Health Problems of Professional Ballet Dancers: an Analysis of 1627 Weekly Self-Reports on Injuries, Illnesses and Mental Health Problems During One Season.

BACKGROUND: Several studies have investigated injuries of (pre-)professional ballet dancers, however most used a medical-attention and/or time-loss definition and did not analyse the prevalence of all health problems. The aim was to analyse the frequency and characteristics of all self-reported physical and mental health complaints (i.e. injuries, illnesses and mental health problems) of professional ballet dancers during one season. METHODS: Three professional ballet companies were prospectively monitored weekly during one season with the Performing artist and Athlete Health Monitor (PAHM). Numerical rating scales (ranging 0-10) were used for severity of musculoskeletal pain, all health problems and impairment of the ability to dance at full potential in the previous seven days. If dancers rated the severity of their health problems or their impairment greater than 0, they were asked to answer specific questions on the characteristics of each health problem. RESULTS: Over a period of 44 weeks, 57 dancers (57.9% female) filled in 1627 weekly reports (response rate of 64.9%), in which 1020 (62.7%) health problem were registered. The dancers reported musculoskeletal pain in 82.2% of the weeks. They felt that their ability to dance at their full potential was affected due to a health problem in about every second week (52.6%) or on at least 29.1% of the days documented in the weekly reports. Almost all dancers (96.5%) reported at least one injury, almost two thirds (64.9%) an illness and more than a quarter (28.1%) a mental health problem. On average, every dancer reported 5.6 health problems during the season. Most of the 320 health problems were injuries (73.1%), 16.9% illnesses and 10.0% mental health problems. Injuries affected mainly ankle, thigh, foot, and lower back and were mostly incurred during rehearsal (41.6%) or training (26.1%). The most frequent subjective reasons of injury were "too much workload" (35.3%), "tiredness/exhaustion" (n = 22.4%) and "stress/overload/insufficient regeneration" (n = 21.6%). CONCLUSION: Preventive interventions are urgently required to reduce the prevalence of health problems and especially injuries of professional dancers. Injury prevention measures should regard the balance of the load capacity of professional dancers and the workload in training, rehearsals and performances.

INT-1B3, an LNP formulated miR-193a-3p mimic, promotes anti-tumor immunity by enhancing T cell mediated immune responses via modulation of the tumor microenvironment and induction of immunogenic cell death.

microRNAs (miRNAs) are small, non-coding RNAs that regulate expression of multiple genes. MiR-193a-3p functions as a tumor suppressor in many cancer types, but its effect on inducing specific anti-tumor immune responses is unclear. Therefore, we examined the effect of our lipid nanoparticle (LNP) formulated, chemically modified, synthetic miR-193a-3p mimic (INT-1B3) on anti-tumor immunity. INT-1B3 inhibited distant tumor metastasis and significantly prolonged survival. INT-1B3-treated animals were fully protected against challenge with autologous tumor cells even in absence of treatment indicating long-term immunization. Protection against autologous tumor cell challenge was hampered upon T cell depletion and adoptive T cell transfer abrogated tumor growth. Transfection of tumor cells with our miR-193a-3p mimic (1B3) resulted in tumor cell death and apoptosis accompanied by increased expression of DAMPs. Co-culture of 1B3-transfected tumor cells and immature DC led to DC maturation and these mature DC were able to stimulate production of type 1 cytokines by CD4+ and CD8+ T cells. CD4-CD8- T cells also produced type 1 cytokines, even in response to 1B3-transfected tumor cells directly. Live cell imaging demonstrated PBMC-mediated cytotoxicity against 1B3-transfected tumor cells. These data demonstrate for the first time that miR-193a-3p induces long-term immunity against tumor development via modulation of the tumor microenvironment and induction of immunogenic cell death.

Injury Prevalence Among Elite Adolescent Ballet Dancers is not Affected by Frequency of Questionnaire Administration: A 6-Month Exploratory Prospective Study.

INTRODUCTION: The Oslo Sports Trauma Research Centre Questionnaire on Health Problems (OSTRC-H) is a valid and reliable registration method for self-reported injuries and is regularly used among dancer populations. Monthly questionnaire administration is acceptable in athlete populations but has not been evaluated in dancers. The aim of this exploratory study was to assess the influence of weekly versus monthly administration of the OSTRC-H on estimated injury outcomes among elite adolescent ballet dancers. METHODS: Participants (n = 103) were prospectively followed for 6 months and completed the OSTRC-H online, evaluating perceived consequences of self-reported health problems during the previous week and the previous 4 weeks, respectively. Four definitions of dance-related injury were utilized: (1) all complaints, (2) substantial, (3) medical attention, and (4) time-loss injuries. Descriptive statistics estimated: (1) the number of injuries reported (count), (2) average injury prevalence [proportion, 95% confidence intervals (CI)], (3) average severity score (0-100), and (4) days of time loss (count) for each injury definition. The 4 outcome measures were then compared between weekly and monthly registration with paired sample t-tests (P < .05) and overlapping 95% CI. RESULTS: A significant difference between the number of all complaints injuries (weekly: 133; monthly: 94; P < .001) and substantial injuries (weekly: 64; monthly: 45; P = .012) was found. Regardless of injury definition, there were no significant differences between injury prevalence, severity scores, and days of time loss when reported weekly versus monthly. CONCLUSION: Monthly administration of the OSTRC-H is an acceptable method to estimate injury prevalence, severity scores, and days of time loss amongst elite adolescent ballet dancers.

Total mesorectal excision in MRI-defined low rectal cancer: multicentre study comparing oncological outcomes of robotic, laparoscopic and transanal total mesorectal excision in high-volume centres.

BACKGROUND: The routine use of MRI in rectal cancer treatment allows the use of a strict definition for low rectal cancer. This study aimed to compare minimally invasive total mesorectal excision in MRI-defined low rectal cancer in expert laparoscopic, transanal and robotic high-volume centres. METHODS: All MRI-defined low rectal cancer operated on between 2015 and 2017 in 11 Dutch centres were included. Primary outcomes were: R1 rate, total mesorectal excision quality and 3-year local recurrence and survivals (overall and disease free). Secondary outcomes included conversion rate, complications and whether there was a perioperative change in the preoperative treatment plan. RESULTS: Of 1071 eligible rectal cancers, 633 patients with low rectal cancer were identified. Quality of the total mesorectal excision specimen (P = 0.337), R1 rate (P = 0.107), conversion (P = 0.344), anastomotic leakage rate (P = 0.942), local recurrence (P = 0.809), overall survival (P = 0.436) and disease-free survival (P = 0.347) were comparable among the centres. The laparoscopic centre group had the highest rate of perioperative change in the preoperative treatment plan (10.4%), compared with robotic expert centres (5.2%) and transanal centres (2.1%), P = 0.004. The main reason for this change was stapling difficulty (43%), followed by low tumour location (29%). Multivariable analysis showed that laparoscopic surgery was the only independent risk factor for a change in the preoperative planned procedure, P = 0.024. CONCLUSION: Centres with expertise in all three minimally invasive total mesorectal excision techniques can achieve good oncological resection in the treatment of MRI-defined low rectal cancer. However, compared with robotic expert centres and transanal centres, patients treated in laparoscopic centres have an increased risk of a change in the preoperative intended procedure due to technical limitations.

Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory Multiple Myeloma.

Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients. We found that a significantly higher proportion of RRMM patients (86%) exhibited aberrant co-expression of CD28 compared to newly diagnosed MM (NDMM) patients (19%). Furthermore, SAR442257 mediated significantly higher TC activation, resulting in enhanced MM killing compared to bispecific functional knockout controls for all relapse cohorts (Pearson's r = 0.7). Finally, patients refractory to anti-CD38 therapy had higher levels of TGF-ß (up to 20-fold) compared to other cohorts. This can limit the activity of SAR442257. Vactoserib, a TGF-ß inhibitor, was able to mitigate this effect and restore sensitivity to SAR442257 in these experiments. In conclusion, SAR442257 has high potential for enhancing TC cytotoxicity by co-targeting CD38 and CD28 on MM and CD3/CD28 on T cells.

