Association between the length of in vitro embryo culture, mode of ART, and the initial endogenous hCG rise in ongoing singleton pregnancies.

STUDY QUESTION: Is there an association between the length of in vitro culture, mode of ART and the initial endogenous hCG rise, in cycles with a foetal heartbeat after single embryo transfer (ET) and implantation? SUMMARY ANSWER: Both the length of in vitro culture and the mode of ART have an impact on the initial endogenous rise in hCG in singleton pregnancies. WHAT IS KNOWN ALREADY: Different factors have been identified to alter the kinetics of hCG in pregnancies. Current studies show conflicting results regarding the kinetics of hCG after different types of ART (fresh vs frozen ET (FET)), the inclusion or not of preimplantation genetic testing (PGT), and the length of time in in vitro culture. STUDY DESIGN, SIZE, DURATION: This was a multicentre cohort study, using prospectively collected data derived from 4938 women (5524 treatment cycles) undergoing IUI (cycles, n = 608) or ART (cycles, n = 4916) treatments, resulting a in singleton ongoing pregnancy verified by first-trimester ultrasound scan. Data were collected from the Danish Medical Data Centre, used by the three participating Danish public fertility clinics at Copenhagen University hospitals: Herlev Hospital, Hvidovre Hospital, and Rigshospitalet, from January 2014 to December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: The fresh ET cycles included cleavage-stage (2 or 3 days in vitro) and blastocyst (5 days in vitro) transfers. FET cycles included cleavage-stage (3 days in vitro before cryopreservation) or blastocyst (5 or 6 days in vitro before cryopreservation) transfers. The IUI cycles represented no time in vitro. To attain a comparable interval for serum-hCG (s-hCG), the ovulation induction time was identical: 35-37 h before oocyte retrieval or IUI. The conception day was considered as: the insemination day for pregnancies conceived after IUI, the oocyte retrieval day for fresh ET, or the transfer day minus 3 or 5 as appropriate for FET of Day 3 or 5 embryos. Multiple linear regression analysis was used, including days post-conception for the hCG measurement as a covariate, and was adjusted for the women's age, the cause of infertility, and the centre. For FET, a sensitivity analysis was used to adjust for endometrial preparation. MAIN RESULTS AND THE ROLE OF CHANCE: The study totally includes 5524 cycles: 2395 FET cycles, 2521 fresh ET cycles, and 608 IUI cycles. Regarding the length of in vitro culture, with IUI as reference (for no time in in vitro culture), we found a significantly lower s-hCG in pregnancies achieved after fresh ET (cleavage-stage ET or blastocyst transfer). S-hCG was 18% (95% CI: 13-23%, P < 0.001) lower after fresh cleavage-stage ET, and 23% (95% CI: 18-28%, P < 0.001) lower after fresh blastocyst transfer compared to IUI. In FET cycles, s-hCG was significantly higher after blastocyst transfers compared to cleavage-stage FET, respectively, 26% (95% CI: 13-40%, P < 0.001) higher when cryopreserved on in vitro Day 5, and 14% (95% CI: 2-26%, P = 0.02) higher when cryopreserved on in vitro Day 6 as compared to Day 3. Regarding the ART treatment type, s-hCG after FET blastocyst transfer (Day 5 blastocysts) cycles was significantly higher, 33% (95% CI: 27-45%, P < 0.001), compared to fresh ET (Day 5 blastocyst), while there was no difference between cleavage-stage FET (Days 2 + 3) and fresh ET (Days 2 + 3). S-hCG was 12% (95% CI: 4-19%, 0.005) lower in PGT FET (Day 5 blastocysts) cycles as compared to FET cycles without PGT (Day 5 blastocysts). LIMITATIONS, REASONS FOR CAUTION: The retrospective design is a limitation which introduces the risk of possible bias and confounders such as embryo score, parity, and ovarian stimulation. WIDER IMPLICATIONS OF THE FINDINGS: This study elucidates how practices in medically assisted reproduction treatment are associated with the hCG kinetics, underlining a potential impact of in vitro culture length and mode of ART on the very early embryo development and implantation. The study provides clinicians knowledge that the type of ART used may be relevant to take into account when evaluating s-hCG for the prognosis of the pregnancy. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. AP has received consulting fees, research grants, or honoraria from the following companies: Preglem, Novo Nordisk, Ferring Pharmaceuticals, Gedeon Richter, Cryos, Merck A/S, and Organon. AZ has received grants and honoraria from Gedeon Richter. NLF has received grants from Gedeon Richter, Merck A/S, and Cryos. MLG has received honoraria fees or research grants from Gedeon Richter, Merck A/S, and Cooper Surgical. CB has received honoraria from Merck A/S. MB has received research grants and honoraria from IBSA. MPR, KM, and PVS all report no conflicts of interest. TRIAL REGISTRATION NUMBER: The study was registered and approved by the Danish Protection Agency, Capital Region, Denmark (Journal-nr.: 21019857). No approval was required from the regional ethics committee according to Danish law.

