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Introduction: Coagulation disorders occur during the first 48 h after major burn injury, affecting mainly PT/INR and aPTT. Some authors consider them burn specific. The aim was to assess the magnitude of coagulation disorders during the first 10 days after severe burn injury and its eventual association with fluid intakes. Methods: Retrospective study of prospectively collected data including patients with burns ≥ 20%BSA (body surface area) who stayed ≥ 24 h at the burn-intensive care unit (ICU). Predetermined data for the analysis of fluid and blood products administration and laboratory values were extracted from the computerized information system. Descriptive statistics, data as median. Results: 167 patients included. The volumes of fluid resuscitation decreased over the first 10 days (median 6815 ml on day 1 decreasing to 4190 ml by day 10, p

The opioid crisis is a national health emergency with immense morbidity, mortality, and socioeconomic cost. Emergency department (ED) pain management is tightly linked to the issue of opioid use disorder (OUD), because opioid exposure is necessary for development of OUD. Emergency nurses are on the frontlines of this complex problem, yet little, if any, attention has been paid to the role they play in the prevention and management of either pain or OUD in this unique and important setting. A framework that conceptualizes and optimizes emergency nurses as change agents in the opioid epidemic is urgently needed. While ED pain management and OUD prevention is dependent on the entire care team, this innovative study qualitatively characterizes emergency nurse perceptions of pain management, OUD prevention, and their potential role in each. Content analysis produced 14 categories that were clustered into two themes, “nurses influence ED pain management” and “adjustments in ED pain management”, and an overarching message that “pain management depends on the care team.” By generating a more comprehensive and nuanced understanding of the role played by emergency nurses, our findings provide essential insights into potential interventions and frameworks.

Introduction Cytokines might play a key role in the pathophysiology of major depressive disorder (MDD). The speed of onset of depressive episodes has been discussed as an important clinical parameter in MDD. The aim of this study was to investigate a potential influence of the speed of onset of the depressive episode on cytokine serum levels. Method Serum level of the cytokines interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ) granulocyte and monocyte colony stimulating factor (GM-CSF) were measured in a total of 92 patients with MDD that did not respond to at least one previous antidepressant treatment. Patients were retrospectively divided in two groups: Faster (≤4 weeks) and slower (>4 weeks) onset of the depressive episode defined as the time passing from the first depressive symptoms to a full-blown depressive episode by using information from a clinical interview. Results We found significantly lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ in patients with a faster onset compared to patients with a slower onset of the depressive episodes. Furthermore, lower cytokine serum levels of IL-2, IL-8, IL-10 and IFN-γ were found in patients with a shorter duration (less than 6 months) compared to a longer duration (6–24 months) of the current depressive episode. This effect on cytokines was independent from the effect of the speed of onset of the depressive episode. Conclusions Patients with faster onset of the depressive episode might represent a biological subtype of MDD with lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ.

Silver diamine fluoride (SDF) is a dental biomaterial used to arrest dental caries. To better understand SDF’s mechanism of action, we examined the localization of silver within the tissues of SDF-treated teeth. Carious primary teeth fixed within 2 min of SDF application (SDF-minutes, n = 3), at 3 wk after SDF application in vivo (SDF-weeks, n = 4), and at 2 y after multiple SDF applications in vivo (SDF-multiple, n = 1) were investigated in this study. Carious primary teeth without SDF application (no-SDF, n = 3) served as controls. Mineral density and structural analyses were performed via micro–X-ray computed tomography and scanning electron microscopy. Elemental analyses were performed through X-ray fluorescence microprobe and energy-dispersive X-ray spectroscopic techniques. SDF-treated teeth revealed higher X-ray–attenuated surface and subsurface regions within carious lesions, and similar regions were not present in no-SDF teeth. Regions of higher mineral density correlated with regions of silver abundance in SDF-treated teeth. The SDF penetration depth was approximated to 0.5 ± 0.02 mm and 0.6 ± 0.05 mm (mean ± SD) for SDF-minutes and SDF-weeks specimens, respectively. A higher percentage of dentin tubular occlusion by silver or calcium phosphate particles was observed in primary teeth treated with SDF-weeks as compared with SDF-minutes. Elemental analysis also revealed zinc abundance in carious lesions and around the pulp chamber. SDF-weeks teeth had significantly increased tertiary dentin than SDF-minutes and no-SDF teeth. These results suggest that SDF treatment on primary teeth affected by caries promotes pathologic biomineralization by altering their physicochemical properties, occluding dentin tubules, and increasing tertiary dentin volume. These seemingly serendipitous effects collectively contribute to the cariostatic activity of SDF.

