Thermal Transport in Nanoelectronic Devices Cooled by On-Chip Magnetic Refrigeration.

On-chip demagnetization refrigeration has recently emerged as a powerful tool for reaching microkelvin electron temperatures in nanoscale structures. The relative importance of cooling on-chip and off-chip components and the thermal subsystem dynamics are yet to be analyzed. We study a Coulomb blockade thermometer with on-chip copper refrigerant both experimentally and numerically, showing that dynamics in this device are captured by a first-principles model. Our work shows how to simulate thermal dynamics in devices down to microkelvin temperatures, and outlines a recipe for a low-investment platform for quantum technologies and fundamental nanoscience in this novel temperature range.

Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium.

BACKGROUND: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies. PATIENTS AND METHODS: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients). RESULTS: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality. CONCLUSIONS: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies. CLINICAL TRIAL IDENTIFIER: NCT04354701.

Circulating tumour DNA for clinicians: current and future clinical applications.

This review introduces clinicians to the basic concepts of the biology of circulating tumour DNA (ctDNA), which is required to understand clinical use of ctDNA technology. We provide an overview of how new technology has improved the sensitivity of ctDNA detection over the last decade and the available techniques for ctDNA analysis including whole-genome sequencing (WGS), targeted cancer-associated gene panels, and methylation analysis. We discuss the most recent evidence from clinical trials for ctDNA in patient care including precision treatment of advanced cancers, disease monitoring, improving adjuvant treatment, and screening for early detection of cancer. Finally, we outline how ctDNA is likely to directly impact radiologists, and identify further research required for ctDNA to progress into routine clinical application.

Are fathers a good substitute for mothers? Paternal care and growth rates in Shodagor children.

Biparental care is a hallmark of human social organization, though paternal investment varies between and within societies. The facultative nature of paternal care in humans suggests males should invest when their care improves child survival and/or quality, though testing this prediction can be challenging because of the difficulties of empirically isolating paternal effects from those of other caregivers. Additionally, the broader context in which care is provided, vis-à-vis care from mothers and others, may lead to different child outcomes. Here, we examine the effects of paternal care on child growth among Shodagor fisher-traders, where fathers provide high levels of both additive and substitutive care, relative to mothers. We modeled seasonal z-scores and velocities for height, weight, and body mass index (BMI) outcomes using linear mixed models. Our evidence indicates that, as predicted, the context of paternal care is an important predictor of child outcomes. Results show that environmental seasonality and alloparental help contribute to a nuanced understanding of the impact of Shodagor paternal care on child physiology.

The Clinical Utility of Kidney Cortical Thickness in assessing severity of CKD in Low Income Setting.

BACKGROUND: Renal Ultrasound Scan (RUS) is known to have an important role in assessing kidney function in healthy people and people with Chronic Kidney Disease (CKD) with the kidney length (KL) being the most commonly used measure. The Glomerular Filtration Rate (GFR) is the gold standard in kidney function assessment and its strength of correlation with a RUS measure is used in ascertaining the reliability of that RUS measure. OBJECTIVES: To compare the strength of correlations between the GFR and RUS measures like KL and cortical thickness (CT) in healthy people and people with CKD. METHODS: One hundred and forty study participants who had kidney ultrasound scan were studied. Creatinine based GFR was determined and linear correlation coefficients (r) were used to determine the relationship between the GFR and RUS measures. RESULTS: Seventy CKD cohorts with stage 2-4 disease and 70 healthy volunteers (each with 35 males and 35 females) took part. The total mean eGFR, KL and CT for the study participants were 70.5 ± 12.5ml/min, 10.0 ± 3.1cm, and 8.6 ± 2.7mm respectively. There was a progressive decline in eGFR and renal CT as CKD worsened down the stages. The mean eGFR, KL and CT of the CKD cohorts were 44.7 + 3.6 ml/min, 9.1 + 3.3 cm and 7.4 + 2.4 mm respectively. Among the CKD cohorts, the eGFR was highest in CGN and, the KL and CT were highest in obstructive uropathy. The GFR, was positively correlated with KL and CT, the strength of association being more with the CT. The mean age and GFR independently predicted the kidney cortical thickness. CONCLUSION: Kidney sizes were smaller in females, with aging and with declining kidney function. The CT being more positively correlated with GFR than the KL, is a more reliable RUS measure in assessing kidney function.

