Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis

The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10−11), chr5p15.3 (SLC9A3; P=6.8 × 10−12), chr6p21.3 (HLA Class II; P=1.2 × 10−8) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10−9) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10−10), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF

A História da Alimentação: balizas historiográficas

Os M. pretenderam traçar um quadro da História da Alimentação, não como um novo ramo epistemológico da disciplina, mas como um campo em desenvolvimento de práticas e atividades especializadas, incluindo pesquisa, formação, publicações, associações, encontros acadêmicos, etc. Um breve relato das condições em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biológica, a econômica, a social, a cultural e a filosófica!, assim como da identificação das contribuições mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histórica, foi ela organizada segundo critérios morfológicos. A seguir, alguns tópicos importantes mereceram tratamento à parte: a fome, o alimento e o domínio religioso, as descobertas européias e a difusão mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rápido balanço crítico da historiografia brasileira sobre o tema

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Advancing personalized care in hemophilia A: ten years' experience with an advanced category antihemophilic factor prepared using a plasma/albumin-free method.

Detailed analysis of data from studies of recombinant antihemophilic factor produced using a plasma/albumin-free method (rAHF-PFM) in previously treated patients showed a substantial level of interpatient variation in pharmacokinetics (PKs), factor VIII dosing, and annualized bleed rate (ABR), suggesting that individual patient characteristics contributed to outcome. For example, plasma half-life (t1/2), recovery, and clearance appeared to differ between patients aged <6 years and 10-65 years. Prophylaxis resulted in lower ABRs than episodic treatment in both age groups; better adherence to the prophylactic regimen resulted in a lower ABR in patients aged 10-65 years. The weekly frequency of dosing and adherence to dosing were both significantly and inversely related to the rate of bleeding (young children, P<0.0001 for both all bleeds and joint bleeds; older patients, P<0.0001 for all bleeds and P<0.05 for joint bleeds), as was adherence to dosing frequency (P<0.0001 for all comparisons). A post-marketing randomized study of prophylaxis demonstrated that a PK-guided dosing regimen, based on an individual patient's rAHF-PFM PK (infusion interval, estimated t1/2, and recovery), was as effective as standard prophylaxis and that both prophylactic regimens were superior to episodic treatment with respect to ABR and quality of life measures. Thus, compared with standard prophylaxis, the PK-guided regimen achieved comparable efficacy with fewer weekly infusions. A two-compartment population PK model describes the PK data across the entire age range and forms the basis for future PK-guided therapy with rAHF-PFM. The model confirmed a shorter t1/2 and faster clearance of rAHF-PFM in children <6 years of age versus patients ≥10 years and predicted similar PK parameters with either a full or reduced blood sampling schedule, offering the potential for the use of PK-guided, individualized treatment in the routine clinical care setting

Optimization of Peripheral Blood Mononuclear Cell Extraction from Small Volume of Blood Samples: Potential Implications for Children-Related Diseases

Managing medical procedures for children with problematic disorders is a challenging approach, especially in the case of blood withdrawal for autism spectrum disorder-affected children. Peripheral blood mononuclear cells (PBMC) represent an important cellular model to study immune responses and drug toxicity. The monocytic cells, a fraction of PBMC, are strongly involved in some pathophysiological processes, such as inflammation and immune system changes. Here, we propose a simple, reliable protocol for obtaining peripheral blood-derived mononuclear cells from small volumes of blood samples

Target Balloon-Assisted Antegrade and Retrograde Use of Re-Entry Catheters in Complex Chronic Total Occlusions