Salt-inducible kinases (SIKs) are key metabolic regulators. The imbalance in SIK function is associated with the development of diverse cancers, including breast, gastric, and ovarian cancers. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based p21-activated kinase (PAK) inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets, MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.

Background The enormous health impact of the COVID-19 pandemic has refocused attention on measures to optimize immune function and vaccine response. Dietary deficiencies of micronutrients can weaken adaptive immunity. The aim of this review was to examine links between micronutrients, immune function and COVID-19 infection, with a focus on nutritional risks in subgroups of the Swiss population. Methods Scoping review on the associations between selected micronutrients (vitamins D and C, iron, selenium, zinc, and n-3 PUFAs) and immunity, with particular reference to the Swiss population. These nutrients were chosen because previous EFSA reviews have concluded they play a key role in immunity. Results The review discusses the available knowledge on links between sufficient nutrient status, optimal immune function, and prevention of respiratory tract infections. Because of the rapid spread of the COVID-19 pandemic, controlled intervention studies of micronutrients in the context of COVID-19 infection are now underway, but evidence is not yet available to draw conclusions. The anti-inflammatory properties of n-3 PUFAs are well established. In Switzerland, several subgroups of the population are at clear risk of nutrient deficiencies; e.g., older adults, multiple comorbidities, obesity, pregnancy, and institutionalized. Low intakes of n-3 PUFA are present in a large proportion of the population. Conclusion There are clear and strong relationships between micronutrient and n-3 PUFA status and immune function, and subgroups of the Swiss population are at risk for deficient intakes. Therefore, during the COVID-19 pandemic, as a complement to a healthy and balanced diet, it may be prudent to consider supplementation with a combination of moderate doses of Vitamins C and D, as well as of Se, Zn and n-3 PUFA, in risk groups., Clinical Nutrition ESPEN, 43, ISSN:2405-4577

BACKGROUND The US Preventive Services Task Force (USPSTF) includes multitarget stool DNA (mt-sDNA) testing as a colorectal cancer (CRC) screening option in average-risk individuals, but data on colonoscopy outcomes after positive mt-sDNA tests in community settings are needed. AIM The aim of this study was to investigate colonoscopy outcomes and quality following positive mt-sDNA in the population-based New Hampshire Colonoscopy Registry. METHODS We compared colonoscopy outcomes and quality between age-matched, sex-matched, and risk-matched patients from 30 endoscopy practices with and without a preceding positive mt-sDNA test. Main outcomes were colonoscopy findings of CRC, advanced noncancerous neoplasia, nonadvanced neoplasia, or normal examination. Quality measures included withdrawal time, bowel preparation quality, examination completion, and percentage of average-risk individuals with normal colonoscopies receiving a USPSTF-recommended 10 year rescreening interval. RESULTS Individuals with positive mt-sDNA tests (N=306, average age 67.0 y; 61.8% female) were significantly more likely than colonoscopy-only patients (N=918, 66.2 y; 61.8% female) to have CRC (1.3% vs. 0.4%) or advanced noncancerous neoplasia (27.1% vs. 8.2%) (P