NSGO-OV-UMB1/ENGOT-OV30: A phase II study of durvalumab in combination with the anti-CD73 monoclonal antibody Oleclumab in patients with relapsed ovarian cancer.

OBJECTIVES: In patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. METHODS: In this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. RESULTS: This trial included 25 patients with a median age of 66 years (47-77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2-4.2) and the median overall survival was 8.4 months (95% CI: 5.0-13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. CONCLUSIONS: Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

The midpoint of cortical thinning between late childhood and early adulthood differs between individuals and brain regions: Evidence from longitudinal modelling in a 12-wave neuroimaging sample.

Charting human brain maturation between childhood and adulthood is a fundamental prerequisite for understanding the rapid biological and psychological changes during human development. Two barriers have precluded the quantification of maturational trajectories: demands on data and demands on estimation. Using high-temporal resolution neuroimaging data of up to 12-waves in the HUBU cohort (N = 90, aged 7-21 years) we investigate changes in apparent cortical thickness across childhood and adolescence. Fitting a four-parameter logistic nonlinear random effects mixed model, we quantified the characteristic, s-shaped, trajectory of cortical thinning in adolescence. This approach yields biologically meaningful parameters, including the midpoint of cortical thinning (MCT), which corresponds to the age at which the cortex shows most rapid thinning - in our sample occurring, on average, at 14 years of age. These results show that, given suitable data and models, cortical maturation can be quantified with precision for each individual and brain region.

Diabetes and COVID-19: psychosocial consequences of the COVID-19 pandemic in people with diabetes in Denmark-what characterizes people with high levels of COVID-19-related worries?

AIM: To map COVID-19-specific worries and overall psychosocial health among people with diabetes in the initial phase of the COVID-19 pandemic in Denmark, and to explore characteristics of people with diabetes and high levels of worries related to the COVID-19 pandemic. METHODS: A cross-sectional survey was conducted by distributing online questionnaires to 2430 adult members (> 18 years) of two user panels consisting of people with diabetes who have volunteered to share information about their life with diabetes. The questionnaire included items on COVID-19-specific worries as well as such worries related to diabetes, sociodemographic and health status, social relations, diabetes-specific social support, diabetes distress and changes in diabetes-specific behaviours. Responses were analysed with descriptive statistics and logistic regressions. RESULTS: People with diabetes have COVID-19-specific worries related to their diabetes. More than half were worried about being overly affected due to diabetes if infected with COVID-19, about one-third about being characterized as a risk group due to diabetes and not being able to manage diabetes if infected. Logistic regressions showed that being female, having type 1 diabetes, diabetes complications and diabetes distress, feeling isolated and lonely, and having changed diabetes behaviours were associated with being more worried about COVID-19 and diabetes. CONCLUSION: People with diabetes have COVID-19-specific worries related to their diabetes which is associated with poorer psychosocial health. These worries should be addressed through support targeting specific questions and needs of individuals with diabetes as well as frequent updates on new knowledge regarding COVID-19 and diabetes.

Asymmetries in core-collapse supernovae from maps of radioactive 44Ti in Cassiopeia A.

Asymmetry is required by most numerical simulations of stellar core-collapse explosions, but the form it takes differs significantly among models. The spatial distribution of radioactive (44)Ti, synthesized in an exploding star near the boundary between material falling back onto the collapsing core and that ejected into the surrounding medium, directly probes the explosion asymmetries. Cassiopeia A is a young, nearby, core-collapse remnant from which (44)Ti emission has previously been detected but not imaged. Asymmetries in the explosion have been indirectly inferred from a high ratio of observed (44)Ti emission to estimated (56)Ni emission, from optical light echoes, and from jet-like features seen in the X-ray and optical ejecta. Here we report spatial maps and spectral properties of the (44)Ti in Cassiopeia A. This may explain the unexpected lack of correlation between the (44)Ti and iron X-ray emission, the latter being visible only in shock-heated material. The observed spatial distribution rules out symmetric explosions even with a high level of convective mixing, as well as highly asymmetric bipolar explosions resulting from a fast-rotating progenitor. Instead, these observations provide strong evidence for the development of low-mode convective instabilities in core-collapse supernovae.

