Implications thermorégulatrices et perceptuelles de la variation de la couverture d’armures de protection modulaires pendant la marche sur tapis roulant en environnement chaud

Introduction : Les armures modulaires (MSA) permettent aux soldats d’ajuster le niveau de couverture de l’armure en fonction du niveau de menace. L’hypothèse émise est qu’un niveau inférieur de couverture balistique atténue les réponses physiologiques et perceptuelles pendant l’exercice à la chaleur. Méthode : 15 adultes (5F/10H, 26 ± 5 ans, 24,6 ± 3,7 kg/m2) ont marché (5 km/h, pente de 1 %) dans une chaleur sèche (38°C, 20 % humidité) pendant 1h en portant une des armure de protection : i) une couverture élevée (HC : 0,57 ± 0,09 m2, 18,5 ± 0,3 kg), ii) une couverture modérée (MC : 0,44 ± 0,07 m2, 18,1 ± 0,3 kg), iii) une couverture légère (LC1 : 0,21 ± 0,03 m2, 17,4 ± 0,1 kg), ou iv) une couverture légère avec une égalisation du poids à la couverture élevée (LC2 : 0,21 ± 0,03 m2, 18,6 ± 0,2 kg). Résultats: M-W pendant l’exercice (629 ± 126 W, p=0,30), le changement de la température interne (HC : 0,88 ± 0,37°C, MC : 0,85 ± 0,32°C, LC1 : 0,91 ± 0,38°C, LC2 : 0,89 ± 0,42°C, p=0,93), de la fréquence cardiaque (HC : 97 ± 14 bpm, MC : 103 ± 16 bpm, LC1 : 96 ± 15 bpm, LC2 : 97 ± 20 bpm, p=0,08), et de la production de sueur (HC : 10,2 ± 3,4 g/min, MC : 10,3 ± 4,3 g/min, LC1: 9,9 ± 4,7 g/min, LC2 : 10,4 ± 4,5 g/min, p=0,84) n’était pas différent entre les configurations. Conclusion: Les armures modulaires étudiées ne minimisent pas le stress thermique ou cardiovasculaire lors d’une marche en environnement chaud et sec.Purpose: Modular scalable armour allows soldiers to adjust the level of armour coverage according to the threat level. We hypothesized that armour configurations with lower levels of ballistic coverage attenuate physiological and perceptual responses during exercise in the heat. Methods: Fifteen adults (5 females/10 males, 26±5 years, 24.6±3.7 kg/m2) walked (5 km/h, 1% incline) in dry heat (38°C, 20% humidity) for 1h while wearing body armour that provided; i) high coverage (HC: 0.57 ± 0.09 m2, 18.5 ± 0.3 kg), ii) moderate coverage (MC: 0.44 ± 0.07 m2, 18.1 ± 0.3 kg), iii) low coverage (LC1: 0.21 ± 0.03 m2, 17.4 ± 0.1 kg), or iv) low coverage with weight equalization to HC (LC2: 0.21 ± 0.03 m2, 18.6 ± 0.2 kg). Results: Core temperature (Tcore), heart rate (HR), metabolic heat production (M-W), whole-body sweat rate (WBSR), and perceptual responses were measured. M-W during exercise (629 ± 126 W) did not differ between configurations (p=0.30). The change in Tcore (HC: 0.88 ± 0.37°C, MC: 0.85 ± 0.32°C, LC1: 0.91 ± 0.38°C, LC2: 0.89 ± 0.42°C, p=0.93), HR (HC: 97 ± 14 bpm, MC: 103 ± 16 bpm, LC1: 96 ± 15 bpm, LC2: 97 ± 20 bpm, p=0.08), and WBSR (HC: 10.2 ± 3.4 g/min, MC: 10.3 ± 4.3 g/min, LC1: 9.9 ±4.7 g/min, LC2: 10.4 ± 4.5 g/min, p=0.84) did not differ between configurations. Perceptual responses also did not differ between configurations (all p≥0.15). Conclusion: Reducing torso ballistic armour coverage does not reduce physiological or perceptual strain during treadmill walking in dry heat

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Funder: Victorian Cancer AgencyFunder: NIHR Manchester Biomedical Research CentreFunder: Cancer Research UKFunder: Cancer Council TasmaniaFunder: Instituto de Salud Carlos IIIFunder: Cancer AustraliaFunder: NIHR Oxford Biomedical Research CentreFunder: Fundación Científica de la Asociación Española Contra el CáncerFunder: Cancer Council South AustraliaFunder: Swedish Cancer SocietyFunder: NIHR Cambridge Biomedical Research CentreFunder: Institut Català de la SalutFunder: Cancer Council VictoriaFunder: Prostate Cancer Foundation of AustraliaFunder: National Institutes of HealthBACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A Cross-Sectional Comparison of Arterial Stiffness and Cognitive Performances in Physically Active Late Pre- and Early Post-Menopausal Females

Menopause accelerates increases in arterial stiffness and decreases cognitive performances. The objective of this study was to compare cognitive performances in physically active pre- and post-menopausal females and their relationship with arterial stiffness. We performed a cross-sectional comparison of blood pressure, carotid&ndash;femoral pulse wave velocity (cf-PWV) and cognitive performances between physically active late pre- and early post-menopausal females. Systolic (post-menopause&mdash;pre-menopause: +6 mmHg [95% CI &minus;1; +13], p = 0.27; &#331;2 = 0.04) and diastolic (+6 mmHg [95% CI +2; +11], p = 0.06; &#331;2 = 0.12) blood pressures, and cf-PWV (+0.29 m/s [95% CI &minus;1.03; 1.62], p = 0.48; &#331;2 = 0.02) did not differ between groups. Post-menopausal females performed as well as pre-menopausal females on tests evaluating executive functions, episodic memory and processing speed. Group differences were observed on the computerized working memory task. Post-menopausal females had lower accuracy (p = 0.02; &#331;2 = 0.25) but similar reaction time (p = 0.70; &#331;2 &lt; 0.01). Moreover, this performance was inversely associated with the severity of menopausal symptoms (r = &minus;0.38; p = 0.05). These results suggest that arterial stiffness and performance on tests assessing episodic memory and processing speed and executive functions assessing inhibition and switching abilities did not differ between physically active pre- and post-menopausal females. However, post-menopausal females had lower performance on a challenging condition of a working memory task, and this difference in working memory between groups cannot be explained by increased arterial stiffness

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. Conclusions and Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions