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.

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.

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.

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.

Metastatic atypical renal tumour with metanephric characteristics treated with Sunitinib.

Metanephric Adenoma (MA) is a rare and unclassifiable renal tumour with sparse reported clinical and morphological features. Generally MA's have a benign course without recurrence after nephrectomy, however a few cases received oncological treatment due to malignant progression. We present a 42-year-old woman who years after an initial nephrectomy developed several processes and biopsy confirmed recurrence of MA. Sunitinib was given for only two weeks, as she developed side-effects and currently the patient undergoes control scans with only minimal growth of the processes. This is the first case of MA treated with Tyrosin-Kinase-Inhibitor.

Do outpatients with cancer and their relatives want to use an online booking system to book the appointment and radiographer for their CT examination? A small-scale study in Denmark.

INTRODUCTION: Previous studies have found that online booking systems may be the preferred scheduling tool when booking appointments with healthcare providers. The aim of this study was to examine I) if outpatients with cancer and relatives of cancer patients wanted to use an online booking system to book appointments for the CT examinations, and II) if they wanted to book specific radiographers for the CT examinations. METHODS: An online questionnaire was distributed to outpatients with cancer and relatives of cancer patients registered in the user panel of the Danish Cancer Society. The questionnaires consisted of 13 questions for patients and eight questions for relatives. The study applied statistical analysis and qualitative content analysis with an inductive approach. RESULTS: In total, 555 patients out of 760 (73%) and 115 out of 341 (34%) relatives were included in the present study and 54% of the patients and 65% of the relatives responded that they wanted, "To a high degree" or "To some degree", to use an online system for booking the appointment of the CT examination. Furthermore, 49% of the patients and 60% of the relatives found it important, "To a high degree" or "To some degree", that the appointment of the CT examination also suited their relatives. Only 37% of the patients, in contrast to 56% of the relatives, were interested in the opportunity to book specific radiographers. Approximately half of the patients (48%) and relatives (58%) were interested in being scanned by the same radiographers. CONCLUSION: In this study, a majority of patients and relatives were interested in using an online booking system to book their CT examinations. Furthermore, while a majority of the relatives were more interested in booking specific radiographers for the CT examinations, only a few patients were interested in this function. IMPLICATIONS FOR PRACTICE: Using an online booking system to book the appointment could benefit the overall experience for cancer patients and relatives when attending a CT examination to ensure that the appointment also suits the relatives.

Comparison of reporting radiographers' and medical doctors' performance in reporting radiographs of the appendicular skeleton, referred by the emergency department.

INTRODUCTION: There is an increasing trend towards deploying reporting radiographers in Danish hospitals who, among various professional groups, interpret and report skeletal radiographs from the emergency department (ED). This study aimed to compare the quality of the reports issued by reporting radiographers to three different groups of medical doctors (MDs) who interpret or report skeletal radiographs at the ED. METHODS: Four professional groups (i.e. four reporting radiographers, two radiology trainees, two orthopaedic senior trainees, and two orthopaedic trainees) reported 100 radiographs of the appendicular skeleton. The Consequence of clinical Outcome score (CO-score), accuracy, sensitivity, and specificity of each group were compared. The relative risk of a false-negative, false-positive or wrong result, the risk of a serious error, as well as the odds ratio of a more severe CO-score for each of the three MD groups, were compared to the reporting radiographers. RESULTS: There was a significant difference between the groups in reference to the CO-score (P ≤ 0.001), accuracy (P = .003), specificity (P = .022), and in the proportion of serious errors (P ≤ 0.001). Compared to the reporting radiographers, all three groups of MDs showed a significantly higher CO-score and a significantly increased risk of a wrong result. Moreover, two of the MD groups showed a significantly increased risk of a false-positive result and for severe errors. CONCLUSION: Based on the CO-score, the relative risk of errors, which could potentially cause malpractice in treatment and patient recall, significantly decreased when the reports were completed by reporting radiographers. IMPLICATIONS FOR PRACTICE: To explore the need for a 24-h radiographer reporting service to the EDs, an upscaled study, like the current, with more participants representing the professional groups is highly recommended.

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.

CO-score; a new method for quality assessment of radiology reports.

