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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.

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 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.

Zusammenfassung Hintergrund 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. Material und Methoden 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. Ergebnisse 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). Schlussfolgerung 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.

Aims The follow-up interval of a study represents an important aspect that is frequently mentioned in the title of the manuscript. Authors arbitrarily define whether the follow-up of their study is short-, mid-, or long-term. There is no clear consensus in that regard and definitions show a large range of variation. It was therefore the aim of this study to systematically identify clinical research published in high-impact orthopaedic journals in the last five years and extract follow-up information to deduce corresponding evidence-based definitions of short-, mid-, and long-term follow-up. Methods A systematic literature search was performed to identify papers published in the six highest ranked orthopaedic journals during the years 2015 to 2019. Follow-up intervals were analyzed. Each article was assigned to a corresponding subspecialty field: sports traumatology, knee arthroplasty and reconstruction, hip-preserving surgery, hip arthroplasty, shoulder and elbow arthroplasty, hand and wrist, foot and ankle, paediatric orthopaedics, orthopaedic trauma, spine, and tumour. Mean follow-up data were tabulated for the corresponding subspecialty fields. Comparison between means was conducted using analysis of variance. Results Of 16,161 published articles, 590 met the inclusion criteria. Of these, 321 were of level IV evidence, 176 level III, 53 level II, and 40 level I. Considering all included articles, a long-term study published in the included high impact journals had a mean follow-up of 151.6 months, a mid-term study of 63.5 months, and a short-term study of 30.0 months. Conclusion The results of this study provide evidence-based definitions for orthopaedic follow-up intervals that should provide a citable standard for the planning of clinical studies. A minimum mean follow-up of a short-term study should be 30 months (2.5 years), while a mid-term study should aim for a mean follow-up of 60 months (five years), and a long-term study should aim for a mean of 150 months (12.5 years). Level of Evidence: Level I. Cite this article: Bone Jt Open 2021;2(5):344–350.

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.

Background Physical activity may be a way to increase and maintain fat-free mass (FFM) in later life, similar to the prevention of fractures by increasing peak bone mass. Objectives A study is presented of the association between FFM and physical activity in relation to age. Methods In a cross-sectional study, FFM was analyzed in relation to physical activity in a large participant group as compiled in the International Atomic Energy Agency Doubly Labeled Water database. The database included 2000 participants, age 3–96 y, with measurements of total energy expenditure (TEE) and resting energy expenditure (REE) to allow calculation of physical activity level (PAL = TEE/REE), and calculation of FFM from isotope dilution. Results PAL was a main determinant of body composition at all ages. Models with age, fat mass (FM), and PAL explained 76% and 85% of the variation in FFM in females and males

BackgroundTo address the heterogeneity of response to therapies, the oncology field is moving toward precision medicine (PM), with therapy tailored to a patient‘s disease. Biomarker assessment is now critical when screening for enrollment into clinical studies, such as for T-cell receptor therapies and combination studies, and determining status of a single analyte does not always correlate to clinical benefit.1 This shift may increase enrollment screen-failure rates due to restrictive eligibility criteria (e.g., biomarker prevalence). For oncology patients, the need for timely treatment does not allow for a sequential, complex, and time-consuming screening process for each individual clinical trial. The design and data from studies such as Lung MAP have emphasized a need to change clinical trial screening. As we begin to target less common genomic and immunotherapy subtypes, comprehensive molecular characterization may lead to rapid delivery of therapies to patients while maximizing the quality of data.2The Molecular Disease Characterization Initiative (MDCI; GlaxoSmithKline Study 213299 [NCT04772053]) screens for multiple studies at once by collecting a baseline assessment of disease prior to treatment with different therapeutic modalities, and evaluating the patient‘s tumor and blood genetics. The MDCI creates a platform to accelerate the availability of new therapeutic options for patients through matched investigative and PM clinical trials, while building a scientific database to facilitate the investigation of biological mechanisms underpinning clinical outcomes.MethodsThis multicenter study enrolls patients (N= 400) with advanced/metastatic malignancies, initially non-small cell lung cancer, to collect biospecimens for broad molecular profiling and examining the expression of specific antigens (e.g. NY-ESO-1, LAGE-1a), immune markers (e.g. ICOS, PD-L1), tumor-infiltrating immune cells, differentially expressed genes, and human leukocyte antigen (HLA). In this single-arm, non-interventional, molecular analysis study there is no administration of investigational product. MDCI interrogates patient tumor specimens using CLIA-validated immunohistochemistry assays coupled with next-generation sequencing of DNA and RNA. Blood is also collected for assessment (e.g. HLA typing, ctDNA). Based on this molecular profiling and previous medical history, potential clinical trial options are returned to both physicians and patients with the aim to reduce time-to-treatment (figure 1). Participants may be subsequently matched to ongoing clinical trials of novel immunotherapeutics or adoptive cell therapy. Patients who do not match to a clinical trial but continue with standard of care may choose longitudinal follow-up and re-analyses of disease at progression.AcknowledgementsStudy 213299 (NCT04772053) is funded by GlaxoSmithKline.ReferencesBlons H, Garinet S, Laurent-Puig P, Oudart JB. Molecular markers and prediction of response to immunotherapy in non-small cell lung cancer, an update. J Thorac Dis 2019;11(Suppl 1):S25–S36.Lam, Vincent K, Papadimitrakopoulou V. Master protocols in lung cancer: experience from lung master protocol. Curr Opin Oncol 2018;30:p92–97.Ethics ApprovalThe study was approved by Advarra Central IRB, approval date 4 January 2021.Abstract 390 Figure 1MDCI study design schema. *MDCI will be an optional protocol under select GSK oncology protocols. †Gather Share Know is an optional patient-facing portal where patients can view subsets of their results. ‡Subset of data to be shared on Gather Share Know. §Patient‘s molecular profile and medical history will be compared against the eligibility criteria of select GSK oncology protocols to identify potential trial options. MDCI, Molecular Disease Characterization Initiative.

