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To describe effects of the COVID-19 pandemic on older adults living in non-institutionalized settings in New York City (NYC) we used random digit dial sampling of landlines phones to sample then interview residents 70 years and older in NYC from December 2020–March 2021. Socio-demographic, health characteristics and effects of the COVID-19 pandemic were solicited. Of 676 respondents, the average age was 78, 60% were female, and 63% had ever been tested for SARS-CoV-2, with 12% testing positive. Sixty-three percent of respondents knew someone who had been diagnosed with COVID-19 and 51% reported knowing at least one person who had died from COVID-19. Eight percent of respondents reported sometimes or often not having enough to eat, with 31% receiving food from a food pantry program. Significantly more Latinx respondents (24%) reported a positive SARS-CoV-2 test, whereas 17% of those of another race, 8% of white, and 7% of Black respondents had a positive COVID-19 test (p

The potential of artificial intelligence (AI) applied to clinical data from electronic health records (EHRs) to improve early detection for pancreatic and other cancers remains underexplored. The Kenner Family Research Fund, in collaboration with the Cancer Biomarker Research Group at the National Cancer Institute, organized the workshop entitled: “Early Detection of Pancreatic Cancer: Opportunities and Challenges in Utilizing Electronic Health Records (EHR)” in March 2021. The workshop included a select group of panelists with expertise in pancreatic cancer, EHR data mining, and AI-based modeling. This review article reflects the findings from the workshop and assesses the feasibility of AI-based data extraction and modeling applied to EHRs. It highlights the increasing role of data sharing networks and common data models in improving the secondary use of EHR data. Current efforts using EHR data for AI-based modeling to enhance early detection of pancreatic cancer show promise. Specific challenges (biology, limited data, standards, compatibility, legal, quality, AI chasm, incentives) are identified, with mitigation strategies summarized and next steps identified.

Background Iatrogenic Cushing’s syndrome induced by oral and parenteral glucocorticoid administration is a well-known complication. Immediate withdrawal from exogenous steroids can lead to life-threatening adrenal insufficiency. However, Cushing’s syndrome caused by topical treatment with glucocorticoids, such as dexamethasone eye drops or dermal application, is rarely recognized. Young infants in particular are at high risk of suffering from iatrogenic Cushing’s syndrome when treated with highly potent topical glucocorticoids. Case presentation We present a 6-month-old Syrian boy with cushingoid face after dermal clobetasol cream treatment and a 2-year-old Iranian girl with severe growth retardation after application of dexamethasone eye drops. Both families have a migration background and language barriers. In both cases no endogenous cortisol secretion was initially detected in serum and in 24-hour collected urine. After dose reduction of glucocorticoids, severity of symptoms was reversible and serum cortisol was detectable. Discussion and conclusion Young infants are at high risk of developing Cushing’s syndrome from topically applied highly potent glucocorticoids. Precise recommendations of treatment dosage, duration, and frequency must be given to the parents, and if necessary, with the help of an interpreter. Monitoring of height and weight as well as regular pediatric follow-ups should be scheduled. Physicians should be aware of potential adrenal insufficiency following withdrawal from long-term topical glucocorticoid treatment, and hydrocortisone treatment should be considered.

Total daily energy expenditure (“total expenditure”, MJ/d) reflects daily energy needs and is a critical variable in human health and physiology, yet it is unclear how daily expenditure changes over the life course. Here, we analyze a large, globally diverse database of total expenditure measured by the doubly labeled water method for males and females aged 8 days to 95 yr. We show that total expenditure is strongly related to fat free mass in a power-law manner and identify four distinct metabolic life stages. Fat free mass-adjusted daily expenditure accelerates rapidly in neonates (0-1yr) to ~46% above adult values at ~1 yr, declines slowly throughout childhood and adolescence (1-20 yr) to adult levels at ~20 yr, remains stable in adulthood (20-60 yr) even during pregnancy, and declines in older adults (60+ yr). These changes in total expenditure shed new light on human development and aging and should help shape nutrition and health strategies across the lifespan.

BACKGROUND HIV population viral load (PVL) can reflect antiretroviral therapy program effectiveness and transmission potential in a community. Using nationally representative data from household surveys conducted in Zimbabwe, Malawi, and Zambia in 2015-16, we examined the association between various VL measures and the probability of at least one recent HIV-1 infection in the community. METHODS We used limiting-antigen avidity enzyme immunoassay, viral load suppression (VLS) (HIV RNA

Background The population-based HIV impact assessment (population-based HIV impact assessments) surveys are among the first to estimate national adult HIV incidence, subnational prevalence of viral load suppression, and pediatric HIV prevalence. We summarize the survey methods implemented in Zimbabwe, Malawi, and Zambia, as well as response rates and quality metrics. Methods Each cross-sectional, household-based survey used a 2-stage cluster design. Survey preparations included sample design, questionnaire development, tablet programming for informed consent and data collection, community mobilization, establishing a network of satellite laboratories, and fieldworker training. Interviewers collected demographic, behavioral, and clinical information using tablets. Blood was collected for home-based HIV testing and counseling (HBTC) and point-of-care CD4+ T-cell enumeration with results immediately returned. HIV-positive blood samples underwent laboratory-based confirmatory testing, HIV incidence testing, RNA polymerase chain reaction (viral load), DNA polymerase chain reaction (early infant diagnosis), and serum antiretroviral drug detection. Data were weighted for survey design, and chi square automatic interaction detection-based methods were used to adjust for nonresponse. Results Each survey recruited a nationally representative, household-based sample of children and adults over a 6-10-month period in 2015 and 2016. Most (84%-90%) of the 12,000-14,000 eligible households in each country participated in the survey, with 77%-81% of eligible adults completing an interview and providing blood for HIV testing. Among eligible children, 59%-73% completed HIV testing. Across the 3 surveys, 97.8% of interview data were complete and had no errors. Conclusion Conducting a national population-based HIV impact assessment with immediate return of HIV and other point-of-care test results was feasible, and data quality was high.

