Health Care Utilization and Clinical Management of All-Cause and Norovirus-Associated Acute Gastroenteritis Within a US Integrated Health Care System.

Background: Norovirus-associated acute gastroenteritis (AGE) exacts a substantial disease burden, yet the health care utilization for and clinical management of norovirus-associated AGE are not well characterized. Methods: We describe the health care encounters and therapeutics used for patients with all-cause and norovirus-associated AGE in the Kaiser Permanente Northwest health system from 1 April 2014 through 30 September 2016. Medical encounters for patients with AGE were extracted from electronic health records, and encounters within 30 days of one another were grouped into single episodes. An age-stratified random sample of patients completed surveys and provided stool samples for norovirus testing. Results: In total, 40 348 individuals had 52 509 AGE episodes; 460 (14%) of 3310 participants in the substudy tested positive for norovirus. An overall 35% of all-cause AGE episodes and 29% of norovirus-associated AGE episodes had ≥2 encounters. While 80% of norovirus-associated AGE episodes had at least 1 encounter in the outpatient setting, all levels of the health care system were affected: 10%, 22%, 10%, and 2% of norovirus-associated AGE episodes had at least 1 encounter in virtual, urgent care, emergency department, and inpatient settings, respectively. Corresponding proportions of therapeutic use between norovirus-positive and norovirus-negative episodes were 13% and 10% for intravenous hydration (P = .07), 65% and 50% for oral rehydration (P < .001), 7% and 14% for empiric antibiotic therapy (P < .001), and 33% and 18% for antiemetics (P < .001). Conclusions: Increased health care utilization and therapeutics are likely needed for norovirus-associated AGE episodes during peak norovirus winter seasons, and these data illustrate that effective norovirus vaccines will likely result in less health care utilization.

Methodological Considerations for Investigating Iron Status and Regulation in Exercise and Sport Science Studies.

Iron deficiency is a common health issue in active and athlete populations. Accordingly, research into iron status, regulation, absorption, and iron deficiency treatment strategies is increasing at a rapid rate. However, despite the increase in the quantity of research, various methodological issues need to be addressed as we progress our knowledge in this area. The purpose of this review is to highlight specific considerations for conducting iron-related research in active and athlete populations. First, we discuss the methodological importance of assessment and interpretation of iron status, with reference to blood collection protocols, participant screening procedures, and biomarker selection. Next, we consider numerous variables that should be accounted for in the design of iron-related research studies, such as the iron regulatory hormone hepcidin and its interaction with exercise, in addition to an examination of female physiology and its impact on iron metabolism. Subsequently, we explore dietary iron and nutrient interactions that impact iron regulation and absorption, with recommendations made for optimal methodological control. Consideration is then given to key features of long-term study designs, such as the monitoring of training load, oral iron supplementation, dietary analysis, and general lifestyle factors. Finally, we conclude our recommendations with an exploration of stable iron isotope tracers as a methodology to measure iron absorption. Ultimately, it is our intention that this review can be used as a guide to improve study design, biomarker analysis, and reporting of findings, to maximize the quality of future research outputs in iron-related research focused on active and athlete populations.

Neither Beetroot Juice Supplementation nor Increased Carbohydrate Oxidation Enhance Economy of Prolonged Exercise in Elite Race Walkers.

Given the importance of exercise economy to endurance performance, we implemented two strategies purported to reduce the oxygen cost of exercise within a 4 week training camp in 21 elite male race walkers. Fourteen athletes undertook a crossover investigation with beetroot juice (BRJ) or placebo (PLA) [2 d preload, 2 h pre-exercise + 35 min during exercise] during a 26 km race walking at speeds simulating competitive events. Separately, 19 athletes undertook a parallel group investigation of a multi-pronged strategy (MAX; n = 9) involving chronic (2 w high carbohydrate [CHO] diet + gut training) and acute (CHO loading + 90 g/h CHO during exercise) strategies to promote endogenous and exogenous CHO availability, compared with strategies reflecting lower ranges of current guidelines (CON; n = 10). There were no differences between BRJ and PLA trials for rates of CHO (p = 0.203) or fat (p = 0.818) oxidation or oxygen consumption (p = 0.090). Compared with CON, MAX was associated with higher rates of CHO oxidation during exercise, with increased exogenous CHO use (CON; peak = ~0.45 g/min; MAX: peak = ~1.45 g/min, p < 0.001). High rates of exogenous CHO use were achieved prior to gut training, without further improvement, suggesting that elite athletes already optimise intestinal CHO absorption via habitual practices. No differences in exercise economy were detected despite small differences in substrate use. Future studies should investigate the impact of these strategies on sub-elite athletes' economy as well as the performance effects in elite groups.

Development of a Clinical Global Impression of Change (CGI-C) and a Caregiver Global Impression of Change (CaGI-C) measure for ambulant individuals with Duchenne muscular dystrophy.