Health consultations at a performing arts health centre among classical music students based on electronic health record data: a cross-sectional study.

Physical and mental health problems in music students are usually identified using self-reported data. The use of an Electronic Health Record database can avoid biases to give an overview of the extent of health problems in this population. Therefore, the aim of this study is to gain insight into both physical and mental health related issues in classical music students using this type of data collection. An Electronic Health Record database including five years of data from a Performing Arts Health Centre (PAHC) of a university or the arts, was used to analyze the number and characteristics of health consultations in music students. The total number of students, health consultations and the average number of visits per health consultation were calculated over five years. Furthermore, numbers and percentages of both physical and mental health consultations were registered. Also, the number and percentage of health consultations per instrument group were compared to the proportion of each instrument group within the specific sample. Over a period of five years, 230 students visited the PAHC and 417 health consultations were reported. 43.5% of the students who visited a health professional indicated at least one physical health consultation, 29.1% at least one mental health consultation and 27.4% at least one in both categories. An injury was the most frequently registered physical health consultation (40.2%), followed by performance improvement (9.8%) and stress (9.6%). Voice students registered relatively most health consultations. As far as we know, this is the first cross-sectional study using Electronic Health Record data from a PAHC to gain insight into both physical and mental health related issues in a population of classical music students. Looking at the variety of health consultations registered in the database, a multidisciplinary team and multidisciplinary approach are necessary to meet the needs of the students in terms of physical and mental health support and performance improvement.

Advances in preclinical TCR characterization: leveraging cell avidity to identify functional TCRs.

T-cell therapy has emerged as an effective approach for treating viral infections and cancers. However, a significant challenge is the selection of T-cell receptors (TCRs) that exhibit the desired functionality. Conventionally in vitro techniques, such as peptide sensitivity measurements and cytotoxicity assays, provide valuable insights into TCR potency but are labor-intensive. In contrast, measuring ligand binding properties (z-Movi technology) could provide an accelerated processing while showing robust correlations with T-cell functions. In this study, we assessed whether cell avidity can predict functionality also in the context of TCR-engineered T cells. To this end, we developed a flexible system for TCR re-expression by generating a Jurkat-derived T cell clone lacking TCR and CD3 expression through CRISPR-Cas9-mediated TRBC knockout. The knockin of a transgenic TCR into the TRAC locus restored TCR/CD3 expression, allowing for CD3-based purification of TCR-engineered T cells. Subsequently, we characterized these engineered cell lines by functional readouts, and assessment of binding properties through the z-Movi technology. Our findings revealed a strong correlation between the cell avidities and functional sensitivities of Jurkat TCR-T cells. Altogether, by integrating cell avidity measurements with our versatile T cell engineering platform, we established an accelerated system for enhancing the in vitro selection of clinically relevant TCRs.

Physical and psychosocial work-related exposures and the occurrence of disorders of the shoulder: A systematic review update.

This review is an update of a previous systematic review and assesses the evidence for the association of work-related physical and psychosocial risk factors and specific disorders of the shoulders. Medline, Embase, Web of Science Core Collection, Cochrane Central and PsycINFO were searched and study eligibility and risk of bias assessment was performed by two independent reviewers. A total of 14 new articles were added with the majority focusing on rotator cuff syndrome (RCS) with seven studies. Nine articles reported psychosocial exposures in addition to physical exposures. The strongest evidence was found for the association between elevation, repetition, force and vibration and the occurrence of SIS and tendinosis/tendonitis. Evidence also suggests that psychosocial exposures are associated with the occurrence of RCS and tendinosis/tendonitis. Other findings were inconsistent which prevents drawing strong conclusions.