Achieving optimal HIV outcomes, as measured by global 90-90-90 targets, that is awareness of HIV-positive status, receipt of antiretroviral (ARV) therapy among aware and viral load (VL) suppression among those on ARVs, respectively, is critical. However, few data from sub-Saharan Africa (SSA) are available on older people (50+) living with HIV (OPLWH). We examined 90-90-90 progress by age, 15-49 (as a comparison) and 50+ years, with further analyses among 50+ (55-59, 60-64, 65+ vs. 50-54), in 13 countries (Cameroon, Cote d'Ivoire, Eswatini, Ethiopia, Kenya, Lesotho, Malawi, Namibia, Rwanda, Tanzania, Uganda, Zambia and Zimbabwe).Using data from nationally representative Population-based HIV Impact Assessments, conducted between 2015and 2019, participants from randomly selected households provided demographic and clinical information and whole blood specimens for HIV serology, VL and ARV testing. Survey weighted outcomes were estimated for 90-90-90 targets. Country-specific Poisson regression models examined 90-90-90 variation among OPLWH age strata.Analyses included 24,826 HIV-positive individuals (15-49 years: 20,170; 50+ years: 4656). The first, second and third 90 outcomes were achieved in 1, 10 and 5 countries, respectively, by those aged 15-49, while OPLWH achieved outcomes in 3, 13 and 12 countries, respectively. Among those aged 15-49, women were more likely to achieve 90-90-90 targets than men; however, among OPLWH, men were more likely to achieve first and third 90 targets than women, with second 90 achievement being equivalent. Country-specific 90-90-90 regression models among OPLWH demonstrated minimal variation by age stratum across 13 countries. Among OLPWH, no first 90 target differences were noted by age strata; three countries varied in the second 90 by older age strata but not in a consistent direction; one country showed higher achievement of the third 90 in an older age stratum.While OPLWH in these 13 countries were slightly more likely than younger people to be aware of their HIV-positive status (first 90), this target was not achieved in most countries. However, OPLWH achieved treatment (second 90) and VL suppression (third 90) targets in more countries than PLWH50. Findings support expanded HIV testing, prevention and treatment services to meet ongoing OPLWH health needs in SSA.

International audience; Tuberculosis claims significantly more than one million lives each year. A feasible way to face the issue of drug resistance is the development of new antibiotics. Bacterial uridine 5’-monophosphate (UMP) kinase is a promis- ing target for novel antibiotic discovery as it is essential for bacterial sur- vival and has no counterpart in human cells. The UMP kinase from M. tuberculosis is also a model of particular interest for allosteric regula- tion with two effectors, GTP (positive) and UTP (negative). In this study, using X-ray crystallography and cryo-electron microscopy, we report for the first time a detailed description of the negative effector UTP-binding site of a typical Gram-positive behaving UMP kinase. Comparison between this snapshot of low affinity for Mg-ATP with our previous 3D-structure of the GTP-bound complex of high affinity for Mg-ATP led to a better understanding of the cooperative mechanism and the allosteric regulation of UMP kinase. Thermal shift assay and circular dichroism experiments corroborate our model of an inhibition by UTP linked to higher flexibility of the Mg-ATP-binding domain. These new structural insights provide valuable knowledge for future drug discovery strategies targeting bacterial UMP kinases.

Cell therapy is one of the fastest growing areas in the pharmaceutical industry, with considerable therapeutic potential. However, substantial challenges regarding the utility of these therapies will need to be addressed before they can become mainstream medicines with applicability similar to that of small molecules or monoclonal antibodies. Engineered T cells have achieved success in the treatment of blood cancers, with four chimeric antigen receptor (CAR)-T cell therapies now approved for the treatment of B cell malignancies based on their unprecedented efficacy in clinical trials. However, similar results have not yet been achieved in the treatment of the much larger patient population with solid tumours. For cell therapies to become mainstream medicines, they may need to offer transformational clinical effects for patients and be applicable in disease settings that remain unaddressed by simpler approaches. This Perspective provides an industry perspective on the progress achieved by engineered T cell therapies to date and the opportunities and current barriers for accessing broader patient populations, and discusses the solutions and new development strategies required to fully industrialize the therapeutic potential of engineered T cells as medicines.

Large public-health training events may result in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Universal SARS-CoV-2 testing during trainings for the Uganda Population-based HIV Impact Assessment identified 28 of 475 (5.9%) individuals with coronavirus disease 2019 (COVID-19) among attendees; most (89.3%) were asymptomatic. Until COVID-19 vaccine is readily available for staff and participants, effective COVID-19 mitigation measures, along with SARS-CoV-2 testing, are recommended for in-person trainings, particularly when trainees will have subsequent contact with survey participants.

In mammals, trait variation is often reported to be greater among males than females. However, to date, mainly only morphological traits have been studied. Energy expenditure represents the metabolic costs of multiple physical, physiological, and behavioral traits. Energy expenditure could exhibit particularly high greater male variation through a cumulative effect if those traits mostly exhibit greater male variation, or a lack of greater male variation if many of them do not. Sex differences in energy expenditure variation have been little explored. We analyzed a large database on energy expenditure in adult humans (1494 males and 3108 females) to investigate whether humans have evolved sex differences in the degree of interindividual variation in energy expenditure. We found that, even when statistically comparing males and females of the same age, height, and body composition, there is much more variation in total, activity, and basal energy expenditure among males. However, with aging, variation in total energy expenditure decreases, and because this happens more rapidly in males, the magnitude of greater male variation, though still large, is attenuated in older age groups. Considerably greater male variation in both total and activity energy expenditure could be explained by greater male variation in levels of daily activity. The considerably greater male variation in basal energy expenditure is remarkable and may be explained, at least in part, by greater male variation in the size of energy-demanding organs. If energy expenditure is a trait that is of indirect interest to females when choosing a sexual partner, this would suggest that energy expenditure is under sexual selection. However, we present a novel energetics model demonstrating that it is also possible that females have been under stabilizing selection pressure for an intermediate basal energy expenditure to maximize energy available for reproduction. (C) 2022 The Author(s). Published by Elsevier Ltd.

