Use of diagnostic tests in elderly patients consulting the emergency department. Analysis of the emergency department and elder needs cohort (EDEN-8).

OBJECTIVE: Analyse the association between the use of diagnostic tests and the characteristics of older patients 65 years of age or more who consult the emergency department (ED). METHODS: We performed an analysis of the EDEN cohort that includes patients who consulted 52 Spanish EDs. The association of age, sex, and ageing characteristics with the use of diagnostic tests (blood tests, electrocardiogram (ECG), microbiological cultures, X-ray, computed tomography, ultrasound, invasive techniques) was studied. The association was analysed by calculating the adjusted odds ratios (aOR) and their 95 % confidence intervals (CI) using a logistic regression model. RESULTS: A total of 25,557 patients were analysed. There was an increase in the use of diagnostic tests based on age, with an aOR for blood test of 1.805 (95 %CI 1.671 - 1.950), ECG 1.793 (95 %CI 1.664 - 1.932) and X-ray 1.707 (95 %CI 1.583 - 1.840) in the group of 85 years or more. The use of diagnostic tests is lower in the female population. Most ageing characteristics (cognitive impairment, previous falls, polypharmacy, dependence, and comorbidity) were independently associated with increased use of diagnostic tests. CONCLUSIONS: Age, and the characteristics of ageing itself are generally associated with a greater use of diagnostic tests in the ED.

The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect.

Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes in addition to bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in IFITM5. Here, we generated a conditional Rosa26 knock-in mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in OI type V patients. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with increase in the skeletal progenitor population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 showed decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupts early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.

Impact of dementia on 30-, 180-, and 365-day mortality during the first pandemic wave in older adults seen in spanish emergency departments diagnosed with or without COVID-19.

OBJECTIVES: To assess whether dementia is an independent predictor of death after a hospital emergency department (ED) visit by older adults with or without a COVID-19 diagnosis during the first pandemic wave. METHOD: We used data from the EDEN-Covid (Emergency Department and Elderly Needs during Covid) cohort formed by all patients ≥65 years seen in 52 Spanish EDs from March 30 to April 5, 2020. The association of prior history of dementia with mortality at 30, 180 and 365 d was evaluated in the overall sample and according to a COVID-19 or non COVID diagnosis. RESULTS: We included 9,770 patients aged 78.7 ± 8.3 years, 51.1% men, 1513 (15.5%) subjects with prior history of dementia and 3055 (31.3%) with COVID-19 diagnosis. 1399 patients (14.3%) died at 30 d, 2008 (20.6%) at 180 days and 2456 (25.1%) at 365 d. The adjusted Hazard Ratio (aHR) for age, sex, comorbidity, disability and diagnosis for death associated with dementia were 1.16 (95% CI 1.01-1.34) at 30 d; 1.15 at 180 d (95% CI 1.03-1.30) and 1.19 at 365 d (95% CI 1.07-1.32), p < .001. In patients with COVID-19, the aHR were 1.26 (95% CI: 1.04-1.52) at 30 days; 1.29 at 180 d (95% CI: 1.09-1.53) and 1.35 at 365 d (95% CI: 1.15-1.58). CONCLUSION: Dementia in older adults attending Spanish EDs during the first pandemic wave was independently associated with 30-, 180- and 365-day mortality. This impact was lower when adjusted for age, sex, comorbidity and disability, and was greater in patients diagnosed with COVID-19.

Machine learning in time-lapse imaging to differentiate embryos from young vs old mice†.

Time-lapse microscopy for embryos is a non-invasive technology used to characterize early embryo development. This study employs time-lapse microscopy and machine learning to elucidate changes in embryonic growth kinetics with maternal aging. We analyzed morphokinetic parameters of embryos from young and aged C57BL6/NJ mice via continuous imaging. Our findings show that aged embryos accelerated through cleavage stages (from 5-cells) to morula compared to younger counterparts, with no significant differences observed in later stages of blastulation. Unsupervised machine learning identified two distinct clusters comprising of embryos from aged or young donors. Moreover, in supervised learning, the extreme gradient boosting algorithm successfully predicted the age-related phenotype with 0.78 accuracy, 0.81 precision, and 0.83 recall following hyperparameter tuning. These results highlight two main scientific insights: maternal aging affects embryonic development pace, and artificial intelligence can differentiate between embryos from aged and young maternal mice by a non-invasive approach. Thus, machine learning can be used to identify morphokinetics phenotypes for further studies. This study has potential for future applications in selecting human embryos for embryo transfer, without or in complement with preimplantation genetic testing.

Generation of a humanized mAce2 and a conditional hACE2 mouse models permissive to SARS-COV-2 infection.

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains a public health concern and a subject of active research effort. Development of pre-clinical animal models is critical to study viral-host interaction, tissue tropism, disease mechanisms, therapeutic approaches, and long-term sequelae of infection. Here, we report two mouse models for studying SARS-CoV-2: A knock-in mAce2F83Y,H353K mouse that expresses a mouse-human hybrid form of the angiotensin-converting enzyme 2 (ACE2) receptor under the endogenous mouse Ace2 promoter, and a Rosa26 conditional knock-in mouse carrying the human ACE2 allele (Rosa26hACE2). Although the mAce2F83Y,H353K mice were susceptible to intranasal inoculation with SARS-CoV-2, they did not show gross phenotypic abnormalities. Next, we generated a Rosa26hACE2;CMV-Cre mouse line that ubiquitously expresses the human ACE2 receptor. By day 3 post infection with SARS-CoV-2, Rosa26hACE2;CMV-Cre mice showed significant weight loss, a variable degree of alveolar wall thickening and reduced survival rates. Viral load measurements confirmed inoculation in lung and brain tissues of infected Rosa26hACE2;CMV-Cre mice. The phenotypic spectrum displayed by our different mouse models translates to the broad range of clinical symptoms seen in the human patients and can serve as a resource for the community to model and explore both treatment strategies and long-term consequences of SARS-CoV-2 infection.

An oocyte-specific Cas9-expressing mouse for germline CRISPR/Cas9-mediated genome editing.

Cas9 transgenes can be employed for genome editing in mouse zygotes. However, using transgenic instead of exogenous Cas9 to produce gene-edited animals creates unique issues including ill-defined transgene integration sites, the potential for prolonged Cas9 expression in transgenic embryos, and increased genotyping burden. To overcome these issues, we generated mice harboring an oocyte-specific, Gdf9 promoter driven, Cas9 transgene (Gdf9-Cas9) targeted as a single copy into the Hprt1 locus. The X-linked Hprt1 locus was selected because it is a defined integration site that does not influence transgene expression, and breeding of transgenic males generates obligate transgenic females to serve as embryo donors. Using microinjections and electroporation to introduce sgRNAs into zygotes derived from transgenic dams, we demonstrate that Gdf9-Cas9 mediates genome editing as efficiently as exogenous Cas9 at several loci. We show that genome editing efficiency is independent of transgene inheritance, verifying that maternally derived Cas9 facilitates genome editing. We also show that paternal inheritance of Gdf9-Cas9 does not mediate genome editing, confirming that Gdf9-Cas9 is not expressed in embryos. Finally, we demonstrate that off-target mutagenesis is equally rare when using transgenic or exogenous Cas9. Together, these results show that the Gdf9-Cas9 transgene is a viable alternative to exogenous Cas9.

Relationship between Hydration Status and Muscle Catabolism in the Aged Population: A Cross-Sectional Study.