Potential impact of a new sepsis prediction model for the primary care setting: early health economic evaluation using an observational cohort.

OBJECTIVES: To estimate the potential referral rate and cost impact at different cut-off points of a recently developed sepsis prediction model for general practitioners (GPs). DESIGN: Prospective observational study with decision tree modelling. SETTING: Four out-of-hours GP services in the Netherlands. PARTICIPANTS: 357 acutely ill adult patients assessed during home visits. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is the cost per patient from a healthcare perspective in four scenarios based on different cut-off points for referral of the sepsis prediction model. Second, the number of hospital referrals for the different scenarios is estimated. The potential impact of referral of patients with sepsis on mortality and hospital admission was estimated by an expert panel. Using these study data, a decision tree with a time horizon of 1 month was built to estimate the referral rate and cost impact in case the model would be implemented. RESULTS: Referral rates at a low cut-off (score 2 or 3 on a scale from 0 to 6) of the prediction model were higher than observed for patients with sepsis (99% and 91%, respectively, compared with 88% observed). However, referral was also substantially higher for patients who did not need hospital assessment. As a consequence, cost-savings due to referral of patients with sepsis were offset by increased costs due to unnecessary referral for all cut-offs of the prediction model. CONCLUSIONS: Guidance for referral of adult patients with suspected sepsis in the primary care setting using any cut-off point of the sepsis prediction model is not likely to save costs. The model should only be incorporated in sepsis guidelines for GPs if improvement of care can be demonstrated in an implementation study. TRIAL REGISTRATION NUMBER: Dutch Trial Register (NTR 7026).

CD7 activation regulates cytotoxicity-driven pathology in systemic sclerosis, yielding a target for selective cell depletion.

OBJECTIVES: Cytotoxic T cells and natural killer (NK) cells are central effector cells in cancer and infections. Their effector response is regulated by activating and inhibitory receptors. The regulation of these cells in systemic autoimmune diseases such as systemic sclerosis (SSc) is less defined. METHODS: We conducted ex vivo analysis of affected skin and blood samples from 4 SSc patient cohorts (a total of 165 SSc vs 80 healthy individuals) using single-cell transcriptomics, flow cytometry and multiplex immunofluorescence staining. We further analysed the effects of costimulatory modulation in functional assays, and in a severely affected SSc patient who was treated on compassionate use with a novel anti-CD3/CD7 immunotoxin treatment. RESULTS: Here, we show that SSc-affected skin contains elevated numbers of proliferating T cells, cytotoxic T cells and NK cells. These cells selectively express the costimulatory molecule CD7 in association with cytotoxic, proinflammatory and profibrotic genes, especially in recent-onset and severe disease. We demonstrate that CD7 regulates the cytolytic activity of T cells and NK cells and that selective depletion of CD7+ cells prevents cytotoxic cell-induced fibroblast contraction and inhibits their profibrotic phenotype. Finally, anti-CD3/CD7 directed depletive treatment eliminated CD7+ skin cells and stabilised disease manifestations in a severely affected SSc patient. CONCLUSION: Together, the findings imply costimulatory molecules as key regulators of cytotoxicity-driven pathology in systemic autoimmune disease, yielding CD7 as a novel target for selective depletion of pathogenic cells.

SIGLEC-5/14 Inhibits CD11b/CD18 Integrin Activation and Neutrophil-Mediated Tumor Cell Cytotoxicity.

