains were performed if needed. The following data were collected for each patient when available: age, gender, nationality, HIV status, and other co-morbid conditions when noted. We attempted to determine whether patients were treated for spirochetosis and if so, the treatment regimen used as well as the results. RESULTS: The database search detected 29 patients with biopsies showing IS. Three patients were subsequently removed due to incorrect identification. A total of 26 patients with an average age of 45 years were reviewed. The most common symptoms were abdominal pain, diarrhea, and rectal bleeding. Most patients did not exhibit inflammatory changes despite the presence of spirochetosis. Pathologic examination revealed a relative increase in intra-epithelial lymphocytes in a subset of cases, a non-specific finding. Acute colitis or architectural distortion was not seen in any of the study cases. We were only able to obtain follow-up of two patients after treatment with metronidazole and both responded to therapy. CONCLUSIONS: To date, our study is the largest case series that includes both endoscopic and pathologic descriptions and confirms the "bland" nature of the condition. In <20 % of our patients inflammation was present microscopically and it did not correlate well with endoscopic appearance. Symptoms reported by our patients were similar to those reported in previous studies, although our lack of endoscopic changes was different from one previous paper. There is no established standard of care for the treatment of IS and our study, reflects the enigmatic nature of IS as a disease process. In the absence of rigorous literature, physicians will need to use a logical and pragmatic approach to the evaluation and treatment of IS.

Molecular mechanisms underpinning favourable physiological adaptations to exercise prehabilitation for urological cancer surgery.

BACKGROUND: Surgery for urological cancers is associated with high complication rates and survivors commonly experience fatigue, reduced physical ability and quality of life. High-intensity interval training (HIIT) as surgical prehabilitation has been proven effective for improving the cardiorespiratory fitness (CRF) of urological cancer patients, however the mechanistic basis of this favourable adaptation is undefined. Thus, we aimed to assess the mechanisms of physiological responses to HIIT as surgical prehabilitation for urological cancer. METHODS: Nineteen male patients scheduled for major urological surgery were randomised to complete 4-weeks HIIT prehabilitation (71.6 ± 0.75 years, BMI: 27.7 ± 0.9 kg·m2) or a no-intervention control (71.8 ± 1.1 years, BMI: 26.9 ± 1.3 kg·m2). Before and after the intervention period, patients underwent m. vastus lateralis biopsies to quantify the impact of HIIT on mitochondrial oxidative phosphorylation (OXPHOS) capacity, cumulative myofibrillar muscle protein synthesis (MPS) and anabolic, catabolic and insulin-related signalling. RESULTS: OXPHOS capacity increased with HIIT, with increased expression of electron transport chain protein complexes (C)-II (p = 0.010) and III (p = 0.045); and a significant correlation between changes in C-I (r = 0.80, p = 0.003), C-IV (r = 0.75, p = 0.008) and C-V (r = 0.61, p = 0.046) and changes in CRF. Neither MPS (1.81 ± 0.12 to 2.04 ± 0.14%·day-1, p = 0.39) nor anabolic or catabolic proteins were upregulated by HIIT (p > 0.05). There was, however, an increase in phosphorylation of AS160Thr642 (p = 0.046) post-HIIT. CONCLUSIONS: A HIIT surgical prehabilitation regime, which improved the CRF of urological cancer patients, enhanced capacity for skeletal muscle OXPHOS; offering potential mechanistic explanation for this favourable adaptation. HIIT did not stimulate MPS, synonymous with the observed lack of hypertrophy. Larger trials pairing patient-centred and clinical endpoints with mechanistic investigations are required to determine the broader impacts of HIIT prehabilitation in this cohort, and to inform on future optimisation (i.e., to increase muscle mass).

Lifelong physical activity prevents an age-related reduction in arterial and skeletal muscle nitric oxide bioavailability in humans.

Ageing has been proposed to be associated with increased levels of reactive oxygen species (ROS) that scavenge nitric oxide (NO). In eight young sedentary (23 ± 1 years; Y), eight older lifelong sedentary (66 ± 2 years; OS) and eight older lifelong physically active subjects (62 ± 2 years; OA), we studied the effect of ROS on systemic and skeletal muscle NO bioavailability and leg blood flow by infusion of the antioxidant N-acetylcysteine (NAC). Infusion of NAC increased the bioavailability of NO in OS, as evidenced by an increased concentration of stable metabolites of NO (NOx) in the arterial and venous circulation and in the muscle interstitium. In OA, infusion of NAC only increased NOx concentrations in venous plasma whereas in Y, infusion of NAC did not affect NOx concentrations. Skeletal muscle protein levels of endothelial and neuronal NO synthase were 32% and 24% higher, respectively, in OA than in OS. Exercise at 12 W elicited a lower leg blood flow response that was associated with a lower leg oxygen uptake in OS than in Y. The improved bioavailability of NO in OS did not increase blood flow during exercise. These data demonstrate that NO bioavailability is compromised in the systemic circulation and in the musculature of sedentary ageing humans due to increased oxidative stress. Lifelong physical activity opposes this effect within the trained musculature and in the arterial circulation. The lower blood flow response to leg exercise in ageing humans is not associated with a reduced NO bioavailability.