BACKGROUND: The physiopathology of sarcopenia is still not completely understood. AIM: To assess the relationship between dehydration and skeletal muscle catabolism, muscle mass, and sarcopenia in an aged population. METHODS: Observational cross-sectional study of community-dwelling subjects aged 70 years and older. Dehydration was assessed by plasma osmolarity; bioimpedance analysis (BIA) was used to assess body composition and water content; sarcopenia was established according to the EWGSOP-2 criteria; and 3-methyl-histidine (3MH) was used as an indicator of muscle catabolism. RESULTS: 190 participants were recruited (77.4 years; 51.6% women). In total, 22.6% and 20.5% presented plasma osmolarity of 295-300 mOsm/L and >300 mOsm/L, respectively. Age was correlated with plasma osmolarity (rs = 0.439; p < 0.001). Plasma osmolarity was correlated with 3MH (rs = 0.360; p < 0.001) and showed an effect on 3MH levels, with an adjusted (by age, sex, and number of medications) beta of 0.283 (p < 0.001). BIA water content indicators showed no correlation with 3MH. Lower in sarcopenic compared to non-sarcopenic subjects were the intracellular water percentage (60.3 vs. 61.2%; p = 0.004) and intracellular water/free-fat mass ratio (44.3 vs. 45.0; p = 0.004). CONCLUSIONS: Dehydration is a highly prevalent clinical condition in aged populations, increases with age, and is associated with muscle catabolism but not sarcopenia.

Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance.

SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6×129/SvEv F2) recapitulate LPI phenotypes, including growth failure. Our main objective in this study was to characterize the skeletal phenotype in these mice. Compared to wild-type littermates, juvenile Slc7a7 knockout mice demonstrated 70% lower body weights, 87% lower plasma IGF-1 concentrations and delayed skeletal development. Because poor survival prevents evaluation of mature knockout mice, we generated a conditional Slc7a7 deletion in mature osteoblasts or mesenchymal cells of the osteo-chondroprogenitor lineage, but no differences in bone architecture were observed. Overall, global Slc7a7 deficiency caused growth failure with low plasma IGF-1 concentrations and delayed skeletal development, but Slc7a7 deficiency in the osteoblastic lineage was not a major contributor to these phenotypes. Future studies utilizing additional tissue-specific Slc7a7 knockout models may help dissect cell-autonomous and non-cell-autonomous mechanisms underlying phenotypes in LPI.

Utility of Genomic Platforms in Treatment Decisions in Axilla-Positive Breast Cancer.

Genomic platforms have proven to be more accurate as a prognostic tool than immunohistochemistry studies in patients with early, hormone receptor positive, HER 2 negative breast cancer and, in some cases, have also demonstrated predictive ability for chemotherapy benefit. They are now widely applied in node-negative disease, but their use in node-positive disease is more recent and more controversial, especially in premenopausal patients. In this article, we review the use of these tests in node-positive disease.

Surgical complications in a population-based colorectal cancer screening program: Incidence and associated factors. / Complicaciones posquirúrgicas en un programa de cribado poblacional de cáncer colorrectal: incidencia y factores asociados.

INTRODUCTION: Colorectal cancer (CRC) screening programs produce risks, including those derived from colorectal surgeries. The objective of this analysis is to evaluate the complications associated with the surgery. PATIENTS AND METHODS: Retrospective analysis including patients who required colorectal surgery within the population-based CRC screening program in Galicia (May 2013-June 2019). We analyzed the indication for surgery and the rate of in-hospital (mildI-II, severeIII-V, Clavien-Dindo classification) and at discharge complications. We performed a multivariate analysis to determine the variables independently associated. RESULTS: In the analyzed period, 1092 patients underwent surgery (benign lesion 16.5%, pT1 CRC 18.2%, rest of CRC 64.6%) laparoscopic approach in 69.8% of the cases. In-hospital complications were detected in 19.2% of patients (mild: 13.4%; severe: 5.9%; deaths: 0.2%) and at discharge in 159 (14.6%) patients. Male sex was associated with in-hospital complications (OR: 2.0; 95%CI: 1.3-3.0). The variables associated with severe complications were: male sex (OR: 2.6; 95%CI: 1.2-5.5), tertiary hospital (OR: 0.5; 95%CI: 0.2-0.9) and ECOGI (OR: 0.2; 95%CI: 0.05-0.6). The factors associated with complications after discharge were age ≥60years (OR: 1.5; 95%CI: 1.0-2.3), rectal location (OR: 1.6; 95%CI: 1.1-2.3) and in-hospital complications (OR: 2.2; 95%CI: 1.5-3.2). CONCLUSIONS: Surgery is the main cause of morbidity and mortality associated with a CRC screening program. These results must be taken into account in the decision making of lesions that are candidates for endoscopic resection.