Amino acid (AA) metabolism is severely disturbed in critically ill ICU patients. To be able to make a more scientifically based decision on the type of protein or AA nutrition to deliver in ICU patients, comprehensive AA phenotyping with measurements of plasma concentrations and whole body production (WBP) is needed. Therefore, we studied ICU patients and matched control subjects using a novel pulse isotope method to obtain in-depth metabolic analysis. In 51 critically ill ICU patients (SOFA~6.6) and 49 healthy controls, we measured REE and body composition/phase-angle using BIA. In the postabsorptive state, we collected arterial (ized) blood for CRP and AA. Then, we administered an 8 mL solution containing 18 stable AA tracers as a pulse and calculated WBP. Enrichments: LC-MS/MS and statistics: t-test, ANCOVA. Compared to healthy, critically ill ICU patients had lower phase-angle (p 0.00001), and higher CRP (p 0.0001). Most AA concentrations were lower in ICU patients (p 0.0001), except tau-methylhistidine and phenylalanine. WBP of most AA were significantly (p 0.0001) higher with increases in glutamate (160%), glutamine (46%), and essential AA. Remarkably, net protein breakdown was lower. There were only weak relationships between AA concentrations and WBP. Critically ill ICU patients (SOFA 8-16) had lower values for phase angle (p = 0.0005) and small reductions of most plasma AA concentrations, but higher tau-methylhistidine (p = 0.0223) and hydroxyproline (p = 0.0028). Remarkably, the WBP of glutamate and glutamine were lower (p 0.05), as was their clearance, but WBP of tau-methylhistidine (p = 0.0215) and hydroxyproline (p = 0.0028) were higher. Our study in critically ill ICU patients shows that comprehensive metabolic phenotyping was able to reveal severe disturbances in specific AA pathways, in a disease severity dependent way. This information may guide improving nutritional compositions to improve the health of the critically ill patient. CLINICAL TRIAL REGISTRY: Data are from the baseline measurements of study NCT02770092 (URL: https://clinicaltrials.gov/ct2/show/NCT02770092) and NCT03628365 (URL: https://clinicaltrials.gov/ct2/show/NCT03628365).

Reaching the goals set by the Health Care Payment and Learning Action Network requires an unyielding and unrelenting focus on encouraging providers to adopt advanced alternative payment models (APMs). Many of these models will continue to be voluntary because they either are in early stages or have not yet proven their effectiveness. The models that have proven their effectiveness should become permanent, comprising the new way that providers are paid in the Medicare program. Either way, getting today's high performers into those programs and keeping them engaged to continue to innovate and set new benchmarks is as important as attracting and improving the performance of poorer performers. That will require a shift in Medicare's policy on pricing and evaluating APMs.

AIM Due to scarce available national data, this study assessed current attitudes of neonatal caregivers regarding decisions on life-sustaining interventions, and their views on parents' aptitude to express their infant's best interest in shared decision-making. METHODS Self-administered web-based quantitative empirical survey. All 552 experienced neonatal physicians and nurses from all Swiss NICUs were eligible. RESULTS There was a high degree of agreement between physicians and nurses (response rates 79% and 70%, respectively) that the ability for social interactions was a minimal criterion for an acceptable quality of life. A majority stated that the parents' interests are as important as the child's best interest in shared decision-making. Only a minority considered the parents as the best judges of what is their child's best interest. Significant differences in attitudes and values emerged between neonatal physicians and nurses. The language area was very strongly associated with the attitudes of neonatal caregivers. CONCLUSION Despite clear legal requirements and societal expectations for shared decision-making, survey respondents demonstrated a gap between their expressed commitment to shared decision-making and their view on parental aptitude to formulate their infant's best interest. National guidelines need to address these barriers to shared decision-making to promote a more uniform nationwide practice.

