Shoulder muscle activation strategies differ when lifting or lowering a load

Purpose Lowering a load could be associated with abnormal shoulder and scapular motion. We tested the hypothesis that lowering a load involves different shoulder muscle coordination strategies compared to lifting a load. Methods EMG activity of 13 muscles was recorded in 30 healthy volunteers who lifted and lowered a 6, 12 or 18 kg box between three shelves. Kinematics, EMG levels and muscle synergies, extracted using non-negative matrix factorization, were analyzed. Results We found greater muscle activity level during lowering in four muscles (+ 1–2% MVC in anterior deltoid, biceps brachii, serratus anterior and pectoralis major). The movements were performed faster during lifting (18.2 vs. 15.9 cm/s) but with similar hand paths and segment kinematics. The number of synergies was the same in both tasks. Two synergies were identified in ~ 75% of subjects, and one synergy in the others. Synergy #1 mainly activated prime movers’ muscles, while synergy #2 co-activated several antagonist muscles. Synergies’ structure was similar between lifting and lowering (Pearson’s r ≈ 0.9 for synergy #1 and 0.7–08 for synergy #2). Synergy #2 was more activated during lowering and explained the greater activity observed in anterior deltoid, serratus anterior and pectoralis. Conclusion Lifting and lowering a load were associated with similar synergy structure. In 3/4 of subjects, lowering movements involved greater activation of a “multiple antagonists” synergy. The other subjects co-contracted all shoulder muscles as a unit in both conditions. These inter-individual differences should be investigated in the occurrence of shoulder musculoskeletal disorders

A phase 1, first-in-child, multicenter study to evaluate the safety and efficacy of the oncolytic herpes virus talimogene laherparepvec in pediatric patients with advanced solid tumors

BACKGROUND The survival rates for pediatric patients with relapsed and refractory tumors are poor. Successful treatment strategies are currently lacking and there remains an unmet need for novel therapies for these patients. We report here the results of a phase 1 study of talimogene laherparepvec (T-VEC) and explore the safety of this oncolytic immunotherapy for the treatment of pediatric patients with advanced non-central nervous system tumors. METHODS T-VEC was delivered by intralesional injection at 10$^{6}$ plaque-forming units (PFU)/ml on the first day, followed by 10$^{8}$ PFU/ml on the first day of week 4 and every 2 weeks thereafter. The primary objective was to evaluate the safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs). Secondary objectives included efficacy indicated by response and survival per modified immune-related response criteria simulating the Response Evaluation Criteria in Solid Tumors (irRC-RECIST). RESULTS Fifteen patients were enrolled into two cohorts based on age: cohort A1 (n = 13) 12 to ≤21 years old (soft-tissue sarcoma, n = 7; bone sarcoma, n = 3; neuroblastoma, n = 1; nasopharyngeal carcinoma, n = 1; and melanoma, n = 1) and cohort B1 (n = 2) 2 to <12 years old (melanoma, n = 2). Overall, patients received treatment for a median (range) of 5.1 (0.1, 39.4) weeks. No DLTs were observed during the evaluation period. All patients experienced at least one treatment-emergent adverse event (TEAE), and 53.3% of patients reported grade ≥3 TEAEs. Overall, 86.7% of patients reported treatment-related TEAEs. No complete or partial responses were observed, and three patients (20%) overall exhibited stable disease as the best response. CONCLUSIONS T-VEC was tolerable as assessed by the observation of no DLTs. The safety data were consistent with the patients' underlying cancer and the known safety profile of T-VEC from studies in the adult population. No objective responses were observed. TRIAL REGISTRATION ClinicalTrials.gov: NCT02756845. https://clinicaltrials.gov/ct2/show/NCT02756845

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches

Multi-band analyses of the bright GRB~230812B and the associated SN2023pel

GRB~230812B is a bright and relatively nearby ($z =0.36$) long gamma-ray burst that has generated significant interest in the community and therefore has been subsequently observed over the entire electromagnetic spectrum. We report over 80 observations in X-ray, ultraviolet, optical, infrared, and sub-millimeter bands from the GRANDMA (Global Rapid Advanced Network for Multi-messenger Addicts) network of observatories and from observational partners. Adding complementary data from the literature, we then derive essential physical parameters associated with the ejecta and external properties (i.e. the geometry and environment) and compare with other analyses of this event (e.g. Srinivasaragavan et al. 2023). We spectroscopically confirm the presence of an associated supernova, SN2023pel, and we derive a photospheric expansion velocity of v $\sim$ 17$\times10^3$ km $s^{-1}$. We analyze the photometric data first using empirical fits of the flux and then with full Bayesian Inference. We again strongly establish the presence of a supernova in the data, with an absolute peak r-band magnitude $M_r = - 19.41 \pm 0.10$. We find a flux-stretching factor or relative brightness $k_{\rm SN}=1.04 \pm 0.09$ and a time-stretching factor $s_{\rm SN}=0.68 \pm 0.05$, both compared to SN1998bw. Therefore, GRB 230812B appears to have a clear long GRB-supernova association, as expected in the standard collapsar model. However, as sometimes found in the afterglow modelling of such long GRBs, our best fit model favours a very low density environment ($\log_{10}({n_{\rm ISM}/{\rm cm}^{-3}}) = -2.16^{+1.21}_{-1.30}$). We also find small values for the jet's core angle $\theta_{\rm core}={1.70^{+1.00}_{-0.71}} \ \rm{deg}$ and viewing angle. GRB 230812B/SN2023pel is one of the best characterized afterglows with a distinctive supernova bump