Factors associated with short-term mortality after emergency department care of residents living in aged care homes: findings from the multicenter Caregency study. / Factores asociados con mortalidad a corto plazo en personas que viven en residencias atendidas en servicios de urgencias: resultados del estudio multicéntrico Caregency.

OBJECTIVES: To evaluate short-term mortality in people transferred from aged care homes for treatment in a hospital emergency department (ED) and to analyze factors associated with mortality. MATERIAL AND METHODS: Multicenter study of a random sample of retrospective data of patients treated in 5 EDs in Catalonia in 2017. The patients were over the age of 65 years and lived in residential care facilities. In addition to short-term mortality (in the ED or within 30 days of discharge), we analyzed sociodemographic characteristics, prior functional and cognitive status, multimorbidity, triage level on arrival, length of stay in the ED, and hospital admission. Odds ratios (ORs) for factors associated with short-term mortality were calculated by multivariate regression analysis. RESULTS: A total of 2444 ED admissions were analyzed. The patients' mean (SD) age was 85.9 (7.1) years, and 67.7% .were women. Short-term mortality (in 15.5%) was associated with age >90 years (OR, 1.50; 95% CI, 1.5-1.95 years), a Charlson index >2 (OR, 1.47; 95% CI, 1.14-1.90), and dependency assessed as moderate (OR, 1.50; 95% CI, 1.03- 2.20) or severe (OR, 2.56; 95% CI, 1.84-3.55). Other associated factors were a higher level of urgency on triage, duration of ED stay, and hospital admission. CONCLUSION: Aged residents with the characteristics associated with short-term mortality could benefit from interventions for potentially avoiding unnecessary transfers to an ED, and from the implementation of comprehensive geriatric care within the ED. This could be useful to support good quality of care at the end of life.

OBJETIVO: Evaluar la frecuencia y los factores asociados con la mortalidad a corto plazo de personas que viven en residencias tras ingreso en urgencias. METODO: Análisis retrospectivo multicéntrico de una muestra aleatoria de admisiones de personas $ 65 años que viven en residencias en cinco servicios de urgencias de Cataluña, a lo largo de 2017. Se analizaron características sociodemográficas, el estado funcional y cognitivo previo, multimorbilidad, nivel de triaje de las urgencias, duración de la estancia en urgencias, hospitalización y mortalidad a corto plazo (en urgencias o en los 30 días posteriores al alta). Se utilizó un análisis de regresión multivariante para investigar los factores asociados con la mortalidad a corto plazo. RESULTADOS: Se analizaron 2.444 admisiones en urgencias, con una edad media de 85,9 (DE 7,1) años, 67,7% mujeres. La mortalidad a corto plazo (15,5%) se asoció con una edad > 90 años (OR 1,50; IC 95%: 1,5-1,95), un índice de Charlson > 2 (OR 1,47; IC 95%: 1,14-1,90), y un grado de dependencia moderado (OR 1,50; IC 95%: 1,03-2,20) y grave (OR 2,56; IC 95%: 1,84-3,55). También se asoció con un mayor nivel de triaje de la urgencia, duración de la estancia en urgencias e ingreso en planta de hospitalización. CONCLUSIONES: Los ancianos residentes con las características descritas podrían beneficiarse especialmente de intervenciones dirigidas a la prevención de traslados potencialmente innecesarios a urgencias y a la implementación de una atención integral geriátrica dentro de los servicios de urgencias, a fin de garantizar una buena calidad de los cuidados en fases finales de la vida.

Overtreatment in nonmalignant lesions detected in a colorectal cancer screening program: a retrospective cohort study.