BACKGROUND: In clinical trials for rare diseases, such as Duchenne muscular dystrophy, clinical outcome assessments (COA) used to assess treatment benefit are often generic and may not be sensitive enough to detect change in specific patient populations. Thus, there is a need for disease specific COAs that track meaningful change among individuals. When developing such measures, input from clinicians, caregivers and patients is critical for assessing clinically relevant concepts and ensuring validity of the measure. METHOD: The aim of this study was to develop two Duchenne-specific global impression items for use in clinical trials. The development of the Duchenne Clinical Global Impression of Change (CGI-C) and Caregiver Global Impression of Change (CaGI-C) was informed by findings from concept elicitation (CE) interviews with clinicians, caregivers and individuals with Duchenne. Through cognitive debriefing (CD) interviews, clinicians and caregivers evaluated draft CGI-C and CaGI-C items to ensure relevance and understanding of the items and instructions. Suggestions made during the CD interviews were incorporated into the finalized CGI-C and CaGI-C measures. RESULTS: The symptoms most frequently reported by clinicians, caregivers and individuals with Duchenne were muscle weakness, fatigue, cardiac difficulties and pain. Regarding physical functioning, all three populations noted that small changes in functional ability were meaningful, particularly when independence was impacted. Caregivers and clinicians reported that changes in speed, endurance and quality of movement were important, as was improvement in the ability of individuals to keep up with their peers. A change in the ability to complete everyday activities was also significant to families. These results were used to create two global impression of change items and instruction documents for use by clinicians (CGI-C) and caregivers (CaGI-C). Overall, both items were well understood by participants. The descriptions and examples developed from the CE interviews were reported to be relevant and appropriate for illustrating different levels of meaningful change in patients with Duchenne. Modifications were made based on caregiver and clinician CD feedback . CONCLUSIONS: As part of a holistic measurement strategy, such COA can be incorporated into the clinical trial setting to assess global changes in relevant symptoms and functional impacts associated with Duchenne.

Acute Ketogenic Diet and Ketone Ester Supplementation Impairs Race Walk Performance.

PURPOSE: This study aimed to determine if LCHF and ketone ester (KE) supplementation can synergistically alter exercise metabolism and improve performance. METHODS: Elite race walkers (n = 18, 15 males and 3 females; V˙O2peak, 62 ± 6 mL·min-1·kg-1) undertook a four-stage exercise economy test and real-life 10,000-m race before and after a 5-d isoenergetic high-CHO (HCHO, ~60%-65% fat; CHO, 20% fat; n = 9) or LCHF (75%-80% fat, <50 g·d-1 CHO, n = 9) diet. The LCHF group performed additional economy tests before and after diet after supplementation with 573 mg·kg-1 body mass KE (HVMN; HVMN Inc., San Francisco, CA), which was also consumed for race 2. RESULTS: The oxygen cost of exercise (relative V˙O2, mL·min-1·kg-1) increased across all four stages after LCHF (P < 0.005). This occurred in association with increased fat oxidation rates, with a reciprocal decrease in CHO oxidation (P < 0.001). Substrate utilization in the HCHO group remained unaltered. The consumption of KE before the LCHF diet increased circulating KB (P < 0.05), peaking at 3.2 ± 0.6 mM, but did not alter V˙O2 or RER. LCHF diet elevated resting circulating KB (0.3 ± 0.1 vs 0.1 ± 0.1 mM), but concentrations after supplementation did not differ from the earlier ketone trial. Critically, race performance was impaired by ~6% (P < 0.0001) relative to baseline in the LCHF group but was unaltered in HCHO. CONCLUSION: Despite elevating endogenous KB production, an LCHF diet does not augment the metabolic responses to KE supplementation and negatively affects race performance.

Nutrition and Altitude: Strategies to Enhance Adaptation, Improve Performance and Maintain Health: A Narrative Review.

Training at low to moderate altitudes (~ 1600-2400 m) is a common approach used by endurance athletes to provide a distinctive environmental stressor to augment training stimulus in the anticipation of increasing subsequent altitude- and sea-level-based performance. Despite some scientific progress being made on the impact of various nutrition-related changes in physiology and associated interventions at mountaineering altitudes (> 3000 m), the impact of nutrition and/or supplements on further optimization of these hypoxic adaptations at low-moderate altitudes is only an emerging topic. Within this narrative review we have highlighted six major themes involving nutrition: altered energy availability, iron, carbohydrate, hydration, antioxidant requirements and various performance supplements. Of these issues, emerging data suggest that particular attention be given to the potential risk for poor energy availability and increased iron requirements at the altitudes typical of elite athlete training (~ 1600-2400 m) to interfere with optimal adaptations. Furthermore, the safest way to address the possible increase in oxidative stress associated with altitude exposure is via the consumption of antioxidant-rich foods rather than high-dose antioxidant supplements. Meanwhile, many other important questions regarding nutrition and altitude training remain to be answered. At the elite level of sport where the differences between winning and losing are incredibly small, the strategic use of nutritional interventions to enhance the adaptations to altitude training provides an important consideration in the search for optimal performance.

Single versus Split Dose of Iron Optimizes Hemoglobin Mass Gains at 2106 m Altitude.