Feline house soiling, or the elimination of waste products outside the litter box on horizontal and/or vertical surfaces, is one of the most common owner-reported reasons for cat relinquishment. Because these cats’ perceived low potential for adoption, many sheltering organizations do not accept cats with house-soiling histories or euthanize without further interventions. In this study, cats with periuria were accepted into a limited intake shelter and rehomed. Retrospective data were collected from 294 cats with periuria to assess adoption outcomes over a six-year period. Outcome data included length of stay within the shelter, returns, and euthanasias. Nonparametric statistical tests of significance were used to determine differences in outcomes between cats with periuria and the general cat population in this shelter. Year-by-year analyses demonstrated no significant differences in length of stay for four of the six years analyzed. The rates of returns and euthanasias for both populations were low. These results provide evidence that cats with urinary house-soiling behaviors had similar outcomes as the general cat population. These results argue against immediate refusal or disposal of cats who present to shelters with house-soiling behaviors.

Cardiovascular diseases (CVDs) are the most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) and dyslipidemia is considered at least partially responsible for the increased CVD risk in NAFLD patients. The aim of the present study is to understand how hepatic de novo lipogenesis influences hepatic cholesterol content as well as its effects on the plasma lipid levels. Hepatic lipogenesis was induced in mice by feeding a fat-free/high-sucrose (FF/HS) diet and the metabolic pathways associated with cholesterol were then analyzed. Both liver triglyceride and cholesterol contents were significantly increased in mice fed an FF/HS diet. Activation of fatty acid synthesis driven by the activation of sterol regulatory element binding protein (SREBP)-1c resulted in the increased liver triglycerides. The augmented cholesterol content in the liver could not be explained by an increased cholesterol synthesis, which was decreased by the FF/HS diet. HMG-CoA reductase protein level was decreased in mice fed an FF/HS diet. We found that the liver retained more cholesterol through a reduced excretion of bile acids, a reduced fecal cholesterol excretion, and an increased cholesterol uptake from plasma lipoproteins. Very low-density lipoprotein-triglyceride and -cholesterol secretion were increased in mice fed an FF/HS diet, which led to hypertriglyceridemia and hypercholesterolemia in Ldlr-/- mice, a model that exhibits a more human like lipoprotein profile. These findings suggest that dietary cholesterol intake and cholesterol synthesis rates cannot only explain the hypercholesterolemia associated with NAFLD, and that the control of fatty acid synthesis should be considered for the management of dyslipidemia.

The majority of alleged abuse or neglect reports to the U.S. child welfare system are either screened out prior to an investigation (i.e., at the “hotline” stage) or investigated only to be closed with no finding of immediate child safety concerns. Yet while many of these children and families are at risk of subsequent incidents of child maltreatment or child welfare system involvement, they are not systematically offered services or benefits intended to reduce this risk at the point that child protective services (CPS) ends its involvement. This article provides an overview of the “front end” of the child welfare system, commonly referred to as CPS, highlighting which families are served and which are not. We then argue for a systematic and coordinated child maltreatment prevention infrastructure that incorporates elements of “community response” programs that several U.S. states have implemented in recent years. Such programs are focused on families that have been reported to, and sometimes investigated by, CPS, but no ongoing CPS case is opened. We further argue that such programs need to pay particular attention to economic issues that these families face.

BACKGROUND & AIMS: Hypophosphatemia (HypoP) is associated with organ dysfunction and mortality. Despite its potential severe consequences, HypoP remains poorly characterized in terms of real prevalence and timing of onset. The primary objective was to determine the prevalence of HypoP defined as blood phosphate