BACKGROUND: Although colorectal cancer (CRC) screening programs reduce CRC incidence and mortality, they are associated with risks in healthy subjects. However, the risk of overtreatment and overdiagnosis has not been determined yet. The aim of this study was to report the surgery rates in patients with nonmalignant lesions detected within the first round of a fecal immunochemical test (FIT) based CRC screening program and the factors associated with it. METHODS: We included in this analysis all patients with nonmalignant lesions detected between May 2013 and June 2019 in the Galician (Spain) CRC screening program. We calculated surgery rate according to demographic variables, the risk classification according to the colonoscopy findings (European guidelines for quality assurance), the endoscopist's adenoma detection rate (ADR) classified into quartiles and the hospital's complexity level. We determined which variables were independently associated with surgery rate and expressed the association as Odds Ratio and its 95% confidence interval (CI). RESULTS: We included 15,707 patients in the analysis with high (19.9%), intermediate (26.9%) low risk (23.3%) adenomas and normal colonoscopy (29.9%) detected in the analyzed period. Colorectal surgery was performed in 162 patients (1.03, 95% CI 0.87-1.19), due to colonoscopy complications (0.02, 95% CI 0.00-0.05) and resection of colorectal benign lesions (1.00, 95% CI 0.85-1.16). Median hospital stay was 6 days with 17.3% patients developing minor complications, 7.4% major complications and one death. After discharge, complications developed in 18.4% patients. In benign lesions, an endoscopic resection was performed in 25.4% and a residual premalignant lesion was detected in 89.9%. The variables independently associated with surgery in the multivariable analysis were age (≥60 years = 1.57, 95% CI 1.11-2.23), sex (female = 2.10, 95% CI 1.52-2.91), the European guidelines classification (high risk = 67.94, 95% CI 24.87-185.59; intermediate risk = 5.63, 95% CI 1.89-16.80; low risk = 1.43; 95% CI 0.36-5.75), the endoscopist's ADR (Q4 = 0.44, 95% CI 0.28-0.68; Q3 = 0.44, 95% CI 0.27-0.71; Q2 = 0.71, 95% CI 0.44-1.14) and the hospital (tertiary = 0.54, 95% CI 0.38-0.79). CONCLUSIONS: In a CRC screening program, the surgery rate and the associated complications in patients with nonmalignant lesions are low, and related to age, sex, endoscopic findings, endoscopist's ADR and the hospital's complexity.

Reproductive Outcomes from Maternal Loss of Nlrp2 Are Not Improved by IVF or Embryo Transfer Consistent with Oocyte-Specific Defect.

Nlrp2 encodes a protein of the oocyte subcortical maternal complex (SCMC), required for embryo development. We previously showed that loss of maternal Nlrp2 in mice causes subfertility, smaller litters with birth defects, and growth abnormalities in offspring, indicating that Nlrp2 is a maternal effect gene and that all embryos from Nlrp2-deficient females that were cultured in vitro arrested before the blastocysts stage. Here, we used time-lapse microscopy to examine the development of cultured embryos from superovulated Nlrp2-deficient and wild-type mice after in vivo and in vitro fertilization. Embryos from Nlrp2-deficient females had similar abnormal cleavage and fragmentation and arrested by blastocyst stage, irrespective of fertilization mode. This indicates that in vitro fertilization does not further perturb or improve the development of cultured embryos. We also transferred embryos from superovulated Nlrp2-deficient and wild-type females to wild-type recipients to investigate if the abnormal reproductive outcomes of Nlrp2-deficient females are primarily driven by oocyte dysfunction or if a suboptimal intra-uterine milieu is a necessary factor. Pregnancies with transferred embryos from Nlrp2-deficient females produced smaller litters, stillbirths, and offspring with birth defects and growth abnormalities. This indicates that the reproductive phenotype is oocyte-specific and is not rescued by development in a wild-type uterus. We further found abnormal DNA methylation at two maternally imprinted loci in the kidney of surviving young adult offspring, confirming persistent DNA methylation disturbances in surviving offspring. These findings have implications for fertility treatments for women with mutations in NLRP2 and other genes encoding SCMC proteins.

pT1 Colorectal Cancer Detected in a Colorectal Cancer Mass Screening Program: Treatment and Factors Associated with Residual and Extraluminal Disease.

