Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles

The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10) diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC) and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles

Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere’s Disease

Meniere’s disease (MD) is a rare disorder characterized by episodic vertigo, sensorineural hearing loss, tinnitus, and aural fullness. It is associated with a fluid imbalance between the secretion of endolymph in the cochlear duct and its reabsorption into the subarachnoid space, leading to an accumulation of endolymph in the inner ear. Epidemiological evidence, including familial aggregation, indicates a genetic contribution and a consistent association with autoimmune diseases (AD). We conducted a case–control study in two phases using an immune genotyping array in a total of 420 patients with bilateral MD and 1,630 controls. We have identified the first locus, at 6p21.33, suggesting an association with bilateral MD [meta-analysis leading signal rs4947296, OR = 2.089 (1.661–2.627); p = 1.39 × 10−09]. Gene expression profiles of homozygous genotype-selected peripheral blood mononuclear cells (PBMCs) demonstrated that this region is a trans-expression quantitative trait locus (eQTL) in PBMCs. Signaling analysis predicted several tumor necrosis factor-related pathways, the TWEAK/Fn14 pathway being the top candidate (p = 2.42 × 10−11). This pathway is involved in the modulation of inflammation in several human AD, including multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In vitro studies with genotype-selected lymphoblastoid cells from patients with MD suggest that this trans-eQTL may regulate cellular proliferation in lymphoid cells through the TWEAK/Fn14 pathway by increasing the translation of NF-κB. Taken together; these findings suggest that the carriers of the risk genotype may develop an NF-κB-mediated inflammatory response in MD

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Is a low Functional Movement Screen score (≤14/21) associated with injuries in sport? A systematic review and meta-analysis

ObjectiveTo assess whether Functional Movement Screen (FMS) score is associated with subsequent injuries in healthy sportspeople.DesignSystematic review and meta-analysis.Data sourcesThe following electronic databases were searched to December 2017: Medline, PubMed, PsycINFO, SPORTDiscus, Cumulative Index of Nursing and Allied Health Literature, Scopus, Embase, and Physiotherapy Evidence Database.Eligibility criteria for selecting studiesEligibility criteria included (1) prospective cohort studies that examined the association between FMS score (≤14/21) and subsequent injuries, (2) a sample of healthy and active participants without restrictions in gender or age, and (3) the OR was the effect size and the main outcome.ResultsThirteen studies met the criteria for the systematic review and 12 were included in the meta-analysis. In 5 of the 12 studies, and among female athletes in 1 study, FMS score ≤14 out of 21 points was associated with subsequent injuries. The overall OR of the selected studies in the meta-analysis was 1.86 (95% CI 1.32 to 2.61) and showed substantial heterogeneity (I2=70%).Summary/ConclusionWhether or not a low FMS score ≤14 out of 21 points is associated with increased risk of injury is unclear. The heterogeneity of the study populations (type of athletes, age and sport exposure) and the definition of injury used in the studies make it difficult to synthesise the evidence and draw definitive conclusions.Trial registration numberCRD42015015579

Effects of lactic, malic and fumaric acids on Salmonella spp. counts and on chicken meat quality and sensory characteristics

The aim of this work was to assess the effectiveness of dipping chicken breast in lactic, malic and fumaric acid 3% solutions for 15 s on Salmonella counts, as well as on chicken meat quality and sensory characteristics. All three treatments effectively reduced Salmonella counts. The values of Salmonella log reduction were 2.22, 1.55 and 1.30 log CFU/g for fumaric, malic and lactic treatments, respectively. Although fumaric acid was the most effective for reducing Salmonella counts, chicken meat quality and sensory characteristics were significantly affected, even in cooked samples. Conversely, malic and lactic acids treatments caused minimal changes in chicken meat quality and sensory characteristics compared to control samples. This study shows effective alternatives to reduce Salmonella contamination on chicken breast fillets, although further studies should be considered to improve the effects on quality and sensory attributes.Fil: Fernández, Mariano Manuel. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Tecnología de Alimentos; Argentina.Fil: Rodriguez, Anabel. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Tecnología de Alimentos; Argentina.Fil: Rodriguez, Anabel. Instituto de Ciencia y Tecnología de Sistemas Alimentarios Sustentables (UEDD INTA CONICET); Argentina.Fil: Fulco, Micaela. Universidad de Morón; Argentina.Fil: Soteras, Trinidad. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Tecnología de Alimentos; Argentina.Fil: Mozgovoj, Marina Valeria. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Tecnología de Alimentos; Argentina.Fil: Mozgovoj, Marina Valeria. Instituto de Ciencia y Tecnología de Sistemas Alimentarios Sustentables (UEDD INTA CONICET); Argentina.Fil: Mozgovoj, Marina Valeria. Universidad de Morón; Argentina.Fil: Cap, Mariana. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Tecnología de Alimentos; Argentina

Inertial Sensors Embedded in Smartphones as a Tool for Fatigue Assessment Based on Acceleration in Survivors of Breast Cancer