CONTEXTE: On sait que l'échographie rénale (ÉR) joue un rôle important dans l'évaluation de la fonction rénale chez les personnes en santé et chez les personnes atteintes d'insuffisance rénale chronique (IRC) avec la longueur des reins (KL) étant la mesure la plus couramment utilisée. Le débit de filtration glomérulaire (DFG) est l'étalon-or de l'évaluation de la fonction rénale et la force de sa corrélation avec une mesure RUS est utilisée pour déterminer la fiabilité de cette mesure RUS. OBJECTIFS: Comparer la force des corrélations entre le DFG et les mesures de l'ÉRU comme le KL et l'épaisseur corticale (EC) chez des personnes en bonne santé et des personnes atteintes d'IRC. MÉTHODES: Cent quarante participants à l'étude ayant subi une échographie rénale ont été étudiés. Le DFG basé sur la créatinine a été déterminé et des coefficients de corrélation linéaire (r) ont été utilisés pour déterminer la relation entre le DFG et les mesures de RUS. RÉSULTATS: Soixante-dix cohortes d'IRC avec une maladie de stade 2-4 et 70 volontaires sains (35 hommes et 35 femmes) ont participé à l'étude. Les moyennes totales du DFGe, du KL et du CT pour les participants à l'étude étaient respectivement de 70,5 ± 12,5 ml/min, 10,0 ± 3,1 cm et 8,6 ± 2,7 mm respectivement. On a constaté un déclin progressif du DFGe et du CT rénal au fur et à mesure de l'aggravation de l'IRC. Le DFGe moyen, le KL et le CT des cohortes d'IRC étaient de 44,7 + 3,6 ml/min, 9,1 + 3,3 cm et 7,4 + 2,4 mm respectivement. Parmi les cohortes d'IRC, le DFGeT était le plus élevé dans la NGC et le KL et le CT étaient les plus élevés dans l'uropathie obstructive.Le DFG était positivement corrélé avec le KL et le CT. La force de l'association étant plus importante avec le CT. L'âge moyen et le GFR prédisent indépendamment l'épaisseur corticale des reins. CONCLUSION: La taille des reins est plus petite chez les femmes, avec le vieillissement et le déclin de la fonction rénale. Le CT étant plus corrélée plus positivement avec le DFG que le KL, est une mesure plus fiable de l'EFR pour évaluer la fonction rénale. MOTS CLÉS: Taux de filtration glomérulaire, longueur du rein, épaisseur de la corticale.

Constitutive melanin density is associated with prevalent and short-term, but not long-term, incident fracture risk in older Caucasian adults.

Higher cutaneous melanin reduces vitamin D3 production. This may increase fracture risk. We found that cutaneous melanin density was associated with prevalent and short-term, but not long-term, incident fracture risk in older Caucasian adults. Melanin density either acts as a surrogate marker or its relationship with fracture changes with time. INTRODUCTION: Higher cutaneous melanin reduces vitamin D3 production. This may impact lifetime vitamin D status and increase fracture risk. This study aimed to describe the relationship between spectrophotometrically determined constitutive melanin density, prevalent and incident fractures in a cohort of exclusively older Caucasian adults. METHODS: 1072 community-dwelling adults aged 50-80 years had constitutive melanin density quantified using spectrophotometry. Participants were followed up at 2.5 (n = 879), 5 (n = 767), and 10 (n = 571) years after the baseline assessment. Prevalence and number of symptomatic fractures were assessed by questionnaire. RESULTS: Higher melanin density was independently associated with greater prevalence of any fracture (RR 1.08, p = 0.03), vertebral fracture (RR 1.41, p = 0.04) and major fracture (RR 1.12, p = 0.04) and the number of fractures (RR 1.09, p = 0.04) and vertebral fractures (RR 1.47, p = 0.04) in cross-sectional analysis. At the 2.5-year follow-up, higher melanin density was associated with incident fractures (RR 1.42, p = 0.01) and major fractures (RR 1.81, p = 0.01) and the number of incident fractures (RR 1.39, p = 0.02) and major fractures (RR 2.14, p = 0.01). The relationship between melanin density and incident fracture attenuated as the duration of follow-up increased and was not significant at the 5- or 10-year follow-up. CONCLUSIONS: Constitutive melanin density was associated with prevalent and short-term, but not long-term, incident fracture risk in older Caucasian adults. This suggests melanin density either acts as a surrogate marker for an unmeasured fracture risk factor or the relationship between melanin density and fracture changes with time.

Skin Photosensitivity is Associated with 25-Hydroxyvitamin D and BMD but not Fractures Independent of Melanin Density in Older Caucasian Adults.

Whether skin photosensitivity modulates sun exposure behaviours, consequent vitamin D status and skeletal health outcomes independently of constitutive pigmentation have not been systematically investigated. 1072 community-dwelling adults aged 50-80 years had skin photosensitivity quantified by questionnaire and melanin density by spectrophotometry. Bone mineral density (BMD), falls risk and 25-hydroxyvitamin D (25OHD) were measured using DXA, short form physiological profile assessment and radioimmunoassay, respectively. Sun exposure and symptomatic fractures were assessed by questionnaire. Participants were followed up at 2.5 (n = 879), 5 (n = 767) and 10 (n = 571) years. Higher resistance to sunburn and greater ability to tan were associated with reduced sun protection behaviours (RR 0.87, p < 0.001 & RR 0.88, p < 0.001), higher lifetime discretionary sun exposure in summer (RR 1.05, p = 0.001 & RR 1.07, p = 0.001) and winter (RR 1.07, p = 0.001 & RR 1.08, p = 0.02) and fewer lifetime sunburns (RR 0.86, p < 0.001 & RR 0.91, p = 0.001). Higher resistance to sunburn was associated with lower total body (ß = - 0.006, p = 0.047) and femoral neck (ß = - 0.006, p = 0.038) BMD, but paradoxically, fewer prevalent fractures (RR 0.94, p = 0.042). Greater ability to tan was associated with higher 25OHD (ß = 1.43, p = 0.04), lumbar spine (ß = 0.014, p = 0.046) and total body (ß = 0.013, p = 0.006) BMD, but not fracture or falls risk. These associations were independent of constitutive melanin density. Cutaneous photosensitivity was associated with sun exposure behaviours, cutaneous sequelae and, consequently, 25OHD and BMD in older Caucasian adults independent of constitutive melanin density. There was no consistent association with fracture outcomes, suggesting environmental factors are at least as important.