INTRODUCTION: Studies on assessing radiology reports commonly calculates sensitivity, specificity and accuracy, which estimates if the observer has tendency to overdiagnose, overlook pathology, or both. This pilot study examines a new method for assessing the quality of radiology reports, based on the patients' clinical outcome. METHODS: Two observers evaluated five hundred reports by four experienced reporting radiographers on X-ray images of the appendicular skeleton. The observers categorised the reports as true or false and gradated the quality of the report from 1 to 3 based on the patients' clinical outcome. We developed a new performance score, called the Consequence of Clinical Outcome (CO-score), which combines the amount of incorrect reports and the severity of errors, to assess the overall quality of the reports. A low CO-score represents high quality with few or inconsiderate errors. RESULTS: The results showed no direct connection between high accuracy and low CO-score. All radiographers achieved high levels of accuracy (range: 96.8%-100%) but varied in CO-score (range: 0.00-0.14). One radiographer achieved an accuracy of 97.6% but a high CO-score of 0.14 as four reports had clinical consequence for the patients and five reports lacked minor details. One report was classified as true positive but was inadequate and led to wrong treatment. CONCLUSION: This study shows that true reports can affect the patients' clinical outcome and reports classified as false can represent insignificant errors. The new CO-score gives a more nuanced view of the reporting quality by including the patients' clinical outcome in the performance score. IMPLICATIONS FOR PRACTICE: We suggest that the CO-score is included as a supplement to the common methods in future studies assessing the quality of radiology reports as well as in clinical audits.

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.

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.

Associations between community programmes and policies and children's physical activity: the Healthy Communities Study.

BACKGROUND: Community initiatives to promote physical activity in children are common, but evidence supporting their effectiveness is limited. OBJECTIVES: The objective of this study is to examine the relationships between community programmes and policies and children's physical activity in a large and diverse sample of US communities. METHODS: Programmes and policies to promote children's physical activity were assessed in 130 communities by key informant interviews, and physical activity behaviours were measured by self-report and parental report in samples of children in each community (total n = 5138). Associations between composite indices of community programmes and policies and indicators of total and moderate-to-vigorous physical activity were examined without and with adjustment for demographic factors. RESULTS: An index reflecting the 6-year history of the number of behaviour change strategies used in community programmes and policies was positively associated with children's moderate-to-vigorous physical activity. This association was attenuated with adjustment for demographic factors. Effect modification analyses found that the association was positive among non-Hispanic children but was negative for Hispanic children. CONCLUSIONS: Community initiatives to promote physical activity in children were positively associated with children's physical activity in non-Hispanic children. Such initiatives were negatively associated with physical activity in Hispanic children, suggesting that future research should consider unique cultural factors when designing community initiatives to promote activity in this population sub-group.

Swift and NuSTAR observations of GW170817: Detection of a blue kilonova.

With the first direct detection of merging black holes in 2015, the era of gravitational wave (GW) astrophysics began. A complete picture of compact object mergers, however, requires the detection of an electromagnetic (EM) counterpart. We report ultraviolet (UV) and x-ray observations by Swift and the Nuclear Spectroscopic Telescope Array of the EM counterpart of the binary neutron star merger GW170817. The bright, rapidly fading UV emission indicates a high mass (≈0.03 solar masses) wind-driven outflow with moderate electron fraction (Ye ≈ 0.27). Combined with the x-ray limits, we favor an observer viewing angle of ≈30° away from the orbital rotation axis, which avoids both obscuration from the heaviest elements in the orbital plane and a direct view of any ultrarelativistic, highly collimated ejecta (a γ-ray burst afterglow).

Fecal Microbial Transplantation in Inflammatory Bowel Disease: A Movement Too Big to Be Ignored.

The development of new therapies for inflammatory bowel disease is plagued by high costs, potential side effects, and variable levels of effectiveness. Fecal microbial transplant in inflammatory bowel diseases can offer an alternative to traditionally developed pharmacologic therapies and has demonstrated the ability to induce disease remission in randomized control trials. However, questions remain about the ultimate role of this therapy in disease management, including long term safety, and the optimal composition of transplanted stool.

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.

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.

PGM1 deficiency: Substrate use during exercise and effect of treatment with galactose.

Mutations in PGM1 (phosphoglucomutase 1) cause Glycogen Storage Disease type XIV, which is also a congenital disorder of protein N-glycosylation. It presents throughout life as myopathy with additional systemic symptoms. We report the effect of oral galactose treatment during five months in a patient with biochemically and genetically confirmed PGM1 deficiency. The 12-minute-walking distance increased by 225 m (65%) and transferrin glycosylation was restored to near-normal levels. The exercise assessments showed a severe exercise intolerance due to a block in skeletal muscle glycogenolytic capacity and that galactose treatment tended to normalize skeletal muscle substrate use from fat to carbohydrates during exercise.