The aim of this study is to describe the treatment of pT1 colorectal cancer (CRC) in a mass screening program, the surgery-related complications and the factors associated with residual disease after endoscopic resection and extraluminal disease after surgery. We included in this retrospective analysis all the pT1 CRC detected in the Galician CRC screening program between May 2013 and June 2019. We determined which variables were independently associated with the outcomes of the study through a multivariable logistic regression analysis. We included 370-354 pT1 N0(X), 16 pT1N1- out of the 971 CRC detected; 277 (74.9%) were resected endoscopically and 162 (43.8%) were not referred to surgery. There were surgical complications in 30.7% and 16.3% of the patients during hospitalization and after discharge. Residual disease was detected in 12 (4.3%) after endoscopic resection and extraluminal disease in 18 (8.6%) patients after surgery. The variables independently associated with initial endoscopic resection were a pedunculated morphology (OR 33.1, 95% CI 4.3-254), a diameter ≥ 20 mm (OR 3.94, 95% CI 1.39-11.18) and a Site-Morphology-Size-Access score < 9 (OR 428, 95% CI 42-4263). The variables related with surgery rescue were a piecemeal resection (OR 4.48, 95% CI 1.48-13.6), an infiltrated/nonevaluable resection border (OR 7.44, 95% CI 2.12-26.0), a non-well-differentiated histology (OR 4.76, 95% CI 1.07-20.0), vascular infiltration (OR 8.24, 95% CI 2.72-25.0) and a Haggitt 4 infiltration of the submucosa (OR 5.68, 95% CI 2.62-12.3). Residual disease after endoscopic resection was associated with an infiltrated/nonevaluable resection border (OR 34.9, 95% CI 4.08-298), a non-well-differentiated histology (OR 6.67, 95% CI 1.05-50.0), and the vascular infiltration of the submucosa (OR 7.61, 95% CI 1.55-37.4). The variables related with extraluminal disease after surgical resection were no endoscopic resection (OR 4.34, 95% CI 1.26-14.28), a non-well-differentiated histology (OR 4.35, 95% CI 1.39-14.29) and the lymphatic infiltration of the submucosa (OR 4.8, 95% CI 1.32-17.8). In a CRC screening program, although most of pT1 CRC are candidates for endoscopic treatment, surgery is a safe procedure. We have defined some easy to evaluate variables that can be used in the decision-making process.

Intracellular Water Content in Lean Mass as an Indicator of Muscle Quality in an Older Obese Population.

BACKGROUND: In aged populations, muscle strength depends more on muscle quality than on muscle quantity, while all three are criteria for the diagnosis of sarcopenia. Intracellular water content (ICW) in lean mass (LM) has been proposed as an indicator of muscle quality related to muscle strength in older people. OBJECTIVES: To evaluate the relationship between the ICW/LM ratio, muscle strength and indicators of functional performance in obese older adults, and to assess the value of the ICW/LM ratio as an indicator of muscle quality. METHODOLOGY: Design: cross-sectional study. POPULATION: persons aged 65-75 years with a body mass index of 30-39 kg/m2. ICW and LM were estimated by bioelectrical impedance. Hand grip, gait speed, unipedal stance test, timed up-and-go (TUG) test, Barthel score and frailty (Fried criteria) were assessed. Sarcopenia was established according to EWGSOP2 criteria. RESULTS: Recruited were 305 subjects (66% women), mean age 68 years. The ICW/LM ratio correlated with the TUG test, gait speed and grip strength, and was also associated with sex, the unipedal stance test and frailty. Independently of age, sex and muscle mass, the ICW/LM ratio was related with gait speed, the TUG test and unipedal stance capacity. One person (0.3%) had sarcopenia defined as low muscle strength and low muscle mass, while 25 people (8.2%) had sarcopenia defined as low muscle strength and poor muscle quality (ICW/LM). With this last definition, sarcopenia was related to frailty, gait speed and the TUG test. CONCLUSIONS: ICW content in LM could be a useful muscle quality indicator for defining sarcopenia. However, more studies are required to confirm our findings for other populations.

Soft windowing application to improve analysis of high-throughput phenotyping data.

MOTIVATION: High-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors. RESULTS: Here we introduce 'soft windowing', a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources. AVAILABILITY AND IMPLEMENTATION: The method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Ovarian stimulation for oocyte vitrification does not modify disease-free survival and overall survival rates in patients with early breast cancer.