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.

It is well established that individuals with cognitive impairment present with disturbed forms of pain processing of still unknown origin. As a neurocognitive factor, executive functions have become favored candidates for explanation. For further insights, we aimed at comparing executive functions and memory in their association with parameters indicating onset and escalation of pain perception. Subjective ratings of experimentally induced pressure pain applied in ascending series were assessed in older individuals with (N = 32) and without mild cognitive impairments (MCI) (N = 32). We investigated whether executive functioning (Trail Making Test-B (TMT-B), semantic fluency) or memory (word list and figure recall) were more closely linked to the onset and the escalation of pain. For the MCI group, a strong linkage between pain responses and the TMT-B could be found, i.e., poor test performance was associated with weak pain onset but strong pain escalation. The contribution of memory functions was less substantial and systematic. The prominent role of executive function for pain processing in individuals with MCI could be replicated by a test of cognitive flexibility. This lack of adaptability let individuals with MCI be less vigilant to pain at the beginning but allows for escalating pain in the further course. Thus, being first not sufficiently prepared and later overwhelmed as regards pain may be an early problem in MCI individuals with reduced executive functioning.

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.

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.

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 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.

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.

Introduction Inducible T cell co-stimulator (ICOS) is a co-stimulatory receptor that is important for promoting immune activation and function. Despite reported clinical activity and a wide range of non-clinical studies supporting a role for ICOS in lymphocyte activation, proliferation and pro-inflammatory cytokine secretion, little is known regarding the potential of monoclonal agonist antibody-mediated ICOS signaling to drive cytotoxic T cell infiltration into tumors. Feladilimab (GSK3359609) is a non-depleting IgG4 ICOS agonist antibody currently being evaluated in pivotal clinical trials. Here, we used PET/CT imaging to evaluate CD8+ T cell infiltration following treatment with a rodent surrogate of feladilimab (7E.17G9 mouse [m] IgG1) alone or in combination with anti-PD-1 mAb (RMP-14 rat IgG2a) in a syngeneic model of breast cancer (EMT6). Method Female BALB/c mice with established tumors (~150 mm3) received 10µg, IP of either IgG control mAbs, ICOS mAb, or ICOS + PD-1 mAbs on day 0, 3, 5, 7, 9, 10, or 14. Imaging was performed at 24 & 48 hrs post IV dose of 89Zr labeled CD8 minibody (IAB42M1-14, ImaginAb, CA) on day 0, 3, 5, 9, or 14. In addition to the CD8 minibody uptake in tumor & tumor-draining lymph node (TDLN), 3D radiomic features were extracted from PET/CT images. Top ranked features were used for hierarchical clustering to identify treatment effects. Results Tumor size regressed in all treated groups relative to IgG control, with a number of mice clearing tumors (ICOS: 4 mice, ICOS + PD-1: 9 mice). The in vivo uptake of CD8 minibody in TDLN was significantly higher in the ICOS + PD-1 group on day 4, 6, & 7 relative to IgG control P Conclusions Herein, we demonstrated for the first time that treatment of tumor-bearing mice with ICOS agonist mAb alone or in combination with PD-1 blockade can increase CD8+ T cell infiltration into tumors & TDLN, and is correlated with reduced tumor burden. Notably, radiomics features predicted an effect of treatment on CD8+ T cell infiltration earlier than the detection of absolute changes in the CD8 minibody uptake in tumor & TDLN. Overall, these data support the ongoing pivotal investigation of feladilimab. Moreover, this translational imaging method may be a useful tool to non-invasively monitor CD8+ T cell in response to immunotherapies and understand the temporal relationship between CD8+ T cell flux in tumor and in TDLN. Citation Format: Hasan Alsaid, Shih-Hsun Cheng, Meixia Bi, Mary V. Rambo, Tinamarie Skedzielewski, Bao Hoang, Sunish Mohanan, Andrew Gehman, Chih-Yang Hsu, Minh Doan, Fang Xie, M. Reid Groseclose, Christopher Hopson, Sara Brett, Ian A. Wilson, Andrew Nicholls, Marc Ballas, Jeremy D. Waight, Beat M. Jucker, Axel Hoos. Immuno-PET monitoring of CD8+ T cell infiltration post anti-ICOS agonist antibody treatment alone and in combination with PD-1 blocking antibody using a 89Zr anti-CD8+ mouse minibody in EMT 6 syngeneic tumor mouse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2816.

Background: INDUCE-1 is a first-in-human trial investigating FE, an IgG4 ICOS agonist non-T-cell depleting mAb, in monotherapy (mono) and combo with PD-1 inhibitor PE. ICOS is highly expressed in melanoma, an immunotherapy responsive tumor, and is a biomarker of response to anti-CTLA-4 treatment; in nonclinical models, ICOS agonism has enhanced activity in combo with immune checkpoint blockade (ICB). Preliminary data from INDUCE-1 R/R melanoma ECs are presented to support FE expansion in ICB experienced (exp) R/R melanoma patients (pts). Methods: Eligible pts had non-uveal R/R melanoma, ≤5 prior lines of systemic therapy, achieved response or stable disease (SD) on prior anti-PD-1/L1 treatment, and no prior immunotherapy-related Grade ≥3 toxicities leading to treatment discontinuation. In FE mono and FE + PE 200 mg combo ECs, pts were randomized to FE 0.3 or 1 mg/kg; treatment was given every 3 wks up to 35 cycles until disease progression or unacceptable toxicity. Safety and efficacy were assessed. Biomarkers in tumor biopsies were analyzed. Results: By 30 Mar 2020, 39 pts in the mono EC were evaluable (21 pts at 0.3; 18 pts at 1 mg/kg FE); all pts were anti-PD-1/L1 exp; 21/39 (54%) were anti-CTLA-4 exp; 7/39 (18%) had ≥4 prior lines of therapy. Of the 39 pts, 29 (74%) discontinued treatment due to progression. Response rate was 10% (4/39; 1 complete response, 3 partial responses); 8/39 (21%) pts had SD and 2/8 (25%) pts with SD had tumor size reductions (RECIST v1.1) at ≥19%; 5 pts (13%) had SD at ≥18 wks. Duration of response (DoR) was 2.0+ to 6.3 mo. BRAF and NRAS status did not impact clinical activity. Anti-CTLA-4 exp pts had a numerically higher response rate than anti-CTLA-4 naïve pts. In the combo EC, 17 anti-PD-1/L1 exp pts were evaluable (6 pts at 0.3; 11 pts at 1 mg/kg FE); 12/17 (71%) were anti-CTLA-4 exp; 15/17 (88%) discontinued treatment, all due to progression. Response rate was 18% (3/17), DoR was 7.9+ to 8.2 mo, and disease control rate (response or SD) was 53% (9/17); 1 pt with SD had tumor size reduction of 10%. Ongoing analyses with mono EC showed a 28.6% (2/7) response rate, DoR of 2.0+ to 6.3 mo, and mOS of ~26 mo in pts with ICOS high tumor-infiltrating T cells. Sample size limits comparison; however, clinical activity was similar between FE doses and between BRAF+ and BRAF− pts. Adverse events (AEs) were consistent with AEs reported for PE. Conclusions: FE is the first ICOS agonist with reported single-agent activity in ICB exp R/R melanoma, supporting ICOS as a target. FE + PE in combo shows promising clinical activity and manageable safety in R/R melanoma. Continued survival follow-up of ECs is warranted. Updated efficacy and PK/PD data to be presented. Funding: Study 204691 (NCT02723955) funded by GSK in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Citation Format: Michele Maio, Jeffrey S. Weber, Maria Vieito Villar, Frans L. Opdam, Victor Moreno, Omid Hamid, José Trigo, Michael Chisamore, Marco Balas, Sapna Yadavilli, David C. Turner, Courtney Henry, Xiao Ji, Catherine Ellis, Marc Ballas, Axel Hoos, Antoine Italiano. Inducible T cell costimulatory (ICOS) receptor agonist, feladilimab (FE), alone and in combination (combo) with pembrolizumab (PE): Results from INDUCE-1 relapsed/refractory (R/R) melanoma expansion cohorts (EC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT033.