Histological validation of a type 1 diabetes clinical diagnostic model for classification of diabetes.

AIMS: Misclassification of diabetes is common due to an overlap in the clinical features of type 1 and type 2 diabetes. Combined diagnostic models incorporating clinical and biomarker information have recently been developed that can aid classification, but they have not been validated using pancreatic pathology. We evaluated a clinical diagnostic model against histologically defined type 1 diabetes. METHODS: We classified cases from the Network for Pancreatic Organ donors with Diabetes (nPOD) biobank as type 1 (n = 111) or non-type 1 (n = 42) diabetes using histopathology. Type 1 diabetes was defined by lobular loss of insulin-containing islets along with multiple insulin-deficient islets. We assessed the discriminative performance of previously described type 1 diabetes diagnostic models, based on clinical features (age at diagnosis, BMI) and biomarker data [autoantibodies, type 1 diabetes genetic risk score (T1D-GRS)], and singular features for identifying type 1 diabetes by the area under the curve of the receiver operator characteristic (AUC-ROC). RESULTS: Diagnostic models validated well against histologically defined type 1 diabetes. The model combining clinical features, islet autoantibodies and T1D-GRS was strongly discriminative of type 1 diabetes, and performed better than clinical features alone (AUC-ROC 0.97 vs. 0.95; P = 0.03). Histological classification of type 1 diabetes was concordant with serum C-peptide [median < 17 pmol/l (limit of detection) vs. 1037 pmol/l in non-type 1 diabetes; P < 0.0001]. CONCLUSIONS: Our study provides robust histological evidence that a clinical diagnostic model, combining clinical features and biomarkers, could improve diabetes classification. Our study also provides reassurance that a C-peptide-based definition of type 1 diabetes is an appropriate surrogate outcome that can be used in large clinical studies where histological definition is impossible. Parts of this study were presented in abstract form at the Network for Pancreatic Organ Donors Conference, Florida, USA, 19-22 February 2019 and Diabetes UK Professional Conference, Liverpool, UK, 6-8 March 2019.

Cosmetic benefits of a novel biomimetic lamellar formulation containing niacinamide in healthy females with oily, blemish-prone skin in a randomized proof-of-concept study.

OBJECTIVE: A randomized study was designed to evaluate the potential cosmetic benefit of a biomimetic, niacinamide-containing moisturizing cream in oily, blemish-prone skin. METHODS: Healthy adult women with oily, blemish-prone skin were randomized to one of three treatment groups: test, control, or positive control. In the test group, subjects used the test product (containing 4% niacinamide), plus the standard cleanser (Simple® Kind to Skin Moisturizing Facial Wash). In the control group, subjects received no moisturizer but used the standard cleanser. In the positive control group, subjects used Vivatinell Acnecinamide® Gel Cream (containing 4% niacinamide) as a moisturizer and Neutrogena Visibly Clear® Spot Clearing Facial Wash (containing 2% salicylic acid) as a cleanser. The positive control regimen was included to provide a comparison for estimates of effect size. The primary objective was to evaluate skin moisturization as a change from baseline in corneometer values at 8 h for the test regimen vs. the control regimen. Analysis of covariance was applied for the primary efficacy analysis. RESULTS: A total of 132 subjects were randomized with 44 included in each treatment group. A significant difference was observed in the primary endpoint for the test regimen compared with the control regimen (least-squares mean difference [95% CI]: 3.12 [0.68, 5.56], P = 0.0128). A trend was observed in favour of the positive control regimen compared with the control regimen. Secondary measurements of moisturization supported the primary efficacy outcome. Assessment of blemishes showed a significant difference between the test regimen vs. the control regimen for change from baseline in mean total blemish count at Week 8 (least-squares mean difference [95% CI]: -1.80 [-3.41, -0.19], P = 0.0290). No statistical comparisons between the positive control group and the test group were performed. CONCLUSION: This study provides proof-of-concept evidence that a novel lamellar lipid moisturizer containing niacinamide, in combination with a standard cleanser, can help moisturize the skin and provide an overall improvement in the complexion appearance of people with blemish-prone skin. STUDY REGISTRATION: NCT03093181.