Background: Cancer-related fatigue is a symptom commonly reported in survivors of breast cancer and is the most variable symptom. Besides questionnaires like PIPER to assess cancer-related fatigue, there is a need to objectively measure fatigue. Objective: The aim of this study was to assess the physiological dimension of fatigue based on acceleration during a 30-second maximal sit-to-stand test. Design: This was a cross-sectional study. Methods: Linear acceleration from a smartphone placed on the sternum was recorded in 70 survivors of breast cancer. Fourth-degree polynomial adjustment from the acceleration signal to the vertical and anterior-posterior axis was calculated. The fatigue temporal cut-off point was detected as a change in the curve slope of the first maximum point of acceleration. Results: Women were aged 51.8 (8.9) years with a body mass index of 25.4 (5.1) Kg/m2. They performed 23.6 (6.57) number of repetitions. The mean fatigue cut-off point from the total sample was 10.2 (3.1) seconds. Limitations: Further research should employ time-prolonged tests to study acceleration behavior beyond 30 seconds as well as include a physiological criterion that justifies the nonlinear saturation of the acceleration-based criterion. Conclusions: This study assessed fatigue through a low-cost and easy-to-use methodology during a functional and widely used test such as 30-second maximal sit-to-stand. This would allow clinicians to assess fatigue in a short-effort exercise to individualize exercise prescription dose, measure changes during intervention, and track fatigue objectively throughout survivorship.</p

Muscle activity and architecture as a predictor of hand-grip strength

Background: Grip strength is a powerful predictor of disability as well as a good indicator of physical activity. Objectives: This study aimed to relate ultrasound (US) and electromyography (EMG) simultaneously to maximum hand-grip strength during an isometric contraction. Approach: This is a cross-sectional study. Data acquisition was done with a dynamometer, US and EMG. Outcome variables included maximum strength during the hand-grip gesture, maximum muscle activity and change in muscle thickness. A non-linear regression analysis was performed to analyse the relationship between all outcome variables. Main results: A total of 38 subjects (18 men and 20 women) participated in the study. The mean results for hand-grip strength were 25.50 (SD 6.55) kg of maximum strength, a change in muscle thickness of 1.83 (SD 0.75) mm and an EMG activity of 499.29 (SD 224.20) µV. Hand-grip strength had a high correlation with muscle thickness (R 2 = 0.61) and EMG activity (R 2 = 0.95). The correlation between maximum muscle activity and change in muscle thickness was R 2 = 0.83. Significance: The results of the present study demonstrate that this new method based on electromyographic activity and muscule architecture could be important in the development of the hand-grip test. </p

Differences in movement limitations in different low back pain severity in functional tests using an RGB-D camera

Low back pain (LBP) can lead to motor control disturbance which can be one of the causes of reoccurrence of the complaint. It is important to improve our knowledge of movement related disturbances during assessment in LBP and to classify patients according to the severity. The aim of this study is to present differences in kinematic variables using a RGB-D camera in order to classify LBP patients with different severity. A cross-sectional study was carried out. Subjects with non-specific subacute and chronic LBP were screened 6 weeks following an episode. Functional tests were bending trunk test, sock test and sit to stand test. Participants performed as many repetitions as possible during 30 s for each functional test. Angular displacement, velocity and acceleration, linear acceleration, time and repetitions were analysed. Participants were divided into two groups to determine their different LBP severity with a k-means clusters according to the results obtained in Roland Morris questionnaire (RMQ). Comparing different severity groups based on RMQ score (high impact = 17.15, low impact = 7.47), bending trunk test obtained significative differences in linear acceleration (p = 0.002–0.01). The differences of total linear acceleration during the Sit to Stand test were significative (p = 0.004–0.02). Sock test showed not significative differences between groups (p > 0.05). Linear acceleration variables during Sit to Stand test and Bending trunk test were significatively different between the different severity groups. RGB-D camera system and functional tests can detect kinematic differences in different type of LBP according to the functionality. Trial registration: ClinicalTrials.gov NCT03293095 “Functional Task Kinematic in Musculoskeletal Pathology” September 26, 2017.</p

Validation, Reliability, and Responsiveness Outcomes of Kinematic Assessment with an RGB-D Camera to Analyze Movement in Subacute and Chronic Low Back Pain

Background: The RGB-D camera is an alternative to asses kinematics in order to obtain objective measurements of functional limitations. The aim of this study is to analyze the validity, reliability, and responsiveness of the motion capture depth camera in sub-acute and chronic low back pain patients. Methods: Thirty subjects (18–65 years) with non-specific lumbar pain were screened 6 weeks following an episode. RGB-D camera measurements were compared with an inertial measurement unit. Functional tests included climbing stairs, bending, reaching sock, lie-to-sit, sit-to-stand, and timed up-and-go. Subjects performed the maximum number of repetitions during 30 s. Validity was analyzed using Spearman’s correlation, reliability of repetitions was calculated by the intraclass correlation coefficient and the standard error of measurement, and receiver operating characteristic curves were calculated to assess the responsiveness. Results: The kinematic analysis obtained variable results according to the test. The time variable had good values in the validity and reliability of all tests (r = 0.93–1.00, (intraclass correlation coefficient (ICC) = 0.62– 0.93). Regarding kinematics, the best results were obtained in bending test, sock test, and sit-to-stand test (r = 0.53–0.80, ICC = 0.64–0.83, area under the curve (AUC) = 0.55–84). Conclusion: Functional tasks, such as bending, sit-to-stand, reaching, and putting on sock, assessed with the RGB-D camera, revealed acceptable validity, reliability, and responsiveness in the assessment of patients with low back pain (LBP). Trial registration: ClinicalTrials.gov NCT03293095 “Functional Task Kinematic in Musculoskeletal Pathology” September 26, 2017.</p