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.

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.

Background As access to antiretroviral therapy (ART) in Africa has increased dramatically, concerns have been raised regarding patient attrition, an important measure of program quality. Methods We examined aggregate data from 307144 patients initiating ART in 5638 successive cohorts at 638 facilities in 9 African countries from 2005 to 2010, a period characterized by massive treatment expansion. Poisson regression assessed trends in 6- and 12-month cohort attrition (ie, the proportion of patients in each cohort no longer receiving ART at their initiating facility) over calendar time and as ART services matured, and identified factors associated with attrition. Results Across all 9 countries, 6- and 12-month cohort attrition was 21% and 29%, respectively, with no decrease over calendar time (6-month P = .8735; 12-month P = .5717) or as ART services matured (6-month P = .3005; 12-month P = .2277). Additionally, attrition remained stable or decreased across both measures in nearly all countries. Initiating ART in facilities with more documented transfers and fewer women on ART, and in cohorts with poor CD4 count documentation and lower median CD4 count at ART initiation was associated with increased 6-month attrition. Increased 12-month attrition was observed in semiurban facilities and those with more documented transfers, and in cohorts with poor CD4 count documentation, whereas higher patient load was associated with decreased attrition. Conclusions Stable or decreasing trends in attrition for ART patients were observed in most countries, suggesting programs can be expanded without compromising quality. However, further reductions in attrition are needed to maximize individual and population benefits of ART.

Context: Belamaf showed deep and durable single-agent activity in the pivotal DREAMM-2 study primary analysis ( NCT03525678 ) (1–7) in a patient population that historically has a poor prognosis (overall survival [OS] 6–9 months). Objective: To present longer-term efficacy/safety outcomes (13-month follow-up) with single-agent belamaf in DREAMM-2 in the overall patient population and patients with HR cytogenetics and RI, subgroups with poor outcomes. Methods: DREAMM-2 is an ongoing study of belamaf 2.5 mg/kg (n=97) or 3.4 mg/kg (n=99). Primary outcome: overall response rate (ORR; ≥partial response). In post-hoc analyses, HR-cytogenetics included t(4;14), t(14;16), 17p13del, or 1q21 + . RI was based on eGFR (mild: ≥60– Results: Overall population ORRs in the 2.5 mg/kg and 3.4 mg/kg groups were 32% (97.5% CI: 21.7–43.6) and 35% (97.5% CI: 24.8–47.0); 19% and 23% of patients (58% and 66% of responders) achieved very good partial response or better. Median duration of response was 11.0 (95% CI: 4.2–not reached [NR]) and 6.2 months (95% CI: 4.8–NR). Median progression-free survival was 2.8 (95% CI: 1.6–3.6) and 3.9 months (95% CI: 2.0–5.8); median estimated OS was 13.7 (95% CI: 9.9–NR) and 13.8 months (95% CI: 10.0–NR). Most common Grade ≥3 adverse events (AEs) were keratopathy (microcyst-like epithelial changes [MECs] observed on eye examination; 2.5 mg/kg: 46%; 3.4 mg/kg: 42%), thrombocytopenia (2.5 mg/kg: 22%; 3.4 mg/kg: 32%), and anemia (2.5 mg/kg: 21%; 3.4 mg/kg: 27%). AE-related permanent discontinuation occurred in 9% and 12%; discontinuation due to MECs was rare (2.5 mg/kg: 1%; 3.4 mg/kg: 3%). HR cytogenetics and RI subgroup analyses will be presented at the conference. Conclusions: Deep and durable responses to single-agent belamaf were sustained and no new safety signals identified with longer follow-up in this heavily pretreated RRMM population. Funding: GSK (205678). Drug linker technology licensed from Seattle Genetics; mAb produced using POTELLIGENT Technology licensed from BioWa. References: [1] Lonial et al. Lancet Oncol. 2020. [2] Lonial et al. ASCO 2020. EP436. [3] Lonial et al. EHA 2020. EP970. [4] Cohen et al. ASCO 2020. EP441. [5] Trudel et al. EHA 2020. EP1037. [6] Lee et al. ASCO 2020. EP419. [7] Lee et al. EHA 2020. EP1006.