OBJECTIF: Une étude randomisée a été conçue pour évaluer le bénéfice cosmétique potentiel d'une crème hydratante biomimétique contenant du niacinamide sur une peau grasse sujette aux imperfections. MÉTHODES: Des femmes adultes en bonne santé, à peau grasse sujette aux imperfections, ont été randomisées dans l'un des trois groupes de traitement : test, témoin ou témoin positif. Dans le groupe test, les sujets ont utilisé le produit testé (contenant 4 % de niacinamide), plus le nettoyant standard (Nettoyant visage Simple® doux pour la peau). Dans le groupe témoin, les sujets n'ont reçu aucune crème hydratante mais ont utilisé le nettoyant standard. Dans le groupe témoin positif, les sujets ont utilisé le gel crème Vivatinell Acnecinamide® (contenant 4 % de niacinamide) comme crème hydratante et le nettoyant visage pour réduire les imperfections Neutrogena Visibly Clear® (contenant 2 % d'acide salicylique) comme nettoyant. Le schéma de traitement du groupe témoin positif était inclus pour fournir une comparaison des estimations de la taille de l'effet. L'objectif principal était d'évaluer l'hydratation de la peau par le changement par rapport à la référence des valeurs du cornéomètre à 8 h pour le schéma de traitement testé par rapport au schéma de traitement témoin. Une analyse de covariance a été appliquée pour l'analyse de l'efficacité primaire. RÉSULTATS: Un total de 132 sujets ont été randomisés, dont 44 inclus dans chaque groupe de traitement. Une différence significative a été observée dans le critère d'évaluation principal en faveur du schéma de traitement testé par rapport au schéma de traitement témoin (différence moyenne des moindres carrés [IC à 95 %] : 3,12 [0,68, 5,56], P = 0,0128). Une tendance a été observée en faveur du schéma de traitement témoin positif par rapport au schéma de traitement témoin. Les mesures secondaires de l'hydratation ont appuyé le résultat principal d'efficacité. L'évaluation des imperfections a montré une différence significative entre le schéma de traitement testé par rapport au schéma de traitement témoin en ce qui concerne le changement par rapport à la référence dans le nombre moyen total d'imperfections à la semaine 8 (différence moyenne des moindres carrés [IC à 95 %] : _1,80 [_3,41, _0,19], P = 0,0290). Aucune comparaison statistique entre le groupe témoin positif et le groupe test n'a été réalisée. CONCLUSION: Cette étude fournit des éléments de preuve de concept qu'une nouvelle crème hydratante lipidique lamellaire à base de niacinamide, en association avec un nettoyant standard, peut permettre d'hydrater la peau et fournir une amélioration globale de l'aspect du teint chez des personnes dont la peau est sujette aux imperfections. Numéro d'enregistrement de l'étude : NCT03093181.

Mortality prediction following non-traumatic amputation of the lower extremity.

BACKGROUND: Patients who undergo lower extremity amputation secondary to the complications of diabetes or peripheral artery disease have poor long-term survival. Providing patients and surgeons with individual-patient, rather than population, survival estimates provides them with important information to make individualized treatment decisions. METHODS: Patients with peripheral artery disease and/or diabetes undergoing their first unilateral transmetatarsal, transtibial or transfemoral amputation were identified in the Veterans Affairs Surgical Quality Improvement Program (VASQIP) database. Stepdown logistic regression was used to develop a 1-year mortality risk prediction model from a list of 33 candidate predictors using data from three of five Department of Veterans Affairs national geographical regions. External geographical validation was performed using data from the remaining two regions. Calibration and discrimination were assessed in the development and validation samples. RESULTS: The development sample included 5028 patients and the validation sample 2140. The final mortality prediction model (AMPREDICT-Mortality) included amputation level, age, BMI, race, functional status, congestive heart failure, dialysis, blood urea nitrogen level, and white blood cell and platelet counts. The model fit in the validation sample was good. The area under the receiver operating characteristic (ROC) curve for the validation sample was 0·76 and Cox calibration regression indicated excellent calibration (slope 0·96, 95 per cent c.i. 0·85 to 1·06; intercept 0·02, 95 per cent c.i. -0·12 to 0·17). Given the external validation characteristics, the development and validation samples were combined, giving a total sample of 7168. CONCLUSION: The AMPREDICT-Mortality prediction model is a validated parsimonious model that can be used to inform the 1-year mortality risk following non-traumatic lower extremity amputation of patients with peripheral artery disease or diabetes.

Predicting reamputation risk in patients undergoing lower extremity amputation due to the complications of peripheral artery disease and/or diabetes.

BACKGROUND: Patients undergoing amputation of the lower extremity for the complications of peripheral artery disease and/or diabetes are at risk of treatment failure and the need for reamputation at a higher level. The aim of this study was to develop a patient-specific reamputation risk prediction model. METHODS: Patients with incident unilateral transmetatarsal, transtibial or transfemoral amputation between 2004 and 2014 secondary to diabetes and/or peripheral artery disease, and who survived 12 months after amputation, were identified using Veterans Health Administration databases. Procedure codes and natural language processing were used to define subsequent ipsilateral reamputation at the same or higher level. Stepdown logistic regression was used to develop the prediction model. It was then evaluated for calibration and discrimination by evaluating the goodness of fit, area under the receiver operating characteristic curve (AUC) and discrimination slope. RESULTS: Some 5260 patients were identified, of whom 1283 (24·4 per cent) underwent ipsilateral reamputation in the 12 months after initial amputation. Crude reamputation risks were 40·3, 25·9 and 9·7 per cent in the transmetatarsal, transtibial and transfemoral groups respectively. The final prediction model included 11 predictors (amputation level, sex, smoking, alcohol, rest pain, use of outpatient anticoagulants, diabetes, chronic obstructive pulmonary disease, white blood cell count, kidney failure and previous revascularization), along with four interaction terms. Evaluation of the prediction characteristics indicated good model calibration with goodness-of-fit testing, good discrimination (AUC 0·72) and a discrimination slope of 11·2 per cent. CONCLUSION: A prediction model was developed to calculate individual risk of primary healing failure and the need for reamputation surgery at each amputation level. This model may assist clinical decision-making regarding amputation-level selection.

Ultraviolet radiation, both UVA and UVB, influences the composition of the skin microbiome.