Background or objectives Breast cancer is the most frequent cancer in women. Chronic pain following mastectomy remains a significant problem. This study aimed to evaluate risk factors associated with postoperative chronic pain. Methods Medical records were analyzed retrospectively for 147 consecutive patients with breast cancer who underwent mastectomy between July 2016 and February 2018 with one-year follow-up. All patients received a paravertebral block pre-operatively and then general anesthesia for the surgery. Results The median postoperative pain score was 1.3 on the verbal analgesic score. The average total dose of opioids administered postoperatively was 10.4 mg, expressed in morphine milligram equivalents. The incidence of chronic pain after mastectomy was 16.7% at 6 months and 13.3% at 1 year. The satisfaction rate for anesthesia and surgery was 95.7%. Conclusions The data suggested that preoperative paravertebral nerve blocks, appropriate adjuvants, and a balanced general anesthetic may contribute to better postoperative pain control and decreased the incidence of chronic pain. A history of preoperative use of opioids and/or a history of alcohol consumption were both associated with significant increased levels of postoperative pain, and this subgroup warrants attention to diminish the risk of developing chronic pain.

Separation anxiety is one of the most commonly diagnosed behavioral disorders in domestic dogs and a principal reason for relinquishment of dogs to animal shelters. While pharmacologic and behavioral interventions can be effective in treating this disorder, they require a significant investment of time and effort on the part of the owner to be successful. Failures in compliance are frequent. In this case report, a mixed-breed dog presented with hyper-attachment to the owner and severe separation anxiety that was poorly responsive to pharmacologic and behavior-modification treatment. While continuing the pharmacologic treatment, the dog was provided a novel behavioral intervention. This intervention relied on a newly developed device consisting of machine learning–enabled computer vision and a positive reinforcement mechanism, which was used as part of a counter-conditioning and desensitization program in both the owner's presence and, subsequently, absence. This treatment was able to significantly reduce the signs of separation anxiety within 12 weeks of therapy, allowing the dog's owner to leave her apartment for 30 minutes without the dog showing any signs of separation anxiety. Interactive devices that present cognitive challenges requiring engagement may provide a valuable tool for addressing separation distress in dogs.

Objective: Evidence is scant regarding symptom clusters and quality of life (QOL) over 1 year in women who receive adjuvant breast cancer chemotherapy (CTX). Our purpose was to identify the prevalence and severity of individual symptoms, symptom clusters, and QOL in women receiving adjuvant breast cancer CTX from baseline over 1 year. Methods: Symptoms were identified in a sample (n = 219) at three times: baseline (prior to the first adjuvant CTX treatment), 1 month after the last CTX (approximately 6 months after baseline), and 1 year after baseline. The Hospital Anxiety and Depression Scale and Symptom Experience Scale measured symptoms. The Medical Outcomes Study, Short-Form Survey, measured QOL. Exploratory factor analysis identified symptom clusters at each time and core symptoms in clusters over time. Results: The prevalence and severity of 10 symptoms decreased over time (P < 0.05). Fatigue, sleep disturbance, and pain were most prevalent; all were of mild severity. Two symptom clusters were identified at baseline and one met internal consistency reliability criteria at the later times. Core symptoms were identified. Both the physical and mental component scores of QOL improved over time (P < 0.01), but physical was below the general population norms 1 year after baseline. Conclusions: The symptom experience was dynamic, and symptom clusters changed over 1 year. Despite mild severity, core symptoms and clusters persisted over 1 year, and physical health was below the general population norms. Breast cancer survivors with persistent single and co-occurring symptoms need to be taught to manage the patterns of symptoms over time because they may not resolve by 1 year.

Acute mountain sickness (AMS) is a syndrome of nonspecific symptoms (i.e., headache, anorexia, nausea, vomiting, dizziness, and fatigue) that may develop in nonacclimatized individuals after rapid exposure to altitudes ≥2,500 m. In field studies, mean AMS scores usually peak after the first night at a new altitude. Analyses of the individual time courses of AMS in four studies performed at 3,450 m and 4,559 m revealed that three different patterns are hidden in the above-described overall picture. In 41% of those who developed AMS (i.e., AMS-C score >0.70), symptoms peaked on day 1, in 39%, symptoms were most prominent on day 2, and in 20%, symptoms were most prominent on day 3. We suggest to name the different time courses of AMS type I, type II, and type III, respectively. Here, we hypothesize that the variation of time courses of AMS are caused by different pathophysiological mechanisms. This assumption could explain why no consistent correlations between an overall assessment of AMS and single pathophysiological factors have been found in a large number of studies over the past 50 yr. In this paper, we will briefly review the fundamental mechanisms implicated in the pathophysiology of AMS and discuss how they might contribute to the three different AMS time courses.