PURPOSE: To determine if a single versus a split equivalent daily dose of elemental iron was superior for hemoglobin mass (Hbmass) gains at altitude while minimizing gastrointestinal (GI) discomfort. METHODS: Twenty-four elite runners attended a 3.1 ± 0.3 wk training camp (Flagstaff, AZ; 2106 m). A two-group design, randomized and stratified to baseline Hbmass, sex, and ferritin (>30 µ·L), was implemented daily as: 1) single dose of 1 × 200 mg (PM only, SINGLE) versus 2) split dose of 2 × 100 mg (AM and PM; SPLIT) elemental iron (ferrous fumarate). The Hbmass and venipuncture assessments were completed upon arrival and departure (±2 d) from camp for ferritin, hepcidin, and erythroferrone (ERFE) concentrations. Validated food frequency, GI distress, menstrual blood loss (MBL) and training questionnaires were implemented throughout. Univariate analysis was used to compare Hbmass, with baseline ferritin, dietary iron intake, MBL, and training volume used as covariates. RESULTS: Both conditions increased Hbmass from baseline (P < 0.05), with SINGLE (867.3 ± 47.9 g) significantly higher than SPLIT (828.9 ± 48.9 g) (P = 0.048). The GI scores were worse in SINGLE for weeks 1 and 2 combined (SINGLE, 18.0 ± 6.7 points; SPLIT, 11.3 ± 6.9 points; P = 0.025); however, GI scores improved by week 3, resulting in no between-group differences (P = 0.335). Hepcidin significantly decreased over time (P = 0.043) in SINGLE, with a nonsignificant decrease evident in SPLIT (~22%). ERFE significantly decreased in both groups (~28.5%; P < 0.05). No between-group differences existed for ERFE, hepcidin, food frequency, MBL, or daily training outcomes (P > 0.05). CONCLUSIONS: A single nightly 200-mg dose of elemental iron was superior to a split dose for optimizing Hbmass changes at altitude in runners over an approximately 3-wk training camp.

Novel cell-based in vitro screen to identify small-molecule inhibitors against intracellular replication of Cryptococcus neoformans in macrophages.

The fungal pathogen Cryptococcus neoformans poses a major threat to immunocompromised patients and is a leading killer of human immunodeficiency virus (HIV)-infected patients worldwide. Cryptococci are known to manipulate host macrophages and can either remain latent or proliferate intracellularly within the host phagocyte, a favourable niche that also renders them relatively insensitive to antifungal agents. Here we report an attempt to address this limitation by using a fluorescence-based drug screening method to identify potential inhibitors of intracellular proliferation of C. neoformans. The Prestwick Chemical Library(®) of FDA-approved small molecules was screened for compounds that limit the intracellular replication of a fluorescently-tagged C. neoformans reference strain (H99-GFP) in macrophages. Preliminary screening revealed 19 of 1200 compounds that could significantly reduce intracellular growth of the pathogen. Secondary screening and host cell cytotoxicity assays highlighted fendiline hydrochloride as a potential drug candidate for the development of future anticryptococcal therapies. Live cell imaging demonstrated that this Ca(2+) channel blocker strongly enhanced phagosome maturation in macrophages leading to improved fungal killing and reduced intracellular replication. Whilst the relatively high dose of fendiline hydrochloride required renders it unfit for clinical deployment against cryptococcosis, this study highlights a novel approach for identifying new lead compounds and unravels a pharmacologically promising scaffold towards the development of novel antifungal therapies for this neglected disease.

Training speech-in-noise perception in mainstream school children.

OBJECTIVE: Auditory training has been advocated as a management strategy for children with hearing, listening or language difficulties. Because poor speech-in-noise perception is commonly reported, previous research has focused on the use of complex (word/sentence) stimuli as auditory training material to improve sentence-in-noise perception. However, some evidence suggests that engagement with the training stimuli is more important than the type of stimuli used for training. The aim of this experiment was to assess if sentence-in-noise perception could be improved using simpler auditory training stimuli. METHODS: We recruited 41 typically developing, normal-hearing children aged 8-10 years divided into four groups. Groups 1-3 trained over 4 weeks (12 × 30 min sessions) on either: (1) pure-tone frequency discrimination (FD), (2) FD in a modulated noise (FDN) or, (3) mono-syllabic words in a modulated noise (WN). Group 4 was an untrained Control. In the training tasks, either tone frequency (Group 1), or tone (Group 2) or speech (Group 3) level was varied adaptively. All children completed pre- and post-training tests of sentence perception in modulated (SMN) and unmodulated (SUN) noise and a probe measure of each training task. RESULTS: All trained groups improved significantly on the trained tasks. Transfer of training occurred between FDN training and FD, WN and SMN testing, and between WN training and SMN testing. A significant performance suppression on the SUN test resulted from FD and FDN training. CONCLUSION: The pattern of training-induced improvement, relative to Controls, suggests that transfer of training is more likely when some stimulus dimensions (tone frequency, speech, modulated noise) are shared between training tasks and outcomes. This and the finding of suppressed post-training performance, relative to Controls, between tasks not sharing a stimulus dimension both favour the use of outcome-specific material for auditory training.