BACKGROUND: Studies have begun to investigate the complex relationship between host and microorganisms in non-infectious pathologies such as acne, atopic dermatitis and psoriasis. Though the skin is exposed to environmental stressors such as ultraviolet radiation (UVR), no studies exist examining the effects of both UVA and UVB on the skin microbiome. OBJECTIVE: To test the effect of UVA and UVB on human skin microbiome. METHODS: To test whether UV will alter the cutaneous microbiome, participants were exposed to doses of UVA (22-47 J/cm2 ) or UVB (100-350 mJ/cm2 ) and samples were collected. DNA was isolated and sequenced to identify the microbial composition of each sample. RESULTS: There was vast intra- and inter-subject variation at all time points, and phylum and species-level differences were identified. These included an increase in the phylum Cyanobacteria and a decrease in the family Lactobacillaceae and Pseudomonadaceae. The sensitivity of microbes to UVR and their re-colonization potential following exposure differed in UVA vs UVB samples. LIMITATIONS: The sample size was small, and the study was limited to males. CONCLUSION: The results demonstrate that UVR has profound qualitative and quantitative influences on the composition of the skin microbiome, possibly effecting skin pathology in which UVR is a factor.

Cosmetic benefit of a biomimetic lamellar cream formulation on barrier function or the appearance of fine lines and wrinkles in randomized proof-of-concept clinical studies.

OBJECTIVE: Two studies were designed to evaluate the potential cosmetic benefit of a biomimetic, niacinamide-containing moisturizing cream for the first time in humans. METHODS: In both studies, healthy women were randomized to use two treatments, one for the left side of the body and one for the right, from three options: the test cream, a positive control or no treatment (use of standard cleanser only). Treatments were applied twice daily for 4 weeks to the face and forearms (Study 1) or the face only (Study 2). Instrumental and clinical skin assessments were performed by trained technicians. Study 1 involved tape stripping and a 5-day no-treatment ('regression') period at the end of the 4 weeks. Independent lay graders were asked to grade the skin texture of subjects in Study 2 from high-resolution photographs. RESULTS: In Study 1 (n = 66), the test cream significantly decreased the transepidermal water loss (TEWL) values on the forearm, and in the cheek area of the face, relative to baseline and compared to no treatment, and increased skin Corneometer values. The improvements were partially retained during a subsequent 5-day period of no treatment. Increases in TEWL values on skin subjected to tape stripping were significantly lower after 4 weeks of using the test cream compared to no treatment. In Study 2 (n = 72 subjects with visible signs of ageing), there was a favourable trend in the change from baseline of a skin roughness parameter, Ra , for the test cream compared to no treatment. There were statistically significant improvements in the Fitzpatrick wrinkle score compared to no treatment, decreases in TEWL and increased Corneometer values and Cutometer values (R5 elasticity parameter). Grading of high-resolution images failed to detect the improvements in skin texture (defined as pores, smoothness and unevenness) for the test cream vs. no treatment. No treatment-related serious or severe adverse events were reported. CONCLUSION: Twice daily application of the test cream over 4 weeks had beneficial effects on skin barrier function, moisturization, wrinkle dimensions and elasticity compared to no treatment. These studies provide proof-of-concept evidence and highlight the cosmetic benefit of the biomimetic lamellar cream formulation. STUDY REGISTRATION: NCT03216265, NCT03180645.

OBJECTIF: Deux études ont été conçues pour évaluer pour la première fois chez l'être humain l'éventuel bénéfice cosmétique d'une crème hydratante biomimétique contenant de la niacinamide. MÉTHODES: Dans les deux études, des femmes en bonne santé ont été randomisées pour utiliser deux traitements, un pour le côté gauche du corps et un pour le côté droit, choisis entre trois options : la crème testée, un contrôle positif ou aucun traitement (utilisation d'un nettoyant standard uniquement). Les traitements ont été appliqués deux fois par jour pendant 4 semaines sur le visage et les avant-bras (Étude 1) ou seulement sur le visage (Étude 2). Des évaluations instrumentales et cliniques de la peau ont été effectuées par des techniciens qualifiés. L'étude 1 impliquait un stripping et une période de 5 jours sans traitement (« régression ¼) à la fin des 4 semaines. Il a été demandé à des évaluateurs profanes indépendants d'évaluer la texture de la peau des participantes dans l'Étude 2 à partir de photographies à haute résolution. RÉSULTATS: Dans l'Étude 1 (n = 66), la crème testée a diminué de manière significative les valeurs de la perte en eau transépidermique (transepidermal water loss, TEWL) au niveau de l'avant-bras, et au niveau de la joue, par rapport à la valeur de base, et par rapport au groupe sans aucun traitement, et a augmenté les valeurs des paramètres cutanés mesurés avec un cornéomètre. Les améliorations ont été partiellement conservées pendant une période ultérieure de 5 jours sans aucun traitement. Des augmentations des valeurs TEWL sur la peau exposée à un décollement d'un ruban adhésif étaient significativement plus faibles après 4 semaines d'utilisation de la crème testée par rapport à l'absence de traitement. Dans l'Étude 2 (n = 72 participantes avec des signes visibles de vieillissement), il y avait une tendance favorable au niveau de la variation par rapport à la valeur de base du paramètre relatif à la rugosité de la peau, Ra, pour la crème testée par rapport à l'absence de traitement. Il y a eu des améliorations statistiquement significatives du score de Fitzpatrick pour les rides par rapport à l'absence de traitement, des diminutions des valeurs TEWL et une augmentation des valeurs des paramètres mesurés avec un cornéomètre et des valeurs des paramètres mesurés avec un cutomètre (paramètre élasticité R5). L'évaluation des images à haute résolution n'a pas permis de détecter les améliorations de la texture de la peau (définie par les pores, la finesse et les irrégularités) pour la crème testée par rapport à l'absence de traitement. Aucun événement indésirable grave ou sévère lié au traitement n'a été rapporté. CONCLUSION: Une application deux fois par jour de la crème testée pendant 4 semaines a eu des effets bénéfiques sur la fonction barrière de la peau, l'hydratation, l'aspect des rides et l'élasticité par rapport à l'absence de traitement. Ces études fournissent des éléments de preuve de concept et soulignent les bienfaits cosmétiques de la formule lamellaire biomimétique de la crème. Numéro d'enregistrement de l'étude : NCT03216265, NCT03180645.