Background & Aims We aimed to compare the incidence of aerodigestive cancers in persons with negative results from colonoscopies and positive vs negative results from multitarget stool DNA tests for colorectal cancer and vs expected incidence. Methods We performed a retrospective cohort study of 1216 subjects with comprehensive patient records and/or cancer registry data from 3 medical centers in North America. Subjects had no neoplasia or only nonadvanced adenomas, based on screening colonoscopy, and either negative results (concordant with colonoscopy, n = 1011) or positive results (discordant colonoscopy, n = 205) from the multitarget stool DNA test. Outcomes included aerodigestive cancers in discordant vs concordant groups and comparison of observed aerodigestive cancer incidence between the groups and compared with expected incidence for the population, based on the Surveillance, Epidemiology, and End Results (SEER) data. Results Median follow-up times were comparable between subjects in the discordant (5.3 y; interquartile range, 3.5–5.8 y) and concordant (5.4 y; interquartile range, 3.7–5.8 y) groups. Aerodigestive cancers developed in 5 subjects in the discordant group vs 11 subjects in the concordant group (crude risk ratio, 2.3; 95% CI, 0.8–6.6; adjusted risk ratio, 2.2; 95% CI, 0.8–6.2; P = .151). The incidence of aerodigestive cancer was lower in the concordant group than the expected incidence based on SEER data (risk ratio, 0.4; 95% CI, 0.2–0.6; P = .0008). The incidence of aerodigestive cancer was not significantly greater in the population in the discordant group than the expected incidence based on SEER data (risk ratio, 0.8; 95% CI, 0.3–1.9; P = .599). Conclusions In a retrospective study with a median follow-up time of 5.4 years, incident aerodigestive cancers were uncommon among subjects with negative findings from colonoscopies, regardless of discordant or concordant results from multitarget stool DNA tests. Patients with negative results from high-quality colonoscopies therefore should not undergo further testing.

To examine if selected demographic (age, gender), clinical (diabetes, coronary artery disease, hyperlipidemia, myocardial infarction, stroke, lung disease, smoking history, alcohol intake), and biomarker [blood pressure (BP), heart rate, body mass index (BMI), neck circumference, Mallampati score] variables are predictors of apnea-hypopnea index (AHI) from polysomnography (PSG). This cross-sectional study recruited a sample of adults (N = 170) who were being evaluated for OSA. Participants completed self-reported demographic and clinical questionnaires, and then completed PSG (n = 142). Multi-collinearity was assessed. Confounding factors, correlations, and potential interactions were explored. The final regression model was performed on 130 participants; 61 (46.9%) had an AHI ≥ 15. Systolic and diastolic BPs were highly correlated. Interactions were tested between gender and other variables (high cholesterol, BMI, neck circumference, systolic BP) and between systolic BP and other variables (high cholesterol, BMI, neck circumference, and lung disease). No interactions occurred between gender or systolic BP and other variables, meaning that the effects of the variables on AHI levels from PSG did not vary depending on gender or systolic BP. BMI, systolic BP, and absence of lung disease were predictors for AHI levels ≥ 15 from PSG. BMI and systolic BP were significant predictors of OSA in this study. The absence of lung disease as a significant predictor was unique and may be due to the small number of participants who self-reported lung disease. To our knowledge, this is the first study to report this combination of variables to predict AHI levels ≥ 15 from PSG.

