Diminished physical function in older HIV-infected adults in the Southeastern U.S. despite successful antiretroviral therapy

As antiretroviral therapy efficacy improves, HIV is gradually being recognized more as a chronic disease within the aging HIV-infected population. While these individuals are surviving into old age, they may, however, be experiencing “accelerated aging” with greater declines in physical function than that observed among comparably matched individuals free of HIV. This decline is not well understood and it remains unclear if physical decline correlates with the degree of immunosuppression based on CD4 lymphocyte nadir

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

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

Ballon d'occlusion intra-aortique dans la prise en charge de l'hémorragie critique chez le traumatisé sévère : une analyse rétrospective au CHU de Grenoble

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is increasingly used as a non-invasive clamp of the aorta after diverse post-traumatic injuries. Balloon inflation in zone 3 can be performed to stop on-going bleeding after severe pelvic trauma with life-threatening hemorrhage. The aim of our study was to describe our 20-year experience with REBOA use in terms of efficacy and safety in this indication. We performed a retrospective study from 1996 to 2017 in a French Level-I trauma center. All consecutive patients who underwent a REBOA procedure were included. REBOA indication relied on 1) extreme hemodynamic instability (systolic arterial blood pressure (SBP) < 60 mmHg on admission, SBP < 90 mmHg despite initial resuscitation or post-traumatic cardiac arrest) and 2) positive pelvic X-ray. Efficacy endpoints were vital signs and coagulation parameters before and after balloon inflation. Safety endpoints were REBOA-related complications. Within the study period, 32 patients underwent a REBOA procedure. Nineteen patients did not survive at Day 28. REBOA significantly improved SBP from 60 [35-73] mmHg to 115 [91-128] mmHg (p<0.001). We reported a high rate of vascular complications (19%, n= 5 patients) but no amputation. Renal replacement therapy was initiated in eleven patients and fifteen patients had severe rhabdomyolysis. REBOA is safe and effective in improving hemodynamics after severe pelvic trauma and life-threatening hemorrhage. Our study supports the use of REBOA as a bridge to definitive hemostatic treatment after severe pelvic trauma.Le ballon d’occlusion intra-aortique (BOIA) est une technique en plein essor pour le clampage non-invasif de l’aorte dans diverses situations de lésions hémorragiques post-traumatiques. Le déploiement du ballon en zone 3 peut permettre de contrôler une hémorragie active menaçant le pronostic vital après traumatisme sévère du bassin. Le but de notre étude était de décrire notre expérience de 20 ans d’utilisation du BOIA dans cette indication, en terme d’efficacité et de tolérance. Nous avons réalisé une étude rétrospective de 1996 à 2017 dans un centre de traumatologie français de niveau 1, incluant tous les patients consécutifs qui ont bénéficié d’une pose de BOIA dans un contexte traumatique. L’indication de BOIA reposait sur la présence 1) d’une instabilité hémodynamique (pression artérielle systolique (PAS) < 60 mmHg à l’admission, PAS < 90 mmHg malgré la réanimation initiale ou un arrêt cardiaque post-traumatique) et 2) d’une radio de bassin positive. Les critères d’efficacité étaient les paramètres vitaux et les paramètres biologiques de coagulation avant et après inflation du ballon. Les critères de tolérance étaient la survenue de complications associées au BOIA. Durant la période étudiée, 32 patients ont bénéficié de la pose d’un BOIA. Dix-neuf patients étaient décédés au 28ème jour. La pose du BOIA améliorait la PAS de 60 [35-73] mmHg à 115 [91-128] mmHg (p<0.001). Nous avons observé 19% de complications vasculaires (n= 5 patients) mais pas d’amputation. Le BOIA semble une technique sûre et efficace pour améliorer l’état hémodynamique des patients présentant une hémorragie critique après traumatisme sévère du bassin avant réalisation de l’hémostase définitive

Resuscitative endovascular balloon occlusion of the aorta for pelvic blunt trauma and life-threatening hemorrhage

International audienceBACKGROUND:Resuscitative endovascular balloon occlusion of the aorta (REBOA) is increasingly used as a noninvasive clamp of the aorta after diverse posttraumatic injuries. Balloon inflation in zone 3 (from the lower renal artery to the aortic bifurcation) can be performed to stop ongoing bleeding after severe pelvic trauma with life-threatening hemorrhage. The aim of our study was to describe our 20-year experience with REBOA in terms of efficacy and safety in patients with a suspicion of severe pelvic trauma and extreme hemorrhagic shock.METHODS:We performed a retrospective study from 1996 to 2017 in a French Level I trauma center. All consecutive patients who underwent a REBOA procedure were included. REBOA indication relied on (1) extreme hemodynamic instability (systolic arterial blood pressure [SBP] < 60 mm Hg on admission, SBP < 90 mm Hg despite initial resuscitation in the trauma bay or posttraumatic cardiac arrest) and (2) positive pelvic X-ray. Efficacy endpoints were vital signs and coagulation parameters before and after balloon inflation. Safety endpoints were REBOA-related complications: vascular events, acute renal failure, and rhabdomyolysis.RESULTS:Within the study period, 32 patients underwent a REBOA procedure. Only two patients had technical failure and balloon was not inflated in one patient. Nineteen patients did not survive at day 28. The REBOA significantly improved SBP from 60 (35-73) mm Hg to 115 (91-128) mm Hg (p < 0.001). We also reported a high rate of vascular complications (19%, n = 5 patients) but no amputation. Renal replacement therapy was initiated in 11 patients, and 15 patients had severe rhabdomyolysis.CONCLUSION:The REBOA is safe and effective in improving hemodynamics after severe pelvic trauma and life-threatening hemorrhage. Our study supports the use of REBOA as a bridge to definitive hemostatic treatment after severe pelvic trauma

Correlation between clinical characteristics and physical function.

<p>Correlation between clinical characteristics and physical function.</p

Differences in physical function between HIV-infected study participants and normal reference ranges (controlled for age and gender).

<p>Differences in physical function between HIV-infected study participants and normal reference ranges (controlled for age and gender).</p

Physical function compared to normal reference values ranges.

<p>Physical function compared to normal reference values ranges.</p

Overall demographics and clinical characteristics.

<p>Overall demographics and clinical characteristics.</p