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.

Interim analyses of a phase I study with GSK2857916, an antibody–drug conjugate against B cell maturation antigen, have previously reported a 60% overall response and 7.9 months progression-free survival in relapsed/refractory multiple myeloma (MM). We provide updated safety and efficacy results of the BMA117159 trial following an additional 14 months' follow-up. This open-label, first-in-human, phase I study was conducted at nine centres in the USA, Canada and the UK, and included adults with MM and progressive disease after stem cell transplantation, alkylators, proteasome inhibitors, and immunomodulators. In part 1, the recommended dose of 3.4 mg/kg was identified; in part 2, patients received GSK2857916 3.4 mg/kg once every 3 weeks. Selected part 2 safety/tolerability and efficacy endpoints are reported. Twenty-one (60.0%; 95% confidence interval (CI) 42.1–76.1) of 35 patients achieved partial response or better, including two stringent complete responses and three complete responses. The median progression-free survival was 12 months and median duration of response was 14.3 months. Thrombocytopenia and corneal events were commonly reported; no new safety signals were identified. GSK2857916 was well tolerated and demonstrated a rapid, deep and durable response in heavily pre-treated patients with relapsed/refractory MM, consolidating the interim analyses conclusions that GSK2857916 is a promising treatment for these patients.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection in young children. Early detection of RSV infection can avoid unnecessary diagnostic and therapeutic intervention and is required to prevent the nosocomial spread of RSV infection in pediatric hospitals. We developed a web tool to calculate the probability of RSV infection in children hospitalized with acute respiratory tract infection (ARTI) (RSVpredict).During winter seasons 2014/2015 to 2017/2018, 1545 children hospitalized with clinical symptoms of ARTI at the University Hospital Heidelberg/Germany were prospectively included. Medical information was reported on a standardized data sheet, and nasopharyngeal swabs were obtained for multiplex real-time polymerase chain reaction analyses. We applied logistic regression to develop a prediction model and developed a web-based application to predict the individual probability of RSV infection.Duration of clinical symptoms ≥2 days on admission, calendar month of admission, admission for lower respiratory tract infection, the presence of cough and rale and younger age were associated with RSV infection (P0.05). Those data were included in the prediction model (RSVpredict, https://web.imbi.uni-heidelberg.de/rsv/). RSVpredict is a web-based application to calculate the risk of RSV infection in children hospitalized with ARTI. The prediction model is based on easily accessible clinical symptoms and predicts the individual probability of RSV infection risk immediately.Pediatricians might use the RSVpredict to take informed decisions on further diagnostic and therapeutic intervention, including targeted RSV testing in children with relevant RSV infection risk.

Measurement of the non-linear dynamics of physiologic variability in a heart rate time series (HRV) provides new opportunities to monitor cardiac autonomic activity during exercise and recovery periods. Using the Detrended Fluctuation Analysis (DFA) technique to assess correlation properties, the present study examines the influence of exercise intensity and recovery on total variability and complexity in the non-linear dynamics of HRV. Sixteen well-trained cyclists performed interval sessions with active recovery periods. During exercise, heart rate (HR) and beat-to-beat (RR)-intervals were recorded continuously. HRV time domain measurements and fractal correlation properties were analyzed using the short-term scaling exponent alpha1 of DFA. Lactate (La) levels and the rate of perceived exertion (RPE) were also recorded at regular time intervals. HR, La, and RPE showed increased values during the interval blocks (p &lt, 0.05). In contrast, meanRR and DFA-alpha1 showed decreased values during the interval blocks (p &lt, 0.05). Also, DFA-alpha1 increased to the level in the warm-up periods during active recovery (p &lt, 0.05) and remained unchanged until the end of active recovery (p = 1.000). The present data verify a decrease in the overall variability, as well as a reduction in the complexity of the RR-interval-fluctuations, owing to increased organismic demands. The acute increase in DFA-alpha1 following intensity-based training stimuli in active recovery may be interpreted as a systematic reorganization of the organism with increased correlation properties in cardiac autonomic activity in endurance trained cyclists.