Purpose Ascent to high altitude increases right ventricular (RV) afterload and decreases myocardial energy supply. This study evaluates physiologic variables and comprehensive echocardiographic indices of RV and right atrial (RA) function following rapid ascent to high altitude. Methods Fifty healthy volunteers actively ascended from 1130 to 4559 m in Results sPAP increased from baseline (24 ± 4 mmHg) to the first altitude examination (39 ± 8 mmHg, p p = 0.07) secondary to a significant increase of RA contraction strain (19.2 ± 6.4 vs. 25.4 ± 9.6%, p Conclusion Active and rapid ascent of healthy individuals to 4559 m is associated with an increased contractile performance of the RA that compensates for the increased workload of the RV.

Experiments and modeling were performed to determine the surface kinetics of gaseous hydrogen chloride (HCl) with aluminum surfaces subjected to various treatments. HCl and other acid gases are a s...

Purpose of review Mitochondrial dysfunction seems to be the common denominator of several critical care conditions and particularly of sepsis. Faced with relative failure, and limited progress of sepsis therapies aiming at blocking some oxidative and/or inflammatory pathways, the question of antioxidants micronutrient therapy, particularly of selenium, ascorbic acid and thiamine remains open. Recent findings The rationale for the essentiality of numerous micronutrients within the mitochondria is well established. Many studies have tested single micronutrients in animal and in-vitro models and provide positive evidences in favor of reduction of organ failure (cardiac and renal mainly). In clinical settings, high-dose selenium administration in sepsis has been disappointing. The most recent high dose, short-term ascorbic acid trial in sepsis is promising though, with an associated reduction of mortality, but analysis of the impact of this intervention on the various organs remains to be conducted. Summary Results from animal and human studies indicate that there are indeed intervention options at the level of the mitochondria, but neither the optimal dose nor the optimal combination of micronutrients is yet identified.

OBJECTIVES: Multitarget stool DNA (MT-sDNA) testing has grown as a noninvasive screening modality for colorectal cancer (CRC), but real-world clinical data are limited in the post-FDA approval setting. The effect of previous colonoscopy on MT-sDNA performance is not known. We aimed to evaluate findings of colorectal neoplasia (CRN) at diagnostic colonoscopy in patients with positive MT-sDNA testing, stratified by patient exposure to previous colonoscopy. METHODS: We identified consecutive patients completing MT-sDNA testing over a 39-month period and reviewed the records of those with positive tests for neoplastic findings at diagnostic colonoscopy. MT-sDNA test positivity rate, adherence to diagnostic colonoscopy, and the positive predictive value (PPV) of MT-sDNA for any CRN and neoplastic subtypes were calculated. RESULTS: Of 16,469 MT-sDNA tests completed, testing returned positive in 2,326 (14.1%) patients. After exclusion of patients at increased risk for CRC, 1,801 patients remained, 1,558 (87%) of whom underwent diagnostic colonoscopy; 918 of 1,558 (59%) of these patients had undergone previous colonoscopy, whereas 640 (41%) had not. Any CRN was found in 1,046 of 1,558 patients (PPV = 67%). More neoplastic lesions were found in patients without previous colonoscopy (73%); however, the rates remained high among those who had undergone previous colonoscopy (63%, P < 0.0001). The large majority (79%) of patients had right-sided neoplasia. DISCUSSION: MT-sDNA has a high PPV for any CRN regardless of exposure to previous colonoscopy. Right-sided CRN was found at colonoscopy in most patients with positive MT-sDNA testing, representing a potential advantage over other currently available screening modalities for CRC.