Meta-analysis of human genome-microbiome association studies: the MiBioGen consortium initiative

Abstract Background In recent years, human microbiota, especially gut microbiota, have emerged as an important yet complex trait influencing human metabolism, immunology, and diseases. Many studies are investigating the forces underlying the observed variation, including the human genetic variants that shape human microbiota. Several preliminary genome-wide association studies (GWAS) have been completed, but more are necessary to achieve a fuller picture. Results Here, we announce the MiBioGen consortium initiative, which has assembled 18 population-level cohorts and some 19,000 participants. Its aim is to generate new knowledge for the rapidly developing field of microbiota research. Each cohort has surveyed the gut microbiome via 16S rRNA sequencing and genotyped their participants with full-genome SNP arrays. We have standardized the analytical pipelines for both the microbiota phenotypes and genotypes, and all the data have been processed using identical approaches. Our analysis of microbiome composition shows that we can reduce the potential artifacts introduced by technical differences in generating microbiota data. We are now in the process of benchmarking the association tests and performing meta-analyses of genome-wide associations. All pipeline and summary statistics results will be shared using public data repositories. Conclusion We present the largest consortium to date devoted to microbiota-GWAS. We have adapted our analytical pipelines to suit multi-cohort analyses and expect to gain insight into host-microbiota cross-talk at the genome-wide level. And, as an open consortium, we invite more cohorts to join us (by contacting one of the corresponding authors) and to follow the analytical pipeline we have developed

Meta-analysis of human genome-microbiome association studies: The MiBioGen consortium initiative

Background: In recent years, human microbiota, especially gut microbiota, have emerged as an important yet complex trait influencing human metabolism, immunology, and diseases. Many studies are investigating the forces underlying the observed variation, including the human genetic variants that shape human microbiota. Several preliminary genome-wide association studies (GWAS) have been completed, but more are necessary to achieve a fuller picture. Results: Here, we announce the MiBioGen consortium initiative, which has assembled 18 population-level cohorts and some 19,000 participants. Its aim is to generate new knowledge for the rapidly developing field of microbiota research. Each cohort has surveyed the gut microbiome via 16S rRNA sequencing and genotyped their participants with full-genome SNP arrays. We have standardized the analytical pipelines for both the microbiota phenotypes and genotypes, and all the data have been processed using identical approaches. Our analysis of microbiome composition shows that we can reduce the potential artifacts introduced by technical differences in generating microbiota data. We are now in the process of benchmarking the association tests and performing meta-analyses of genome-wide associations. All pipeline and summary statistics results will be shared using public data repositories. Conclusion: We present the largest consortium to date devoted to microbiota-GWAS. We have adapted our analytical pipelines to suit multi-cohort analyses and expect to gain insight into host-microbiota cross-talk at the genome-wide level. And, as an open consortium, we invite more cohorts to join us (by contacting one of the corresponding authors) and to follow the analytical pipeline we have developed

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60&nbsp;years old

Multiband analyses of the bright GRB 230812B and the associated SN2023pel

GRB 230812B is a bright and relatively nearby (z = 0.36) long gamma-ray burst (GRB) that has generated significant interest in the community and has thus been observed over the entire electromagnetic spectrum. We report over 80 observations in X-ray, ultraviolet, optical, infrared, and submillimetre bands from the GRANDMA (Global Rapid Advanced Network for Multimessenger Addicts) network of observatories and from observational partners. Adding complementary data from the literature, we then derive essential physical parameters associated with the ejecta and external properties (i.e. the geometry and environment) of the GRB and compare with other analyses of this event. We spectroscopically confirm the presence of an associated supernova, SN2023pel, and we derive a photospheric expansion velocity of v ∼ 17 × 103 km s-1. We analyse the photometric data first using empirical fits of the flux and then with full Bayesian inference. We again strongly establish the presence of a supernova in the data, with a maximum (pseudo-)bolometric luminosity of 5.75 × 1042 erg s-1, at 15.76+-10.2181 d (in the observer frame) after the trigger, with a half-max time width of 22.0 d. We compare these values with those of SN1998bw, SN2006aj, and SN2013dx. Our best-fitting model favours a very low density environment (log10(nISM/cm-3) = -2.38+-11.6045) and small values for the jet's core angle θcore = 1.54+-01.8102 deg and viewing angle θobs = 0.76+-01.7629 deg. GRB 230812B is thus one of the best observed afterglows with a distinctive supernova bump

Center of Mass behavior during forward and backward walking

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