Time preferences, diabetes self-management behaviours and outcomes: a systematic review.

AIM: Time preferences, i.e. individuals' degree of patience/impatience in intertemporal choice, have been found to be associated with suboptimal health behaviours and health outcomes such as smoking, physical inactivity, unhealthy food intake and obesity. In this systematic review, we aimed to synthesise reported associations between time preferences, diabetes self-management behaviours, including use of diabetes technology, and outcomes. METHODS: We searched MEDLINE, EMBASE, PsycINFO, CINAHL, EconLit and all databases in the Web of Science Core Collection. Peer-reviewed studies of people with diabetes that included at least one diabetes-related behaviour or outcome and a measure of time preferences were included. Non-English language studies were excluded. RESULTS: A total of 961 records were identified, of which 12 articles were included. Three studies analysed both time-consistent and time-inconsistent preferences, three studies solely analysed time-inconsistent preferences and six studies did not explicitly define a time preference model. Measured outcomes across studies included self-care activities, such as medication-taking, exercising and eating a healthy diet, and biomedical outcomes, such as HbA1c and diabetes-related complications. There were 10 cross-sectional studies and two panel-data studies. No studies explicitly analysed the relationship between time preferences and diabetes technology use. CONCLUSIONS: Associations between measures of time preferences, diabetes self-management behaviours and clinical outcomes exist. Higher discount rates determined by both time-consistent and time-inconsistent models predict less diabetes-related self-care and worse outcomes. These findings may add to explanations of the observed variation in diabetes-related health and provide new insights for tailoring interventions and policies aimed at improving diabetes self-management.

A rapidly spinning supermassive black hole at the centre of NGC 1365.

Broad X-ray emission lines from neutral and partially ionized iron observed in active galaxies have been interpreted as fluorescence produced by the reflection of hard X-rays off the inner edge of an accretion disk. In this model, line broadening and distortion result from rapid rotation and relativistic effects near the black hole, the line shape being sensitive to its spin. Alternative models in which the distortions result from absorption by intervening structures provide an equally good description of the data, and there has been no general agreement on which is correct. Recent claims that the black hole (2 × 10(6) solar masses) at the centre of the galaxy NGC 1365 is rotating at close to its maximum possible speed rest on the assumption of relativistic reflection. Here we report X-ray observations of NGC 1365 that reveal the relativistic disk features through broadened Fe-line emission and an associated Compton scattering excess of 10-30 kiloelectronvolts. Using temporal and spectral analyses, we disentangle continuum changes due to time-variable absorption from reflection, which we find arises from a region within 2.5 gravitational radii of the rapidly spinning black hole. Absorption-dominated models that do not include relativistic disk reflection can be ruled out both statistically and on physical grounds.

Trends in social inequality in loneliness among adolescents 1991-2014.

BACKGROUND: Loneliness and social inequality in health are important public health concerns. We examined (i) trends in loneliness among adolescents from 1991 to 2014 in Denmark and (ii) trends in social inequality in loneliness. METHODS: Study population: 11-15-year olds in random samples of schools in 1991, 1994, 1998, 2006 and 2014, n = 19 096. Loneliness was measured by a single item and social background by parents' occupational social class (OSC). We calculated absolute (%) differences in loneliness between high and low OSC and relative differences by odds ratio for loneliness. RESULTS: Across all surveys, 6.3% reported feeling lonely. The prevalence increased from 4.4% in 1991 to 7.2% in 2014. The prevalence of loneliness in high, middle and low OSC was 5.8, 5.9 and 8.0%. The increase in loneliness was more pronounced in higher than lower OSC, resulting in a decreasing absolute social inequality in loneliness. The statistical interaction between OSC and survey year was significant, P = 0.0176, i.e. the relative social inequality in loneliness also decreased from 1991 to 2014. CONCLUSION: The prevalence of loneliness increased from 1991 to 2014. The social inequality in loneliness decreased in both absolute and relative terms because of a rising prevalence of loneliness among children from high OSC.