Clinical and in vitro evaluation of new anti-redness cosmetic products in subjects with winter xerosis and sensitive skin.

OBJECTIVE: To demonstrate the in vitro activities of panthenol, palmitoylethanolamide (PEA), and niacinamide (NAM) and determine the biophysical properties, clinical safety, tolerability together with efficacy of two developmental anti-redness (AR) formulations containing these ingredients, in alleviating facial redness associated with winter xerosis in healthy volunteers with sensitive skin. METHODS: The anti-inflammatory and skin protective properties of panthenol, PEA and NAM were evaluated in vitro. The physical properties of the AR formulations were analysed using measurement of water vapour transport rate (WVTR) and infrared spectroscopy. Clinical studies were performed between the months of December and April (2014-2015) with efficacy assessed during the winter. Facial redness, irritation, sensitization potential, photo-irritation, and photo-sensitization were evaluated. Self-assessed adverse reactions were reported in diaries of use. RESULTS: Panthenol and PEA reduced prostaglandin E2 , interleukin-6, and thymic stromal lymphopoietin levels in vitro, while NAM induced nicotinamide adenine dinucleotide (NAD) levels and the keratinocyte differentiation markers: filaggrin (2-fold increase, P < 0.001), loricrin (2-fold increase, P < 0.05), involucrin (2 fold increase, P < 0.001) & peroxisomal proliferator activated receptor-alpha (1.5 fold increase, P < 0.05). The two AR products exhibited low WVTR vs. no treatment (P < 0.001) and displayed an ordered lipid structure. The day cream formulation protected against ultraviolet B radiation in vitro. A total of 382 participants were included in clinical studies which showed the AR formulations significantly improved facial redness associated with winter xerosis (Day 29 mean change from baseline: AR day cream 0.77 (P < 0.001); AR serum 0.67 (P < 0.001)). No irritation, sensitization, photo-irritation, photo-sensitization or product-related adverse reactions were observed or reported in the clinical studies. CONCLUSION: The new products significantly improved skin redness associated with winter xerosis in participants with self-perceived sensitive skin. Both products were well tolerated with a suitable safety profile for topical use in subjects with sensitive skin.

OBJECTIF: Démontrer l'activité in vitro du panthénol, du palmitoyléthanolamide (PEA), et du nicotinamide (NAM) et déterminer les propriétés biophysiques, la sécurité clinique, la tolérance ainsi que l'efficacité de deux formulations anti-rougeurs (AR) en développement contenant ces ingrédients pour atténuer les rougeurs faciales associées à la xérose hivernale chez des volontaires sains présentant une peau sensible. MÉTHODES: Les propriétés anti-inflammatoires et protectrices du panthénol, du PEA et du NAM ont été évaluées in vitro. Les propriétés physiques des formulations AR ont été analysées en mesurant le taux de transport de vapeur d'eau (WVTR) et par spectroscopie infrarouge. Des études cliniques ont été réalisées entre décembre et avril (2014-2015) et l'efficacité a été évaluée pendant l'hiver. Les rougeurs, l'irritation, le potentiel de sensibilisation, la photo-irritation et la photosensibilisation au niveau du visage ont été évalués. Des effets indésirables auto-évalués ont été signalés dans des journaux d'utilisation. RÉSULTATS: Le panthénol et le PEA ont réduit les niveaux de prostaglandine E2 , d'interleukine-6 et de lymphopoiétine stromale thymique in vitro, tandis que le NAM a généré une augmentation des taux de nicotinamide adénine dinucléotide (NAD) et des marqueurs de différenciation kératinocytaire : filaggrine (multiplication des taux par 2, P < 0,001), loricrine (multiplication des taux par 2, P < 0,05), involucrine (multiplication des taux par 2, P < 0,001) et du récepteur alpha activé de la prolifération peroxysomale (multiplication des taux par 1,5, P < 0,05). Les deux produits antirétroviraux présentaient un faible taux de WVTR par rapport à l'absence de traitement (P < 0,001) et présentaient une structure lipidique ordonnée. La formulation de la crème de jour protège contre le rayonnement ultraviolet B in vitro. Un total de 382 participants ont été inclus dans les études cliniques qui ont montré que les formulations AR amélioraient significativement les rougeurs faciales associées à la xérose hivernale (changement moyen du jour 29 par rapport à la référence : crème de jour AR 0,77 (P < 0,001) ; sérum AR 0,67 (P < 0,001)). Aucune irritation, sensibilisation, photo-irritation, photosensibilisation ni effet indésirable lié au produit n'a été observé ou signalé dans les études cliniques. CONCLUSION: Les nouveaux produits ont considérablement amélioré la rougeur de la peau associée à la xérose hivernale chez les participants présentant une peau sensible auto-perçue. Les deux produits ont été bien tolérés avec un profil de sécurité approprié pour un usage topique chez les sujets présentant une peau sensible.

Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96-week results from two randomized clinical trials.

OBJECTIVES: The single-tablet regimen rilpivirine, emtricitabine and tenofovir alafenamide (RPV/FTC/TAF) for treatment of HIV-1-infected adults was approved based on bioequivalence. We assessed the clinical efficacy, safety and tolerability of switching to RPV/FTC/TAF from either RPV/FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF. METHODS: We conducted two distinct randomized, double-blind, active-controlled, noninferiority trials in participants taking RPV/FTC/TDF (Study 1216) and EFV/FTC/TDF (Study 1160). Each study randomized virologically suppressed (HIV-1 RNA < 50 copies/mL) adults (1:1) to switch to RPV/FTC/TAF or continue their current regimen for 96 weeks. We evaluated efficacy as the proportion with HIV-1 RNA < 50 copies/mL using the Food and Drug Administration snapshot algorithm and prespecified bone and renal endpoints at week 96. RESULTS: We randomized and treated 630 participants in Study 1216 (RPV/FTC/TAF, n = 316; RPV/FTC/TDF, n = 314) and 875 in Study 1160 (RPV/FTC/TAF, n = 438; EFV/FTC/TDF, n = 437). In both studies, the efficacy of switching to RPV/FTC/TAF was noninferior to that of continuing baseline therapy at week 96, with respective percentages of patients with HIV RNA < 50 copies/mL being 89.2% versus 88.5% in Study 1216 [difference 0.7%; 95% confidence interval (CI) -4.3 to +5.8%] and 85.2% versus 85.1% in Study 1160 (difference 0%; 95% CI -4.8 to +4.8%). No participant on RPV/FTC/TAF developed treatment-emergent resistance versus two on EFV/FTC/TDF and one on RPV/FTC/TDF. Compared with continuing baseline therapy, significant improvements in bone mineral density and renal tubular markers were observed in the RPV/FTC/TAF groups (P < 0.001). CONCLUSIONS: Switching to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF was safe and effective and improved bone mineral density and renal biomarkers up to 96 weeks with no cases of treatment-emergent resistance.

Systematic reanalysis of genomic data improves quality of variant interpretation.

As genomic sequencing expands, so does our knowledge of the link between genetic variation and disease. Deeper catalogs of variant frequencies improve identification of benign variants, while sequencing affected individuals reveals disease-associated variation. Accumulation of human genetic data thus makes reanalysis a means to maximize the benefits of clinical sequencing. We implemented pipelines to systematically reassess sequencing data from 494 individuals with developmental disability. Reanalysis yielded pathogenic or likely pathogenic (P/LP) variants that were not initially reported in 23 individuals, 6 described here, comprising a 16% increase in P/LP yield. We also downgraded 3 LP and 6 variants of uncertain significance (VUS) due to updated population frequency data. The likelihood of identifying a new P/LP variant increased over time, as ~22% of individuals who did not receive a P/LP variant at their original analysis subsequently did after 3 years. We show here that reanalysis and data sharing increase the diagnostic yield and accuracy of clinical sequencing.

Comparative analysis of the outcomes of elective abdominal aortic aneurysm repair in England and Sweden.

BACKGROUND: There is substantial international variation in mortality after abdominal aortic aneurysm (AAA) repair; many non-operative factors influence risk-adjusted outcomes. This study compared 90-day and 5-year mortality for patients undergoing elective AAA repair in England and Sweden. METHODS: Patients were identified from English Hospital Episode Statistics and the Swedish Vascular Registry between 2003 and 2012. Ninety-day mortality and 5-year survival were compared after adjustment for age and sex. Separate within-country analyses were performed to examine the impact of co-morbidity, hospital teaching status and hospital annual caseload. RESULTS: The study included 36 249 patients who had AAA treatment in England, with a median age of 74 (i.q.r. 69-79) years, of whom 87·2 per cent were men. There were 7806 patients treated for AAA in Sweden, with a median of age 73 (68-78) years, of whom 82·9 per cent were men. Ninety-day mortality rates were poorer in England than in Sweden (5·0 versus 3·9 per cent respectively; P < 0·001), but were not significantly different after 2007. Five-year survival was poorer in England (70·5 versus 72·8 per cent; P < 0·001). Use of EVAR was initially lower in England, but surpassed that in Sweden after 2010. In both countries, poor outcome was associated with increased age. In England, institutions with higher operative annual volume had lower mortality rates. CONCLUSION: Mortality for elective AAA repair was initially poorer in England than Sweden, but improved over time alongside greater uptake of EVAR, and now there is no difference. Centres performing a greater proportion of EVAR procedures achieved better results in England.