Low total energy expenditure (TEE, MJ/d) has been a hypothesized risk factor for weight gain, but repeatability of TEE, a critical variable in longitudinal studies of energy balance, is understudied. We examine repeated doubly labeled water (DLW) measurements of TEE in 348 adults and 47 children from the IAEA DLW Database (mean ± SD time interval: 1.9 ± 2.9 y) to assess repeatability of TEE, and to examine if TEE adjusted for age, sex, fat-free mass, and fat mass is associated with changes in weight or body composition. Here, we report that repeatability of TEE is high for adults, but not children. Bivariate Bayesian mixed models show no among or within-individual correlation between body composition (fat mass or percentage) and unadjusted TEE in adults. For adults aged 20–60 y (N = 267; time interval: 7.4 ± 12.2 weeks), increases in adjusted TEE are associated with weight gain but not with changes in body composition; results are similar for subjects with intervals >4 weeks (N = 53; 29.1 ± 12.8 weeks). This suggests low TEE is not a risk factor for, and high TEE is not protective against, weight or body fat gain over the time intervals tested., Low total energy expenditure (TEE) has been a hypothesized risk factor for weight gain, but longitudinal repeatability of TEE is incompletely understood. Here the authors report that TEE is repeatable for adults, but not for children, and increases in TEE (adjusted for fat-free mass, fat mass, age and sex) are not associated with body composition changes in short-term longitudinal analyses.

Publisher Copyright: © 2021 The Authors Understanding the impacts of activity on energy balance is crucial. Increasing levels of activity may bring diminishing returns in energy expenditure because of compensatory responses in non-activity energy expenditures.1–3 This suggestion has profound implications for both the evolution of metabolism and human health. It implies that a long-term increase in activity does not directly translate into an increase in total energy expenditure (TEE) because other components of TEE may decrease in response—energy compensation. We used the largest dataset compiled on adult TEE and basal energy expenditure (BEE) (n = 1,754) of people living normal lives to find that energy compensation by a typical human averages 28% due to reduced BEE; this suggests that only 72% of the extra calories we burn from additional activity translates into extra calories burned that day. Moreover, the degree of energy compensation varied considerably between people of different body compositions. This association between compensation and adiposity could be due to among-individual differences in compensation: people who compensate more may be more likely to accumulate body fat. Alternatively, the process might occur within individuals: as we get fatter, our body might compensate more strongly for the calories burned during activity, making losing fat progressively more difficult. Determining the causality of the relationship between energy compensation and adiposity will be key to improving public health strategies regarding obesity.

Supplemental digital content is available in the text., Objectives Pancreatic cancer (PC) and its treatments can result in pancreatic exocrine insufficiency that requires pancreatic enzyme replacement therapy (PERT). Appropriate PERT usage is during meals and snacks. The aim was to determine the frequency of appropriate use of PERT and its impact on symptom alleviation in PC through a patient-reported outcomes online platform. Methods Users in the Pancreatic Cancer Action Network's Patient Registry were prompted to answer a standalone questionnaire about their experience with PERT. Results Two hundred sixty-two users completed the PERT questionnaire (January 2016–January 2018). Patients who reported taking PERT with meals had higher alleviation of symptoms compared with those taking PERT prior to or after meals. Specifically, “feeling of indigestion,” “light-colored or orange stools,” and “visible food particles in stool” were significantly decreased. Patients taking PERT with meals reported weight gain and less weight loss. Conclusions Of the 89% of PC patients prescribed PERT, 65% were prescribed PERT appropriately with all meals and snacks. Overall compliance with PERT administration guidelines was low (50% [105/208]). Improvement in symptoms significantly correlated with appropriate use of PERT. Increase in PC patient and provider education about appropriate PERT usage and administration is warranted.

Preparticipation screening is important in order to make a statement about an athlete's health. The evaluation includes both an internal medicine/cardiology and an orthopaedic section. In professional team sports, players have to undergo medical screening on an annual basis to obtain their license and be cleared for play. Screening delivers information about the acute health condition of the athlete but only gives an indirect statement on his/her functional status and performance. This gap has been tried to be closed with functional, sports-specific performance testing in the past few years. In the event of future injury, the collected data can be used as a baseline level to monitor the progress in an athlete's rehabilitation process. This provides a huge advantage in the return-to-play diagnosis. Based on the assumption that only a healthy player can perform to the best of his or her ability, we have extended our medical screening for a professional basketball team. Since the 2012/2013 season, a test battery was added with a view to basketball-specific conditioning. The collected data was prospectively correlated to injury occurrence. Seventy-one players were tested in 5 different categories. We have documented 142 injuries which lead to a downtime of 23 days (range 1-347 days). The injuries mainly involved the lower extremity, in particular the ankle, the knee and the thigh muscles. There was a clear trend indicating that players performing weaker in the agility tests sustained more injuries (r = 0.34, p = 0.029). Athletes who performed worse in the Yo-Yo test suffered from significantly more thigh muscle injuries (r = 0.266, p = 0.012). Pre-participation screening is a useful tool in injury prevention, which helps to detect injuries or chronic stress complaints, especially in, but not limited to professional sports. Adding sports-specific performance testing may reveal potential deficits in agility and endurance which could lead to an increased injury risk. In addition, it allows to obtain baseline data which could be used to show the progress in rehabilitation in the event of an injury. Eingangsuntersuchungen sind wichtig, um Aussagen über die Gesundheit treffen zu können. Diese Untersuchungen beinhalten etablierte internistisch-kardiologische Testverfahren sowie eine orthopädische Beurteilung des Bewegungsapparats. In den großen Mannschaftsportarten ist die Lizensierung der Spieler eng an die medizinischen Eingangsuntersuchungen geknüpft. Die vorgeschriebenen Eingangsuntersuchungen bilden jedoch lediglich den aktuellen Gesundheitszustand ab und lassen nur indirekte Aussagen über die Funktions- und Leistungsfähigkeit des Athleten zu. Somit wurde in den letzten Jahren versucht, diese Lücke durch eine Erweiterung in Richtung sportartspezifische Leistungsdiagnostik zu schließen. Sollte sich der Athlet verletzen, können die erhobenen Baseline-Werte als Maßstab genutzt werden, um das Monitoring des Sportlers im Rehabilitationsprozess zu unterstützen und einen sicheren Übergang zurück zum Wettkampf zu begleiten. Dies ist ein entscheidender Vorteil in der Return-to-Play-Diagnostik. Aufgrund der Annahme, dass nur ein gesunder Spieler seine volle Leistungsfähigkeit abrufen kann, wurde von der Saison 2012/2013 für 5 aufeinanderfolgende Spielzeiten im Rahmen der medizinischen Eingangsuntersuchungen zusätzlich die Basketball-spezifische, konditionelle Leistungsfähigkeit der Spieler eines Basketball-Bundesligisten überprüft. Diese Werte wurden prospektiv mit den stattgehabten Verletzungen korreliert. Insgesamt wurden 71 Spieler in jeweils 5 verschiedenen Kategorien (u. a. Sprungkraft, Agilität, Sprintfähigkeit) getestet. Im Untersuchungszeitraum ereigneten sich 142 Verletzungen, die im Mittel zu einer Ausfallzeit von 23 Tagen (Range 1–347 Tage) führten. Die Verletzungen betrafen zumeist die untere Extremität, wobei Sprunggelenk, Oberschenkel und Kniegelenk am häufigsten betroffen waren. Es zeigte sich ein deutlicher Trend dahingehend, dass Spieler mit einer schwächer ausgeprägten Richtungsänderungsschnelligkeit häufiger Verletzungen erlitten (r = 0,34; p = 0,029) und Spieler, die im YoYo-Test signifikant schlechter abschnitten, häufiger von Oberschenkelverletzungen betroffen waren (r = 0,266; p = 0,012). Als Instrument zur Prävention sind medizinische Eingangsuntersuchungen nicht nur im Profisport essenziell, um Sportverletzungen oder Sportschäden aufzeigen bzw. ausschließen zu können. Die Erweiterung in Richtung sportartspezifische Leistungsdiagnostik liefert Informationen über Defizite bezogen auf Agilität und Ausdauer, die die Entstehung einer Verletzung begünstigen können. Darüber hinaus bieten die Untersuchungen auch die Möglichkeit, die erhobenen Werte als Baseline zu nutzen, die im Falle einer Verletzung den Fortschritt der Rehabilitation objektiv erfassbar machen und eine sichere Rückkehr zum Wettkampf ermöglichen.