Altered levels of soluble CD18 may associate immune mechanisms with outcome in sepsis.

The pathogenesis of sepsis involves a dual inflammatory response, with a hyperinflammatory phase followed by, or in combination with, a hypoinflammatory phase. The adhesion molecules lymphocyte function-associated antigen (LFA-1) (CD11a/CD18) and macrophage-1 (Mac-1) (CD11b/CD18) support leucocyte adhesion to intercellular adhesion molecules and phagocytosis through complement opsonization, both processes relevant to the immune response during sepsis. Here, we investigate the role of soluble (s)CD18 in sepsis with emphasis on sCD18 as a mechanistic biomarker of immune reactions and outcome of sepsis. sCD18 levels were measured in 15 septic and 15 critically ill non-septic patients. Fifteen healthy volunteers served as controls. CD18 shedding from human mononuclear cells was increased in vitro by several proinflammatory mediators relevant in sepsis. sCD18 inhibited cell adhesion to the complement fragment iC3b, which is a ligand for CD11b/CD18, also known as Mac-1 or complement receptor 3. Serum sCD18 levels in sepsis non-survivors displayed two distinct peaks permitting a partitioning into two groups, namely sCD18 'high' and sCD18 'low', with median levels of sCD18 at 2158 mU/ml [interquartile range (IQR) 2093-2811 mU/ml] and 488 mU/ml (IQR 360-617 mU/ml), respectively, at the day of intensive care unit admission. Serum sCD18 levels partitioned sepsis non-survivors into one group of 'high' sCD18 and low CRP and another group with 'low' sCD18 and high C-reactive protein. Together with the mechanistic data generated in vitro, we suggest the partitioning in sCD18 to reflect a compensatory anti-inflammatory response syndrome and hyperinflammation, respectively, manifested as part of sepsis.

Physiological, biochemical, anthropometric, and biomechanical influences on exercise economy in humans.

Interindividual variation in running and cycling exercise economy (EE) remains unexplained although studied for more than a century. This study is the first to comprehensively evaluate the importance of biochemical, structural, physiological, anthropometric, and biomechanical influences on running and cycling EE within a single study. In 22 healthy males (VO2 max range 45.5-72.1 mL·min-1 ·kg-1 ), no factor related to skeletal muscle structure (% slow-twitch fiber content, number of capillaries per fiber), mitochondrial properties (volume density, oxidative capacity, or mitochondrial efficiency), or protein content (UCP3 and MFN2 expression) explained variation in cycling and running EE among subjects. In contrast, biomechanical variables related to vertical displacement correlated well with running EE, but were not significant when taking body weight into account. Thus, running EE and body weight were correlated (R2 =.94; P<.001), but was lower for cycling EE (R2 =.23; P<.023). To separate biomechanical determinants of running EE, we contrasted individual running and cycling EE considering that during cycle ergometer exercise, the biomechanical influence on EE would be small because of the fixed movement pattern. Differences in cycling and running exercise protocols, for example, related to biomechanics, play however only a secondary role in determining EE. There was no evidence for an impact of structural or functional skeletal muscle variables on EE. Body weight was the main determinant of EE explaining 94% of variance in running EE, although more than 50% of the variability of cycling EE remains unexplained.

Safety evaluation of a novel muramidase for feed application.

Safety evaluation of a muramidase produced by a Trichoderma reesei strain (safe lineage), expressing a muramidase gene isolated from Acremonium alcalophilum is presented. Intended use in feed of this enzyme is as digestive aid in broiler chickens. Muramidase 007, was non-mutagenic and non-clastogenic in vitro, and no adverse effects were observed in 90-day subchronic toxicity studies in rats at doses up to 1132 mg TOS/kg body weight/day. The enzyme did not exhibit, in vitro, skin, nor eye irritation potential. Acute aquatic toxicity evaluated on daphnia and algae showed absence of effect of the enzyme at the standard doses tested. Muramidase 007 was fully tolerated by broiler chickens in a 6-weeks tolerance study showing no adverse effects in any of the dietary treatments (0, 1×, 5× and 10× maximum recommended dose). In conclusion, Muramidase 007 is found to be toxicologically inert, and there are no worker's safety concerns if standard precautions are instituted and a non-dusty formulation is employed. Muramidase 007 is well tolerated by the target species (broiler chickens) and cause no harm to the environment. The beneficial safety evaluation of Muramidase 007 is in line with this type of enzyme that is found ubiquitously in nature.