Since the successful introduction of checkpoint inhibitors targeting the adaptive immune system, monoclonal antibodies inhibiting CD47-SIRPα interaction have shown promise in enhancing anti-tumor treatment efficacy. Apart from SIRPα, neutrophils express a broad repertoire of inhibitory receptors, including several members of the sialic acid-binding receptor (SIGLEC) family. Here, we demonstrate that interaction between tumor cell-expressed sialic acids and SIGLEC-5/14 on neutrophils inhibits antibody-dependent cellular cytotoxicity (ADCC). We observed that conjugate formation and trogocytosis, both essential processes for neutrophil ADCC, were limited by the sialic acid-SIGLEC-5/14 interaction. During neutrophil-tumor cell conjugate formation, we found that inhibition of the interaction between tumor-expressed sialic acids and SIGLEC-5/14 on neutrophils increased the CD11b/CD18 high affinity conformation. By dynamic acoustic force measurement, the binding between tumor cells and neutrophils was assessed. The interaction between SIGLEC-5/14 and the sialic acids was shown to inhibit the CD11b/CD18-regulated binding between neutrophils and antibody-opsonized tumor cells. Moreover, the interaction between sialic acids and SIGLEC-5/14-consequently hindered trogocytosis and tumor cell killing. In summary, our results provide evidence that the sialic acid-SIGLEC-5/14 interaction is an additional target for innate checkpoint blockade in the tumor microenvironment.

Profiling of plasma extracellular vesicles identifies proteins that strongly associate with patient's global assessment of disease activity in rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation and cartilage/bone damage. Intercellular messengers such as IL-1 and TNF play a crucial role in the pathophysiology of RA but have limited diagnostic and prognostic values. Therefore, we assessed whether the protein content of the recently discovered extracellular vesicles (EVs), which have gained attention in the pathogenesis of RA, correlates with disease activity parameters in RA patients. Methods: We identified and quantified proteins in plasma-derived EVs (pEVs), isolated by size exclusion chromatography from 17 RA patients by mass spectrophotometry (MS). Quantified protein levels were correlated with laboratory and clinical parameters and the patient's own global assessment of their disease activity (PGA-VAS). In a second MS run, the pEV proteins of nine other RA patients were quantified and compared to those from nine healthy controls (HC). Results: No differences were observed in the concentration, size, and protein content of pEVs from RA patients. Proteomics revealed >95% overlapping proteins in RA-pEVs, compared to HC-pEVs (data are available via ProteomeXchange with identifier PXD046058). Remarkably, in both runs, the level of far more RA-pEV proteins correlated positively to PGA-VAS than to either clinical or laboratory parameters. Interestingly, all observed PGA-VAS positively correlated RA-pEV proteins were associated with the actin-cytoskeleton linker proteins, ezrin, and moesin. Conclusion: Our observation suggests that PGA-VAS (loss of vitality) may have a different underlying pathological mechanism in RA, possibly related to enhanced muscle actin-cytoskeleton activity. Furthermore, our study contributes to the growing awareness and evidence that pEVs contain valuable biomarkers for diseases, with added value for RA patients.

Ultra-low doses of rituximab for continued treatment of rheumatoid arthritis (REDO study): a randomised controlled non-inferiority trial.