Summary The doubly labeled water (DLW) method measures total energy expenditure (TEE) in free-living subjects. Several equations are used to convert isotopic data into TEE. Using the International Atomic Energy Agency (IAEA) DLW database (5,756 measurements of adults and children), we show considerable variability is introduced by different equations. The estimated rCO2 is sensitive to the dilution space ratio (DSR) of the two isotopes. Based on performance in validation studies, we propose a new equation based on a new estimate of the mean DSR. The DSR is lower at low body masses (, Graphical Abstract, Highlights 5,756 doubly labeled water (DLW) measures highlight variation from calculation equation We derive here new equations for calculating CO2 production when using DLW These equations outperform previous equations in validation studies We recommend these equations should be adopted in future studies using DLW in humans, Speakman et al. use a large database of doubly labeled water measurements to show the choice of equation for the calculation of energy expenditure introduces significant variation into the final estimate. They then derive new equations that outperform previous equations in validation studies against chamber calorimetry.

There is only very limited data examining cardiovascular responses in real-world endurance training/competition. The present study examines the influence of a marathon race on non-linear dynamics of heart rate (HR) variability (HRV). Eleven male recreational runners performed a self-paced marathon road race on an almost flat profile. During the race, heart rate and beat-to-beat (RR) intervals were recorded continuously. Besides HRV time-domain measurements, fractal correlation properties using short-term scaling exponent alpha1 of Detrended Fluctuation Analysis (DFA-alpha1) were calculated. The mean finishing time was 3:10:22 ± 0:17:56 h:min:s with a blood lactate concentration of 4.04 ± 1.12 mmol/L at the end of the race. Comparing the beginning to the end segment of the marathon race (Begin vs. End) significant increases could be found for km split time (p < .001, d = .934) and for HR (p = .010, d = .804). Significant decreases could be found for meanRR (p = .013, d = .798) and DFA-alpha1 (p = .003, d = 1.132). DFA-alpha1 showed an appropriate dynamic range throughout the race consisting of both uncorrelated and anti-correlated values. Lactate was consistent with sustained high intensity exercise when measured at the end of the event. Despite the runners slowing after halfway, DFA-alpha1 continued to fall to values seen in the highest intensity domain during incremental exercise testing in agreement with lactate assessment. Therefore, the discrepancy between the reduced running pace with that of the decline of DFA-alpha1, demonstrate the benefit of using this dimensionless HRV index as a biomarker of internal load during exercise over the course of a marathon race.

Despite considerable research efforts, pancreatic cancer is associated with a dire prognosis and a 5-year survival rate of only 10%. Early symptoms of the disease are mostly nonspecific. The premise of improved survival through early detection is that more individuals will benefit from potentially curative treatment. Artificial intelligence (AI) methodology has emerged as a successful tool for risk stratification and identification in general health care. In response to the maturity of AI, Kenner Family Research Fund conducted the 2020 AI and Early Detection of Pancreatic Cancer Virtual Summit (www.pdac-virtualsummit.org) in conjunction with the American Pancreatic Association, with a focus on the potential of AI to advance early detection efforts in this disease. This comprehensive presummit article was prepared based on information provided by each of the interdisciplinary participants on one of the 5 following topics: Progress, Problems, and Prospects for Early Detection; AI and Machine Learning; AI and Pancreatic Cancer-Current Efforts; Collaborative Opportunities; and Moving Forward-Reflections from Government, Industry, and Advocacy. The outcome from the robust Summit conversations, to be presented in a future white paper, indicate that significant progress must be the result of strategic collaboration among investigators and institutions from multidisciplinary backgrounds, supported by committed funders.

International audience; The multidomain non-structural protein 3 (Nsp3) is the largest protein encoded by coronavirus (CoV) genomes and several regions of this protein are essential for viral replication. Of note, SARS-CoV Nsp3 contains a SARS-Unique Domain (SUD), which can bind Guanine-rich non-canonical nucleic acid structures called G-quadruplexes (G4) and is essential for SARS-CoV replication. We show herein that the SARS-CoV-2 Nsp3 protein also contains a SUD domain that interacts with G4s. Indeed, interactions between SUD proteins and both DNA and RNA G4s were evidenced by G4 pull-down, Surface Plasmon Resonance and Homogenous Time Resolved Fluorescence. These interactions can be disrupted by mutations that prevent oligonucleotides from folding into G4 structures and, interestingly, by molecules known as specific ligands of these G4s. Structural models for these interactions are proposed and reveal significant differences with the crystallographic and modeled 3D structures of the SARS-CoV SUD-NM/G4 interaction. Altogether, our results pave the way for further studies on the role of SUD/G4 interactions during SARS-CoV-2 replication and the use of inhibitors of these interactions as potential antiviral compounds.

Decision making in immuno‐oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno‐assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti‐PD‐1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay., To predict cancer resistance to PD‐1 blockade and design suitable combinations of immunomodulators, a 60‐h functional in sitro assay was set up in 43 tumors that allowed calculation of the “Immune Reactivity Score (IRS)” based on 17 TCR‐dependent‐ cytokines/chemokines.

DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3–72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8–not reached [NR]); median progression-free survival was 5.7 months (2.2–9.7); median overall survival was not reached (8.7 months–NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.

Purpose: To elucidate the role of inter-effort recovery in shuttle running by comparing the metabolic profiles of the 30-15 Intermittent Fitness Test (30-15IFT) and the corresponding continuous version (30-15IFT-CONT). Methods: Sixteen state-level handball players (age = 23 [3] y, height = 185 [7] cm, weight = 85 [14] kg) completed the 30-15IFT and 30-15IFT-CONT, and speed at the last completed stage (in kilometers per hour) and time to exhaustion (in seconds) were assessed. Furthermore, oxygen uptake (in milliliters per kilogram per minute) and blood lactate were obtained preexercise, during exercise, and until 15 minutes postexercise. Metabolic energy (in kilojoules), metabolic power (in Watts per kilogram), and relative (in percentage) energy contribution of the aerobic (WAER, WAERint), anaerobic lactic (WBLC, WBLCint), and anaerobic alactic (WPCr, WPCrint) systems were calculated by PCr-La-O2 method for 30-15IFT-CONT and 30-15IFT. Results: No difference in peak oxygen uptake was found between 30-15IFT and 30-15IFT-CONT (60.6 [6.6] vs 60.5 [5.1] mL·kg−1·min−1, P = .165, d = 0.20), whereas speed at the last completed stage was higher in 30-15IFT (18.3 [1.4] vs 16.1 [1.0] km·h−1, P d = 1.17). Metabolic energy was also higher in 30-15IFT (1224.2 [269.6] vs 772.8 [63.1] kJ, P d = 5.60), and metabolic profiles differed substantially for aerobic (30-15IFT = 67.2 [5.2] vs 30-15IFT-CONT = 85.2% [2.5%], P d = −4.01), anaerobic lactic (30-15IFT = 4.4 [1.4] vs 30-15IFT-CONT = 6.2% [1.8%], P d = −1.04), and anaerobic alactic (30-15IFT = 28.4 [4.7] vs 30-15IFT-CONT = 8.6% [2.1%], P d = 5.43) components. Conclusions: Both 30-15IFT and 30-15IFT-CONT are mainly fueled by aerobic energy, but their metabolic profiles differ substantially in both aerobic and anaerobic alactic energy contribution. Due to the presence of inter-effort recovery, intermittent shuttle runs rely to a higher extent on anaerobic alactic energy and a fast, aerobic replenishment of PCr during the short breaks between shuttles.

Purpose: To evaluate the metabolic relevance of type of locomotion in anaerobic testing by analyzing and comparing the metabolic profile of the Bosco Continuous Jumping Test (CJ30) with the corresponding profile of the Wingate Anaerobic Test (WAnT). Methods: A total of 11 well-trained, male team-sport athletes (age = 23.7 [2.2] y, height = 184.1 [2.8] cm, weight = 82.4 [6.4] kg) completed a CJ30 and WAnT each. During the WAnT, power data and revolutions per minute were recorded, and during the CJ30, jump height and jumping frequency were recorded. In addition, oxygen uptake and blood lactate concentration were assessed, and metabolic profiles were determined via the PCr-LA-O2 method. Results: In the CJ30, metabolic energy was lower (109.3 [18.0] vs 143.0 [13.1] kJ, P d = −2.302), while peak power (24.8 [4.4] vs 11.8 [0.5] W·kg−1, P d = 3.59) and mean power (20.8 [3.6] vs 9.1 [0.5] W·kg−1, P d = 4.14) were higher than in the WAnT. The metabolic profiles of the CJ30 (aerobic energy = 20.00% [4.7%], anaerobic alactic energy [WPCr] = 45.6% [4.5%], anaerobic lactic energy = 34.4% [5.2%]) and the WAnT (aerobic energy = 16.0% [3.0%], anaerobic alactic WPCr = 34.5% [5.0%], anaerobic lactic energy = 49.5% [3.3%]) are highly anaerobic. Absolute energy contribution for the CJ30 and WAnT was equal in WPCr (49.9 [11.1] vs 50.2 [11.2] kJ), but anaerobic lactic energy (37.7 [7.7] vs 69.9 [5.3] kJ) and aerobic energy (20.6 [5.7] vs 23.0 [4.0] kJ) were higher in the WAnT. Mechanical efficiency was substantially higher in the CJ30 (37.9% [4.5%] vs 15.6% [1.0%], P d = 6.86), while the fatigue index was lower (18.5% [3.8%] vs 23.2% [3.1%], P d = −1.38) than in the WAnT. Conclusions: Although the anaerobic share in both tests is similar and predominant, the CJ30 primarily taxes the WPCr system, while the WAnT more strongly relies on the glycolytic pathway. Thus, the 2 tests should not be used interchangeably, and the type of locomotion seems crucial when choosing an anaerobic test for a specific sport.

Hearing is a mechanical and neurochemical process, which occurs in the hair cells of inner ear that converts the sound vibrations into electrical signals transmitted to the brain. The multi-PDZ scaffolding protein whirlin plays a critical role in the formation and function of stereocilia exposed at the surface of hair cells. In this article, we reported seven stereociliary proteins that encode PDZ binding motifs (PBM) and interact with whirlin PDZ3, where four of them are first reported. We solved the atomic resolution structures of complexes between whirlin PDZ3 and the PBMs of myosin 15a, CASK, harmonin a1 and taperin. Interestingly, the PBM of CASK and taperin are rare non-canonical PBM, which are not localized at the extreme C terminus. This large capacity to accommodate various partners could be related to the distinct functions of whirlin at different stages of the hair cell development. (C) 2020 Published by Elsevier Ltd.