Central 5-HT neurotransmission modulates weight loss following gastric bypass surgery in obese individuals.

The cerebral serotonin (5-HT) system shows distinct differences in obesity compared with the lean state. Here, it was investigated whether serotonergic neurotransmission in obesity is a stable trait or changes in association with weight loss induced by Roux-in-Y gastric bypass (RYGB) surgery. In vivo cerebral 5-HT2A receptor and 5-HT transporter binding was determined by positron emission tomography in 21 obese [four men; body mass index (BMI), 40.1 ± 4.1 kg/m(2)] and 10 lean (three men; BMI, 24.6 ± 1.5 kg/m(2)) individuals. Fourteen obese individuals were re-examined after RYGB surgery. First, it was confirmed that obese individuals have higher cerebral 5-HT2A receptor binding than lean individuals. Importantly, we found that higher presurgical 5-HT2A receptor binding predicted greater weight loss after RYGB and that the change in 5-HT2A receptor and 5-HT transporter binding correlated with weight loss after RYGB. The changes in the 5-HT neurotransmission before and after RYGB are in accordance with a model wherein the cerebral extracellular 5-HT level modulates the regulation of body weight. Our findings support that the cerebral 5-HT system contributes both to establish the obese condition and to regulate the body weight in response to RYGB.

Unaffected twins discordant for affective disorders show changes in anterior callosal white matter microstructure.

OBJECTIVE: The neurobiological mechanisms mediating an increased risk to develop affective disorders remain poorly understood. In a group of individuals with a family history of major depressive (MDD) or bipolar disorder (BD), we investigated the microstructural properties of white matter fiber tracts, that is, cingulum bundle, uncinate fasciculus, anterior limb of the internal capsule, and corpus callosum, that facilitate the communication between brain regions implicated in affective disorders. METHOD: Eighty-nine healthy mono- or dizygotic twins with a co-twin diagnosed with MDD or BD (high-risk) and 57 healthy twins with a co-twin with no familial history of affective disorders (low-risk) were included in a diffusion tensor imaging study. RESULT: The high-risk group showed decreased fractional anisotropy (FA), a measure of water diffusion directionality, and increased radial diffusivity in the anterior region of corpus callosum compared to the low-risk group. This abnormality was not associated with zygosity or type of depressive disorder of co-twin. CONCLUSION: The observed decreased anterior callosal fiber FA in the high-risk group may be indicative of a compromised interhemispheric communication between left and right frontal regions critically involved in mood regulation. Reduced anterior callosal FA may act as a vulnerability marker for affective disorders in individuals at familial risk.

Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: a [11C]SB207145 PET study.

Identification of a biomarker that can inform on extracellular serotonin (5-HT) levels in the brains of living humans would enable greater understanding of the way brain circuits are modulated by serotonergic neurotransmission. Substantial evidence from studies in animals and humans indicates an inverse relationship between central 5-HT tonus and 5-HT type 4 receptor (5-HT4R) density, suggesting that 5-HT4R receptor density may be a biomarker marker for 5-HT tonus. Here, we investigated whether a 3-week administration of a selective serotonin reuptake inhibitor, expected to increase brain 5-HT levels, is associated with a decline in brain 5-HT4R binding. A total of 35 healthy men were studied in a placebo-controlled, randomized, double-blind study. Participants were assigned to receive 3 weeks of oral dosing with placebo or fluoxetine, 40 mg per day. Brain 5-HT4R binding was quantified at baseline and at follow-up with [(11)C]SB207145 positron emission tomography (PET). Three weeks of intervention with fluoxetine was associated with a 5.2% reduction in brain 5-HT4R binding (P=0.017), whereas placebo intervention did not change 5-HT4R binding (P=0.52). Our findings are consistent with a model, wherein the 5-HT4R density adjusts to changes in the extracellular 5-HT tonus. Our data demonstrate for the first time in humans that the imaging of central 5-HT4R binding may be used as an in vivo biomarker of the central 5-HT tonus.

Physiological capacity and physical testing in male elite team handball.