Objective To determine cross-sectional adherence with the multi-target stool DNA test used for colorectal cancer screening in a large, fully insured Medicare population. Methods All patients aged 65–85 with a valid multi-target stool DNA test order from 1 September 2016 to 31 August 2017 identified from the Exact Sciences Laboratories (Madison, WI; sole-source national multi-target stool DNA test provider) database were evaluated for test adherence. Cross-sectional adherence, defined as multi-target stool DNA test completion within 365 days from order date, was analyzed overall and by time to adherence, as well as by available patient (age, sex, test order date, Medicare coverage type) and provider (specialty, year of first multi-target stool DNA test order, multi-target stool DNA test order frequency, and practice location) factors. Results Among 368,494 Medicare beneficiaries (64% female), overall cross-sectional adherence was 71%. Cumulative adherence rates increased more rapidly at 30 (44%) and 60 (65%) days, followed by more gradual increases at 90 (67%), 180 (70%), and 365 (71%) days. By provider specialty, primary care clinicians represented a higher percentage of multi-target stool DNA orders than gastroenterologists (88% vs. 6%), but had a lower associated patient adherence rate (71% vs. 78%). Conclusions In this large, national sample of Medicare insured older adults, nearly three-quarters of patients adhered with a multi-target stool DNA order for colorectal cancer screening. These real-world data should inform further clinical and population health applications, reimbursement model simulations, and guideline-endorsed colorectal cancer screening strategies adherence.

Background Beginning in 2014-2015, schools nationwide have had the option of offering free meals to all students in qualifying schools through the Community Eligibility Provision (CEP). The CEP has been linked to greater likelihood of eating school meals, but little is known about its impact on broader outcomes. Objective The purpose of this study was to estimate the association between the CEP and school attendance among elementary school students (grades 1 to 5). Design This was a quasi-experimental study in which students’ attendance records were observed over 1 baseline and 2 follow-up years in a sample of CEP and eligible non-CEP schools. Participants/setting The participants were elementary school students in Wisconsin during three consecutive school years beginning 2013-2014. The main sample included 92,126 observation-years for students in 37 CEP and 108 eligible non-CEP elementary schools. Intervention CEP-participating schools offered breakfast and lunch free to all students through the School Breakfast Program and the National School Lunch Program beginning in 2014-2015. Main outcome measures The outcome measures were the attendance rate (defined as the percentage of school days attended) and low attendance (defined as attending fewer than 95% of available days) during the first and second implementation years. Statistical analyses performed Difference-in-difference regression models with student fixed effects were estimated, with separate impacts for the first and second CEP years. Models adjusted for time-varying school and student characteristics. Results Implementing the CEP had no association with attendance in the initial year. The second year of CEP was associated with a 3.5 percentage point reduction in the percentage of students with low attendance (P=0.045). An association between CEP and attendance was only found for economically disadvantaged students. Conclusions Offering meals free to all students through the CEP may modestly reduce the risk of low attendance among economically disadvantaged students in participating schools.

Negative supercoiling by DNA gyrase is essential for maintaining chromosomal compaction, transcriptional programming, and genetic integrity in bacteria. Questions remain as to how gyrases from different species have evolved profound differences in their kinetics, efficiency, and extent of negative supercoiling. To explore this issue, we analyzed homology-directed mutations in the C-terminal, DNA-wrapping domain of the GyrA subunit of Escherichia coli gyrase (the ‘CTD’). The addition or removal of select, conserved basic residues markedly impacts both nucleotide-dependent DNA wrapping and supercoiling by the enzyme. Weakening CTD–DNA interactions slows supercoiling, impairs DNA-dependent ATP hydrolysis, and limits the extent of DNA supercoiling, while simultaneously enhancing decatenation and supercoil relaxation. Conversely, strengthening DNA wrapping does not result in a more extensively supercoiled DNA product, but partially uncouples ATP turnover from strand passage, manifesting in futile cycling. Our findings indicate that the catalytic cycle of E. coli gyrase operates at high thermodynamic efficiency, and that the stability of DNA wrapping by the CTD provides one limit to DNA supercoil introduction, beyond which strand passage competes with ATP-dependent supercoil relaxation. These results highlight a means by which gyrase can evolve distinct homeostatic supercoiling setpoints in a species-specific manner.