RESEARCH QUESTION: Does ovarian stimulation for oocyte vitrification affect disease-free survival and overall survival rates in women with early breast cancer? DESIGN: This cohort study included 259 patients with early breast cancer; 148 patients underwent ovarian stimulation, whereas 111 patients did not. Patients were treated between January 2008 and December 2016. To calculate the disease-free survival time and overall survival rate, the time of definitive surgery was defined as the starting point. The follow-up was conducted up to 5 years. RESULTS: Exposed and non-exposed groups were comparable in tumour, node and metastases classification, Nottingham grade, hormonal receptor status, tumour molecular phenotype, histology and pathology stage. The exposed group was younger than the non-exposed. Recurrences occurred in 9/148 women (6.1%) in the exposed group and 15/111 women (13.5%) in the non-exposed group, with no significant difference. The mean disease-free survival time was 63.9 months (95% confidence interval [CI]: 61.5-66.4) in the exposed group and 60.6 months (95% CI: 56.9-64.2) in the non-exposed, with no significant difference (log-rank [Mantel-Cox] test). Overall survival rates were comparable; 2/148 (1.4%) and 4/111 (3.6%) patients died, in exposed and non-exposed groups, respectively, during the period analysed. Mean overall survival times were 67.2 months (95% CI: 66.2-68.2) in the exposed group and 65.9 months (95% CI: 64.0-67.9) in the unexposed, with no significant difference (log-rank [Mantel-Cox] test). CONCLUSIONS: This study suggests that ovarian stimulation in patients with early-stage breast cancer is safe in the long term.

The Role of Water Homeostasis in Muscle Function and Frailty: A Review.

Water, the main component of the body, is distributed in the extracellular and intracellular compartments. Water exchange between these compartments is mainly governed by osmotic pressure. Extracellular water osmolarity must remain within very narrow limits to be compatible with life. Older adults lose the thirst sensation and the ability to concentrate urine, and this favours increased extracellular osmolarity (hyperosmotic stress). This situation, in turn, leads to cell dehydration, which has severe consequences for the intracellular protein structure and function and, ultimately, results in cell damage. Moreover, the fact that water determines cell volume may act as a metabolic signal, with cell swelling acting as an anabolic signal and cell shrinkage acting as a catabolic signal. Ageing also leads to a progressive loss in muscle mass and strength. Muscle strength is the main determinant of functional capacity, and, in elderly people, depends more on muscle quality than on muscle quantity (or muscle mass). Intracellular water content in lean mass has been related to muscle strength, functional capacity, and frailty risk, and has been proposed as an indicator of muscle quality and cell hydration. This review aims to assess the role of hyperosmotic stress and cell dehydration on muscle function and frailty.

Intracellular Water Content in Lean Mass is Associated with Muscle Strength, Functional Capacity, and Frailty in Community-Dwelling Elderly Individuals. A Cross-Sectional Study.

High intracellular water (ICW) content has been associated with better functional performance and a lower frailty risk in elderly people. However, it is not clear if the protective effect of high ICW is due to greater muscle mass or better muscle quality and cell hydration. We aimed to assess the relationship between ICW content in lean mass (LM) and muscle strength, functional performance, frailty, and other clinical characteristics in elderly people. In an observational cross-sectional study of community-dwelling subjects aged ≥75 years, ICW and LM were estimated by bioelectrical impedance, and the ICW/LM ratio (mL/kg) calculated. Muscle strength was measured as hand grip, frailty status was assessed according to Fried criteria, and functional status was assessed by Barthel score. For 324 recruited subjects (mean age 80 years), mean (SD) ICW/LM ratio was 408 (29.3) mL/kg. The ICW/LM ratio was negatively correlated with age (rs = -0.249; p < 0.001). A higher ICW/LM ratio was associated with greater muscle strength, better functional capacity, and a lower frailty risk, even when adjusted by age, sex, nº of co-morbidities, and LM. ICW content in LM (including the muscle) may influence muscle strength, functional capacity and frailty. However, further studies are needed to confirm this hypothesis.