AIM: The aim of the present study was to examine the physical demands placed on male elite team handball players in relation to playing position. METHODS: Male elite team handball field players were evaluated during match-play over a six season time span using physiological measurements and by subsequent physical testing. RESULTS: Mean heart rate and relative workload during match-play (N.=41) were 163 ± 5 beats·min⁻¹ (group means±SD) and 70.9 ± 6.0% of VO(2-max), respectively. Relative workload was lower (P<0.01) in the second half vs. the first (66.3 ± 5.9% vs. 75.4 ± 5.6% of VO(2-max)). Post-match blood lactate concentration was 4.8 ± 1.9 mM (range: 2.8-10.8 mM). Mean fluid loss was 0.81 ± 0.41 l pr. match. Mean VO(2max) was 5.18 ± 0.66 l O2·min-1 corresponding to 57.0 ± 4.1 mL O2·min⁻¹·kg⁻¹. Mean total running distance in the Yo-Yo intermittent recovery test (level 2) was 895 ± 184 m (range: 520-1360 m), which was greater in wing players (975 ± 123 m) than backcourt players (897 ± 108 m) and pivots (827 ± 264 m) (P<0.05). Fastest 30-m sprint time was 4.09 ± 0.12 s (range: 3.87-4.28 s). The repeated sprint test (7 x 30 m) yielded a mean fatigue index of -8.1 ± 2.7 %. Maximal jumping height in "Jump and Reach" testing was 0.71 ± 0.08 m (range: 0.61-0.86 m). Maximal ball throwing speed was observed using the set shot with 3-step run-up (92.8 ± 5.3 km·h⁻¹, range: 75.8-108.2 km·h⁻¹). CONCLUSION: Modern male elite team handball imposes moderate-to-high demands on the aerobic energy system and high demands on the anaerobic energy systems during certain periods of the match. Indications of temporary fatigue and a subsequent decline in performance were observed, since the relative workload decreased both in the first and in the second half of the match. Physiological profiles and physical test results differed between playing positions, with wing players covering a greater total distance in the Yo-Yo test and showing superior jumping performance and repeated sprint running capacity than backcourt players and pivots.

Match performance and physiological capacity of female elite team handball players.

The present study evaluated the physical demands imposed on female elite team handball players in relation to playing position. Female elite team handball field players were examined during match-play over a 5-year period using video based computerized locomotion analysis of tournament matches. In addition, physiological measurements during match-play and in separate physical tests were carried out. A total distance of 4002±551 m (group means±SD) was covered per match with a total effective playing time of 50:42±5:50 min:s, while full-time players covered 4693±333 m. On average, each player (n=83) performed 663.8±99.7 activity changes per match, and the mean speed was 5.31±0.33 km · h(-1). High-intensity running constituted 0.8±0.5% of total effective playing time per match corresponding to 2.5±1.8% of the total distance covered. The amount of high-intensity running was reduced (p<0.05) 21.9% in the second half (44.9±16.8 m) compared to the first (57.5±21.3 m). Maximal oxygen uptake (VO2-max) was 3.49±0.37 l O2 · min(-1) corresponding to 49.6±4.8 ml O2 · min(-1) · kg(-1). Mean relative workload during match-play was 79.4±6.4% of VO2-max. Mean total running distance in the Yo-Yo intermittent recovery test (level 1) was 1436±222 m, which was greater in wing players (1516±172 m, p<0.05) than pivots (1360±118 m) and backcourt players (1352±148 m). In conclusion, modern female elite team handball is a physically demanding intermittent team sport, where players are exposed to high relative workloads with substantial estimated aerobic energy expenditure interspersed by short periods of dominant anaerobic energy production as reflected by the limited amount of high-intensity running. Indications of fatigue and a resulting decline in physical performance were identified, since the amount of high-intensity running and the relative workload levels decreased in the second half. Positional differences were observed, with wing players covering a greater total distance than backcourt players, performing more high-intensity running and demonstrating a better intermittent recovery capacity (Yo-Yo test outcome) compared to both backcourt players and pivots.