BACKGROUND: Rituximab is an effective treatment for rheumatoid arthritis, given as either two doses of 1000 mg (2 weeks apart) every 6 months (the dose recommended by the US Food and Drug Administration and European Medicines Agency) or two doses of 500 mg (2 weeks apart) or one dose of 1000 mg (a standard low dose) every 6 months. Findings of several small uncontrolled studies suggest that doses lower than the recommended dose or standard low dose might be sufficient for maintenance treatment, potentially improving safety and reducing costs. Therefore, we aimed to compare the efficacy of ultra-low doses of rituximab (one dose of 500 mg or 200 mg) with a standard low dose of rituximab (one dose of 1000 mg) for patients with rheumatoid arthritis who respond to standard doses of rituximab. METHODS: The REDO study is a randomised, double-blind, non-inferiority trial done at five centres in the Netherlands. Adults (aged ≥18 years) with rheumatoid arthritis responding well to rituximab were randomly allocated (1:2:2) to receive intravenous rituximab as one dose of either 1000 mg, 500 mg, or 200 mg, respectively. Volumes of all doses were equal to achieve masking. Randomisation lists were computer-generated and stratified by rheumatoid factor or anti-citrullinated protein antibody status (positive or negative) and concomitant use of conventional synthetic disease modifying antirheumatic drugs (yes or no). The primary analysis was a per-protocol hierarchical testing procedure comparing ultra-low doses with a standard low dose (500 mg vs 1000 mg at 3 months, followed by 500 mg vs 1000 mg at 6 months, 200 mg vs 1000 mg at 3 months, and 200 mg vs 1000 mg at 6 months), using a non-inferiority margin of 0·60 on change from baseline in the 28-joint disease activity score based on C-reactive protein levels (DAS28-CRP). The study is registered at www.trialregister.nl, NTR6117. FINDINGS: Between Dec 15, 2016, and Sept 20, 2018, 142 patients were randomly allocated to either 1000 mg rituximab (n=29), 500 mg rituximab (n=58), or 200 mg rituximab (n=55). The 500 mg dose was non-inferior to 1000 mg at 3 months (mean change from baseline in DAS28-CRP, -0·07, 95% CI -0·41 to 0·27) but not at 6 months (0·29, -0·08 to 0·65). Because of the hierarchical testing procedure, non-inferiority could not be tested for the 200 mg dose. 13 patients had serious adverse events, three (10%) in the 1000 mg group, six (10%) in the 500 mg group, and four (7%) in the 200 mg group. The most frequently reported serious adverse events were cardiovascular. No deaths occurred during the study. A significantly lower incidence of infections was seen in the ultra-low-dose groups compared with the standard dose group (1·10 infections per patient-year with the 1000 mg dose vs 0·52 per patient-year with the 500 mg dose and 0·51 per patient-year with the 200 mg dose; rate ratio 0·47, 95% CI 0·21-0·83; p=0·013 for 500 mg vs 1000 mg; 0·44, 0·22-0·88; p=0·019 for 200 mg vs 1000 mg). INTERPRETATION: Our study did not show non-inferiority of ultra-low doses of rituximab for continued treatment of patients with rheumatoid arthritis. Nonetheless, in clinical practice, a strategy with an ultra-low dose of rituximab might be considered after evaluation of risks and benefits, although further studies are needed to establish non-inferiority. Further analyses and a 2-year observational extension are ongoing and should provide further insight into efficacy and safety. FUNDING: Menzis and Centraal Ziekenfonds.

Suturas colonicas mecanicas EEA y manuales en cirugia experimental. / Colonic mechanical EEA and manual sutures in experimental surgery

Se analizan los resultados anatomopatologicos obtenidos en una serie de 28 perros, a los que se les efectuo suturas colonicas EEA y manuales. Con el objeto de obtener cifras estadisticamente significativas, se tomaron 18 perros sacrificados en 3 lotes de 6 cada uno a los 5, 15, y 30 dias. Las suturas mecanicas evidenciaron mayor lisura, conservacion de la mucosa, continuidad de la pared muscular, mayor diametro interno, menor necrosis y reparacion angioblastica, como asi tambien ausencia de granulomas por cuerpo extrano. El numero de dehiscencias producido a nivel de sutura manual fue 4 veces mayor que las de la sutura automatica

Suturas colonicas mecanicas EEA y manuales en cirugia experimental. / Colonic mechanical EEA and manual sutures in experimental surgery

Se analizan los resultados anatomopatologicos obtenidos en una serie de 28 perros, a los que se les efectuo suturas colonicas EEA y manuales. Con el objeto de obtener cifras estadisticamente significativas, se tomaron 18 perros sacrificados en 3 lotes de 6 cada uno a los 5, 15, y 30 dias. Las suturas mecanicas evidenciaron mayor lisura, conservacion de la mucosa, continuidad de la pared muscular, mayor diametro interno, menor necrosis y reparacion angioblastica, como asi tambien ausencia de granulomas por cuerpo extrano. El numero de dehiscencias producido a nivel de sutura manual fue 4 veces mayor que las de la sutura automatica