Purpose, Retrograde recanalizations have gained increasing recognition in complex arterial occlusive disease. Re-entry devices are a well described adjunct for antegrade recanalizations. We present our experience with target balloon-assisted antegrade and retrograde recanalizations using re-entry devices in challenging chronic total occlusions. Materials and Methods: We report data from a retrospective multicenter registry. Eligibility criteria included either antegrade or retrograde use of the OutbackTM or GoBackTM re-entry catheter in combination with a balloon as a target to accomplish wire passage, when conventional antegrade and retrograde recanalization attempts had been unsuccessful. Procedural outcomes included technical success (defined as wire passage though the occlusion and delivery of adjunctive therapy with <30% residual stenosis at final angiogram), safety (periprocedural complications, e.g., bleeding, vessel injury, or occlusion of the artery at the re-entry site, and distal embolizations), and clinical outcome (amputation-free survival and freedom from target lesion revascularization after 12-months follow-up). Results: Thirty-six consecutive patients underwent target balloon-assisted recanalization attempts. Fourteen (39 %) patients had a history of open vascular surgery in the index limb. Fifteen patients were claudications (Rutherford Class 2 or 3, 21 presented with chronic limb threatening limb ischemia (Rutherford Class 4 to 6). The locations of the occlusive lesions were as follows: iliac arteries in 3 cases, femoropopliteal artery in 39 cases, and in below-the-knee arteries in 12 cases. In 15 cases, recanalization was attempted in multilevel occlusions. Retrograde access was attempted in 1 case in the common femoral artery, in the femoropopliteal segment in 10 cases, in below-the-knee arteries in 23 cases, and finally in 2 patients via the brachial artery. In 10 cases, the re-entry devices were inserted via the retrograde access site. Technical success was achieved in 34 (94 %) patients. There were 3 periprocedural complications, none directly related to the target balloon-assisted re-entry maneuver. Amputation-free survival was 87.8 % and freedom from clinically driven target lesion revascularization was 86.6 % after 12-months follow-up. Conclusion: Target balloon-assisted use of re-entry devices in chronic total occlusions provides an effective and safe endovascular adjunct, when conventional antegrade and retrograde recanalization attempts have failed

Target Balloon-Assisted Antegrade and Retrograde Use of Re-Entry Catheters in Complex Chronic Total Occlusions

Purpose, Retrograde recanalizations have gained increasing recognition in complex arterial occlusive disease. Re-entry devices are a well described adjunct for antegrade recanalizations. We present our experience with target balloon-assisted antegrade and retrograde recanalizations using re-entry devices in challenging chronic total occlusions. Materials and Methods: We report data from a retrospective multicenter registry. Eligibility criteria included either antegrade or retrograde use of the OutbackTM or GoBackTM re-entry catheter in combination with a balloon as a target to accomplish wire passage, when conventional antegrade and retrograde recanalization attempts had been unsuccessful. Procedural outcomes included technical success (defined as wire passage though the occlusion and delivery of adjunctive therapy with &lt;30% residual stenosis at final angiogram), safety (periprocedural complications, e.g., bleeding, vessel injury, or occlusion of the artery at the re-entry site, and distal embolizations), and clinical outcome (amputation-free survival and freedom from target lesion revascularization after 12-months follow-up). Results: Thirty-six consecutive patients underwent target balloon-assisted recanalization attempts. Fourteen (39 %) patients had a history of open vascular surgery in the index limb. Fifteen patients were claudications (Rutherford Class 2 or 3, 21 presented with chronic limb threatening limb ischemia (Rutherford Class 4 to 6). The locations of the occlusive lesions were as follows: iliac arteries in 3 cases, femoropopliteal artery in 39 cases, and in below-the-knee arteries in 12 cases. In 15 cases, recanalization was attempted in multilevel occlusions. Retrograde access was attempted in 1 case in the common femoral artery, in the femoropopliteal segment in 10 cases, in below-the-knee arteries in 23 cases, and finally in 2 patients via the brachial artery. In 10 cases, the re-entry devices were inserted via the retrograde access site. Technical success was achieved in 34 (94 %) patients. There were 3 periprocedural complications, none directly related to the target balloon-assisted re-entry maneuver. Amputation-free survival was 87.8 % and freedom from clinically driven target lesion revascularization was 86.6 % after 12-months follow-up. Conclusion: Target balloon-assisted use of re-entry devices in chronic total occlusions provides an effective and safe endovascular adjunct, when conventional antegrade and retrograde recanalization attempts have failed