The accumulation of fibrillar amyloid &beta, protein (A&beta, ) in blood vessels of the brain, the condition known as cerebral amyloid angiopathy (CAA), is a common small vessel disease that promotes cognitive impairment and is strongly associated with Alzheimer&rsquo, s disease. Presently, the clinical diagnosis of this condition relies on neuroimaging markers largely associated with cerebral macro/microbleeds. However, these are markers of late-stage disease detected after extensive cerebral vascular amyloid accumulation has become chronic. Recently, we generated a novel transgenic rat model of CAA (rTg-DI) that recapitulates multiple aspects of human CAA disease with the progressive accumulation of cerebral vascular amyloid, largely composed of A&beta, 40, and the consistent emergence of subsequent microbleeds. Here, we investigated the levels of A&beta, 40 in the cerebrospinal fluid (CSF) and plasma of rTg-DI rats as CAA progressed from inception to late stage disease. The levels of A&beta, 40 in CSF and plasma precipitously dropped at the early onset of CAA accumulation at three months of age and continued to decrease with the progression of disease. Notably, the reduction in CSF/plasma A&beta, 40 levels preceded the emergence of cerebral microbleeds, which first occurred at about six months of age, as detected by in vivo magnetic resonance imaging and histological staining of brain tissue. These findings support the concept that reduced CSF/plasma levels of A&beta, 40 could serve as a biomarker for early stage CAA disease prior to the onset of cerebral microbleeds for future therapeutic intervention.

Respiratory syncytial virus (RSV) is the leading cause of hopitalisation in young children with respiratory tract infections (RTI). The aim of this research project was to analyse RSV genotypes and the diversification of RSV strains among hospitalised children in Heidelberg, Germany.We prospectively analysed nasopharyngeal swabs (NPS) from children who were hospitalised with acute RTI at the University Hospital Heidelberg, Germany, during winter seasons 2014 to 2017. RSV RT-PCR and RSV sequence analysis of the G gene coding for the attachment glycoprotein were performed. Clinical data was obtained using a standardised questionnaire.RSV was detected in 405 out of 946 samples from hospitalised children. Most RSV positive children were below the age of two years (84.4%) and had a lower RTI (78.8%). The majority of RSV positive children was male, significantly younger than RSV negative children with a median age of 0.39 years and with more severe respiratory symptoms. Out of 405 positive samples, 317 RSV strains were successfully sub-grouped into RSV subtypes A (57.4%; 182/317) and B (42.6%; 135/317). Both RSV subtypes cocirculated in all analysed winter seasons. Phylogenetic analysis of 317 isolates revealed that the majority of RSV-A strains (180/182) belonged to the ON1 genotype, most RSV-B strains could be attributed to the BAIX genotype (132/135). ON1 and BAIX strains showed a sub-differentiation into different lineages and we were able to identify new (sub)genotypes.Analysis of the molecular epidemiology of RSV from different seasons revealed the cocirculation and diversification of RSV genotypes ON1 and BAIX.

Accumulation of fibrillar amyloid β protein in blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is a common pathology of elderly individuals, a prominent comorbidity of Alzheimer disease, and a driver of vascular cognitive impairment and dementia. Although several transgenic mouse strains have been generated that develop varying levels of CAA, consistent models of associated cerebral microhemorrhage and vasculopathy observed clinically have been lacking. Reliable preclinical animal models of CAA and microhemorrhage are needed to investigate the molecular pathogenesis of this condition. Herein, we describe the generation and characterization of a novel transgenic rat (rTg-DI) that produces low levels of human familial CAA Dutch/Iowa E22Q/D23N mutant amyloid β protein in brain and faithfully recapitulates many of the pathologic aspects of human small-vessel CAA. rTg-DI rats exhibit early-onset and progressive accumulation of cerebral microvascular fibrillar amyloid accompanied by early-onset and sustained behavioral deficits. Comparable to CAA in humans, the cerebral microvascular amyloid in rTg-DI rats causes capillary structural alterations, promotes prominent perivascular neuroinflammation, and produces consistent, robust microhemorrhages and small-vessel occlusions that are readily detected by magnetic resonance imaging. The rTg-DI rats provide a new model to investigate the pathogenesis of small-vessel CAA and microhemorrhages, to develop effective biomarkers for this condition and to test therapeutic interventions.

In recent years, complex models of cardiac regulation have integrated heart rate variability (HRV) as a measure of the cardiac autonomic activity during exercise. Using detrended fluctuation analysis (DFA) technique, the present study examines the influence of cycling cadence and exercise duration on non-linear dynamics of HRV. Sixteen trained cyclists performed a 60-minute exercise bout at 90% of the individual anaerobic threshold on a bicycle ergometer. Cadence was changed every 10 min (90–120–60–120–60–90 rpm). Heart rate (HR) and RR-intervals were recorded continuously during exercise. HRV time domain measures (meanRR, SDNN) and correlation properties were analyzed using short-term scaling exponent alpha1 of DFA. Moreover, blood lactate (La) and rating of perceived exertion (RPE) were recorded at regular intervals at the end of condition. HR, La and RPE increased significantly at 120 rpm compared to 60 rpm. In contrast, all analyzed HRV parameters (meanRR, SDNN, DFA-alpha1) showed a significant decrease during cycling at 120 rpm compared to 60 rpm. The comparison of the first and last 10 min with the same cadence indicates a significant increase in HR and RPE, but also a significant decrease in all analyzed HRV measures. The decrease of HRV values over time and in relation to the increase in cadence indicates a decrease in the overall variability as well as a reduction in complexity of the RR-interval-fluctuations due to the increased organismic demands. Therefore, the decrease of DFA-alpha1 might be associated with a withdrawal of the organismic system aiming at the maintenance of the homeostasis under the control of the central nervous system. In this context, non-linear HRV analyses provide a more systemic view of cardiac regulation during exercise.

Purpose: To analyze the energetic profile of the Basketball Exercise Simulation Test (BEST). Methods: Ten male elite junior basketball players (age 15.5 [0.6] y, height 180 [9] cm, and body mass 66.1 [11.2] kg) performed a modified BEST (20 circuits consisting of jumping, sprinting, jogging, shuffling, and short breaks) simulating professional basketball game play. Circuit time, sprint time, sprint decrement, oxygen uptake (VO2), heart rate, and blood lactate concentration (blc) were obtained. Metabolic energy and metabolic power above rest (Wtot and Ptot), as well as energy share in terms of aerobic (Waer), glycolytic (Wblc), and high-energy phosphates (WPCr), were calculated from VO2 during exercise, net lactate production, and the fast component of postexercise VO2 kinetics, respectively. Results: Waer, Wblc, and WPCr reflect 89% (2%), 5% (1%), and 6% (1%) of total energy needed, respectively. Assuming an aerobic replenishment of PCr energy stores during short breaks, the adjusted energy share yielded Waer 66% (4%), Wblc 5% (1%), and WPCr 29% (1%). Waer and WPCr were negatively correlated (−0.72 and −0.59) with sprint time, which was not the case for Wblc. Conclusions: Consistent with general findings on energy system interaction during repeated high-intensity exercise bouts, the intermittent profile of the BEST relies primarily on aerobic energy combined with repetitive supplementation by anaerobic utilization of high-energy phosphates.

As a part of the Cancer Moonshot, the National Cancer Institute, part of the National Institutes of Health, the Foundation for National Institutes of Health, the US Food and Drug Administration, and 12 pharmaceutical companies have formed a 5-year, $220 million precompetitive public-private research collaboration called the Partnership for Accelerating Cancer Therapies. A systematic cross-sector effort to identify and develop robust, standardized biomarkers and related clinical data, Partnership for Accelerating Cancer Therapies will support the selection and testing of promising immunotherapies for the treatment of cancer, with the goal of bringing effective therapy to more patients.

Purpose Treating solid tumors with cancer immunotherapy (CIT) can result in unconventional responses and overall survival (OS) benefits that are not adequately captured by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. We describe immune-modified RECIST (imRECIST) criteria, designed to better capture CIT responses. Patients and Methods Atezolizumab data from clinical trials in non–small-cell lung cancer, metastatic urothelial carcinoma, renal cell carcinoma, and melanoma were evaluated. Modifications to imRECIST versus RECIST v1.1 included allowance for best overall response after progressive disease (PD) and changes in PD definitions per new lesions (NLs) and nontarget lesions. imRECIST progression-free survival (PFS) did not count initial PD as an event if the subsequent scan showed disease control. OS was evaluated using conditional landmarks in patients whose PFS differed by imRECIST versus RECIST v1.1. Results The best overall response was 1% to 2% greater, the disease control rate was 8% to 13% greater, and the median PFS was 0.5 to 1.5 months longer per imRECIST versus RECIST v1.1. Extension of imRECIST PFS versus RECIST v1.1 PFS was associated with longer or similar OS. Patterns of progression analysis revealed that patients who developed NLs without target lesion (TL) progression had a similar or shorter OS compared with patients with RECIST v1.1 TL progression. Patients infrequently experienced a spike pattern (TLs increase, then decrease) but had longer OS than patients without TL reversion. Conclusion Evaluation of PFS and patterns of response and progression revealed that allowance for TL reversion from PD per imRECIST may better identify patients with OS benefit. Progression defined by the isolated appearance of NLs, however, is not associated with longer OS. These results may inform additional modifications to radiographic criteria (including imRECIST) to better reflect efficacy with CIT agents.

BACKGROUND: Heritable cardiac-sodium channel dysfunction is associated with various arrhythmia syndromes, some predisposing to ventricular fibrillation. Phenotypic diversity among carriers of identical-by-descent mutations is often remarkable, suggesting influences of genetic modifiers.OBJECTIVE: The purpose of this study was to identify a unique SCN5A-mutation founder population with mixed clinical phenotypes and sudden cardiac death, and to investigate the heritability of electromechanical traits besides the SCN5A-mutation effect.METHODS: The 16-generation founder population segregating SCN5A c.4850_4852delTCT, p.(Phe1617del), was comprehensively phenotyped. Variance component analysis was used to evaluate the mutation's effects and assess heritability.RESULTS: In 45 p.(Phe1617del) positives, the mutation associated strongly with QTc prolongation (472 ± 60 ms vs 423 ± 35 ms in 26 mutation negatives; P P P P = .006). p.(Phe1617del) was an important determinant of QTcbaseline, QTcmax, and EMW, explaining 18%, 28%, and 37%, respectively, of the trait’s variance. Significant heritability was observed for PQ interval (P = .003) after accounting for the p.(Phe1617del) effect.CONCLUSION: This SCN5A-p.(Phe1617del) founder population with phenotypic divergence and overlap reveals long-QT syndrome-related and arousal-evoked ventricular tachyarrhythmias with a female preponderance. Variance component analysis indicates additional genetic variance for PQ interval hidden in the genome, besides a dominant p. .(Phe1617del) effect on QTc and EMW.

Introduction Kunitz proteinase inhibitor (KPI) domain-containing forms of the amyloid β-protein precursor (AβPP) inhibit cerebral thrombosis. KPI domain-lacking forms of AβPP are abundant in brain. Regions of AβPP other than the KPI domain may also be involved with regulating cerebral thrombosis. To determine the contribution of the KPI domain to the overall function of AβPP in regulating cerebral thrombosis we generated a reactive center mutant that was devoid of anti-thrombotic activity and studied its anti-thrombotic function in vitro and in vivo . Methods To determine the extent of KPI function of AβPP in regulating cerebral thrombosis we generated a recombinant reactive center KPI R13I mutant devoid of anti-thrombotic activity. The anti-proteolytic and anti-coagulant properties of wild-type and R13I mutant KPI were investigated in vitro . Cerebral thrombosis of wild-type, AβPP knock out and AβPP/KPI R13I mutant mice was evaluated in experimental models of carotid artery thrombosis and intracerebral hemorrhage. Results Recombinant mutant KPI R13I domain was ineffective in the inhibition of pro-thrombotic proteinases and did not inhibit the clotting of plasma in vitro . AβPP/KPI R13I mutant mice were similarly deficient as AβPP knock out mice in regulating cerebral thrombosis in experimental models of carotid artery thrombosis and intracerebral hemorrhage. Conclusions We demonstrate that the anti-thrombotic function of AβPP primarily resides in the KPI activity of the protein.

Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infection in young infants and a major cause of nosocomial infection in pediatric care. Currently available RSV point-of-care tests are of limited sensitivity and relatively expensive. We developed and evaluated a novel RSV rapid test for use at point-of-care, based on reverse-transcription loop-mediated isothermal amplification (RT-LAMP) for direct testing of nasopharyngeal swab specimens. RT-LAMP can detect RSV within 30min, without the need for RNA extraction. The sensitivity of our RT-LAMP assay was 70-80% in comparison to RT-PCR. The RT-LAMP test sensitivity is at least equivalent to currently available rapid antigen detection tests (RADT), and the cost of RT-LAMP test reagents is only approximately 10% of that of commercially available RADT tests. RT-LAMP appears to be an attractive alternative to RADT, particularly in settings with limited financial resources. Future improvements could include lyophilization of test reagents and automated read-out of RT-LAMP results.

Summary Background Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study. Methods DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged ≥18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0–2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (≤4 vs >4) and cytogenetic features to receive 2·5 mg/kg or 3·4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with ClinicalTrials.gov , NCT03525678 , and is ongoing. Findings Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97·5% CI 20·8–42·6) of 97 patients in the 2·5 mg/kg cohort and 34 (34%; 23·9–46·0) of 99 patients in the 3·4 mg/kg cohort achieved an overall response. The most common grade 3–4 adverse events in the safety population were keratopathy (in 26 [27%] of 95 patients in the 2·5 mg/kg cohort and 21 [21%] of 99 patients in the 3·4 mg/kg cohort), thrombocytopenia (19 [20%] and 33 [33%]), and anaemia (19 [20%] and 25 [25%]); 38 (40%) of 95 patients in the 2·5 mg/kg cohort and 47 (47%) of 99 in the 3·4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2·5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3·4 mg/kg cohort). Interpretation Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma. Funding GlaxoSmithKline.

Global Cumulative Treatment Analysis (GCTA) is a novel clinical research model combining expert knowledge, and treatment coordination based upon global information-gain, to treat every patient optimally while efficiently searching the vast space that is the realm of cancer research.

Background Non‐linear measures of heart rate variability (HRV) may provide new opportunities to monitor cardiac autonomic regulation during exercise. In healthy individuals, the HRV signal is mainly composed of quasi‐periodic oscillations, but it also possesses random fluctuations and so‐called fractal structures. One widely applied approach to investigate fractal correlation properties of heart rate (HR) time series is the detrended fluctuation analysis (DFA). DFA is a non‐linear method to quantify the fractal scale and the degree of correlation of a time series. Regarding the HRV analysis, it should be noted that the short‐term scaling exponent alpha1 of DFA has been used not only to assess cardiovascular risk but also to assess prognosis and predict mortality in clinical settings. It has also been proven to be useful for application in exercise settings including higher exercise intensities, non‐stationary data segments, and relatively short recording times. Method Therefore, the purpose of this systematic review was to analyze studies that investigated the effects of acute dynamic endurance exercise on DFA‐alpha1 as a proxy of correlation properties in the HR time series. Results The initial search identified 442 articles (351 in PubMed, 91 in Scopus), of which 11 met all inclusion criteria. Conclusions The included studies show that DFA‐alpha1 of HRV is suitable for distinguishing between different organismic demands during endurance exercise and may prove helpful to monitor responses to different exercise intensities, movement frequencies, and exercise durations. Additionally, non‐linear DFA of HRV is a suitable analytical approach, providing a differentiated and qualitative view of exercise physiology.

Purpose: To analyze the energetic profiles of the Yo-Yo Intermittent Recovery Tests 1 and 2 (YYIR1 and YYIR2). Methods: Intermittent running distance (IR1D and IR2D), time to exhaustion (IR1T and IR2T), and total recovery time between shuttles (IR1R and IR2R) were measured in 10 well-trained male athletes (age 24.4 [2.0] y, height 182 [1] cm, weight 75.8 [7.9] kg). Respiratory gases and blood lactate (BLC) were obtained preexercise, during exercise, and until 15 min postexercise. Metabolic energy, average metabolic power , and energy share (percentage of aerobic [WAER], anaerobic lactic [WBLC], and anaerobic alactic energy system [WPCr]) were calculated using the PCr-La-O2 method. Results: Peak oxygen consumption was possibly higher in YYIR2 (60.3 [5.1] mL·kg−1·min−1) than in YYIR1 (P = .116, 57.7 [4.5] mL·kg−1·min−1, d = −0.58). IR1D, IR1T, and IR1R were very likely higher than IR2D, IR2T, and IR2R, respectively (P d = −2.83; P d = −3.03; and P d = −2.83). Metabolic energy was most likely lower in YYIR2 than in YYIR1 (P d = 3.24). Average metabolic power was most likely higher in YYIR2 than in YYIR1 (P −1, d = 3.54). When considering aerobic phosphocreatine restoration during breaks between shuttles, WAER (P = .693, 49% [10%] vs 48% [5%], d = −0.16) was similar, WPCr (P = .165, 47% [11%] vs 42% [6%], d = −0.54) possibly higher, and WBLC (P d = 1.95) almost certainly lower in YYIR1 than in YYIR2. Conclusions: WAER and WPCr are predominant in YYIR1 and YYIR2 with almost identical WAER. Higher IR1D and IR1T in YYIR1 result in higher metabolic energy but lower average metabolic power and slightly lower peak oxygen consumption. Higher IR1R allows for higher reliance on WPCr in YYIR1, while YYIR2 requires a higher fraction of WBLC.

We review the current state of quality assurance in laboratories of the five Central Asia Republics (CARs), focusing on laboratory equipment, and compare quality assurance approaches with CLSI standards. The laboratories of the CARs faced exceptional challenges including highly-structured laboratory systems that retain centralized and outmoded Soviet-era approaches to quality assurance, considerably jeopardizing the validity of laboratory tests. The relative isolation of the CARs, based on geography and almost exclusive use of the Russian language, further hamper change. CARs must make high-level government decisions to widely implement quality assurance programs within their laboratory systems, within which approaches to the management of laboratory equipment will be a prominent part.