Circulating immune-related proteins associated with immune checkpoint inhibitor efficacy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Most patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint inhibitor treatment. However, the phase II study CheckPAC (NCT02866383) showed a clinical benefit (CB) rate of 37% and a response rate of 14% in patients with metastatic PDAC receiving stereotactic radiation therapy and nivolumab with or without ipilimumab. Translational studies were initiated to characterize the patients who would benefit from this treatment. Here, we evaluated the association between treatment outcome and 92 circulating immuno-oncology-related proteins in patients from the CheckPAC trial. MATERIALS AND METHODS: The study included 78 patients with chemoresistant metastatic PDAC treated with nivolumab ± ipilimumab combined with radiotherapy. Proteins were measured in serum samples collected at baseline and on treatment with the use of the Olink Target 96 Immuno-Oncology panel. A cohort of 234 patients with metastatic PDAC treated with first-line chemotherapy were also included. RESULTS: High levels of Fas ligand (FASLG) and galectin 1 (Gal-1) and low levels of C-C motif chemokine 4 were associated with CB. High FASLG and Gal-1 were associated with longer progression-free survival in univariable analysis. In the multivariable Cox regression analysis, the association was significant for Gal-1 (P < 0.001) but not significant for FASLG (P = 0.06). A focused unsupervised hierarchal clustering analysis, including T-cell activation and immune checkpoint-related proteins, identified clusters of patients with higher CB rate and higher tumor expression of leukocyte or T-cell markers (CD3, CD45, granzyme B). Thirty-six proteins increased significantly during immunotherapy. Several proteins (including FASLG, checkpoint proteins, and immune activation markers) increased independently of response during immunotherapy but did not increase in the cohort of patients treated with chemotherapy. CONCLUSIONS: Circulating levels of immune-related proteins like FASLG and Gal-1 might be used to predict the efficacy of checkpoint inhibitors in patients with metastatic PDAC.

Resting-state connectivity of pre-motor cortex reflects disability in multiple sclerosis.

OBJECTIVE: To characterize the relationship between motor resting-state connectivity of the dorsal pre-motor cortex (PMd) and clinical disability in patients with multiple sclerosis (MS). MATERIALS AND METHODS: A total of 27 patients with relapsing-remitting MS (RR-MS) and 15 patients with secondary progressive MS (SP-MS) underwent functional resting-state magnetic resonance imaging. Clinical disability was assessed using the Expanded Disability Status Scale (EDSS). Independent component analysis was used to characterize motor resting-state connectivity. Multiple regression analysis was performed in SPM8 between the individual expression of motor resting-state connectivity in PMd and EDSS scores including age as covariate. Separate post hoc analyses were performed for patients with RR-MS and SP-MS. RESULTS: The EDSS scores ranged from 0 to 7 with a median score of 4.3. Motor resting-state connectivity of left PMd showed a positive linear relation with clinical disability in patients with MS. This effect was stronger when considering the group of patients with RR-MS alone, whereas patients with SP-MS showed no increase in coupling strength between left PMd and the motor resting-state network with increasing clinical disability. No significant relation between motor resting-state connectivity of the right PMd and clinical disability was detected in MS. CONCLUSIONS: The increase in functional coupling between left PMd and the motor resting-state network with increasing clinical disability can be interpreted as adaptive reorganization of the motor system to maintain motor function, which appears to be limited to the relapsing-remitting stage of the disease.

Effect of whey protein- and carbohydrate-enriched diet on glycogen resynthesis during the first 48 h after a soccer game.

The effect of a whey protein- and carbohydrate (CHO)-enriched diet on the rate of muscle glycogen resynthesis after a soccer match was examined. Sixteen elite soccer players were randomly assigned to a group ingesting a diet rich in carbohydrates and whey protein [CHO, protein, and fat content was 71, 21, and 8E%, respectively; high content of carbohydrates and whey protein (HCP), n = 9] or a group ingesting a normal diet (55, 18, and 26E%; control [CON], n = 7) during a 48-h recovery period after a soccer match. CON and three additional players carried out a 90- and 60-min simulated match without body contacts (SIM90 and SIM60). Muscle glycogen was lowered (P < 0.05) by 54, 48, 53, and 38% after the matches in CON, HCP, SIM90, and SIM60, respectively. Glycogen resynthesis during the first 48 h after the match was not different between CON and HCP, whereas glycogen resynthesis was slower (P < 0.05) during the first 24 h after SIM60 than SIM90 (2.88 ± 0.84 vs 4.32 ± 0.54 mmol/kg dw/h). In HCP, glycogen content in type II muscle fibers was still lowered 48 h after the match. In conclusion, glycogen resynthesis 48 h after a soccer match is not elevated by ingestion of a HCP diet. Furthermore, glycogen resynthesis does not appear to be impaired by body contacts during a match.