Value of risk scores in the decision to palliate patients with ruptured abdominal aortic aneurysm.

BACKGROUND: The aim of this study was to develop a 48-h mortality risk score, which included morphology data, for patients with ruptured abdominal aortic aneurysm presenting to an emergency department, and to assess its predictive accuracy and clinical effectiveness in triaging patients to immediate aneurysm repair, transfer or palliative care. METHODS: Data from patients in the IMPROVE (Immediate Management of the Patient With Ruptured Aneurysm: Open Versus Endovascular Repair) randomized trial were used to develop the risk score. Variables considered included age, sex, haemodynamic markers and aortic morphology. Backwards selection was used to identify relevant predictors. Predictive performance was assessed using calibration plots and the C-statistic. Validation of the newly developed and other previously published scores was conducted in four external populations. The net benefit of treating patients based on a risk threshold compared with treating none was quantified. RESULTS: Data from 536 patients in the IMPROVE trial were included. The final variables retained were age, sex, haemoglobin level, serum creatinine level, systolic BP, aortic neck length and angle, and acute myocardial ischaemia. The discrimination of the score for 48-h mortality in the IMPROVE data was reasonable (C-statistic 0·710, 95 per cent c.i. 0·659 to 0·760), but varied in external populations (from 0·652 to 0·761). The new score outperformed other published risk scores in some, but not all, populations. An 8 (95 per cent c.i. 5 to 11) per cent improvement in the C-statistic was estimated compared with using age alone. CONCLUSION: The assessed risk scores did not have sufficient accuracy to enable potentially life-saving decisions to be made regarding intervention. Focus should therefore shift to offering repair to more patients and reducing non-intervention rates, while respecting the wishes of the patient and family.

Constitutive melanin density is associated with higher 25-hydroxyvitamin D and potentially total body BMD in older Caucasian adults via increased sun tolerance and exposure.

Greater skin pigmentation reduces dose equivalent cutaneous vitamin D3 production, potentially impacting lifetime vitamin D status and fracture risk. We show that melanin density was positively associated with 25-hydroxyvitamin D and total body bone mineral density. These relationships were partially explained by greater sun exposure due to more permissive skin phenotype. INTRODUCTION: Higher cutaneous melanin reduces vitamin D3 production. This may impact lifetime vitamin D status and increase fracture risk. This study aimed to describe the relationship between spectrophotometrically determined constitutive melanin density, osteoporotic risk factors and potential intermediaries in a cohort of exclusively older Caucasian adults. METHODS: One thousand seventy-two community-dwelling adults aged 50-80 years had constitutive melanin density quantified using spectrophotometry. Sun exposure, skin phenotype, non-melanoma skin cancer (NMSC) prevalence and smoking status were assessed by questionnaire. Bone mineral density (BMD), falls risk, physical activity and 25-hydroxyvitamin D were measured using DXA, the short form Physiological Profile Assessment, pedometer and radioimmunoassay, respectively. RESULTS: Higher melanin density was independently associated with greater ability to tan (RR = 1.27, p < 0.001), less propensity to sunburn (RR = 0.92, p < 0.001), fewer lifetime sunburns (RR = 0.94, p = 0.01), current smoking (RR = 1.41, p < 0.001), female sex (RR = 1.24, p < 0.001) and less photodamage (RR = 0.98, p = 0.01). The associations between melanin density and sun exposure (RR = 1.05-1.11, p < 0.001-0.01), sun protection behaviours (RR = 0.89, p < 0.001) and NMSC prevalence (RR = 0.75, p = 0.001) were no longer significant after taking into account skin phenotype and sun exposure, respectively. 25-Hydroxyvitamin D was strongly associated with higher melanin density (ß = 1.71-2.05, p = 0.001). The association between melanin density and total body BMD (ß = 0.007, p = 0.04) became non-significant after adjustment for 25-hydroxyvitamin D. There was no association between melanin density and physical activity, falls risk or BMD at other sites. CONCLUSIONS: Our data support a model of higher constitutive melanin density underpinning a less photosensitive skin phenotype, permitting greater sun exposure with fewer sequelae and yielding higher 25-hydroxyvitamin D and, potentially, total body BMD.

Greater prevalence of post-traumatic stress disorder and depression in deployed Canadian Armed Forces personnel at risk for moral injury.

BACKGROUND: A link between moral injury (i.e., the psychological distress caused by perceived moral transgressions) and adverse mental health outcomes (AMHO) has been recently proposed. However, the prevalence of exposure to morally injurious events and the associated risk of experiencing AMHO remains understudied. METHOD: The impact of exposure to potentially morally injurious experiences (PMIEs) was explored in relation to past-year PTSD and MDD, using the 2013 Canadian Armed Forces Mental Health Survey dataset of Afghanistan mission deployed regular force and reserve personnel. A series of logistic regressions were conducted, controlling for relevant sociodemographic, military, deployment, and trauma-related variables. RESULTS: Over half of the deployed personnel endorsed at least one PMIE. Several demographic and military variables were associated with exposure to PMIEs. Those exposed to PMIEs demonstrated a greater likelihood of having past-year PTSD and MDD; feeling responsible for the death of Canadian or ally personnel demonstrated the strongest association with PTSD and MDD. Mental health training was not a moderator for PMIE exposure and AMHO. CONCLUSIONS: Exposure to PMIEs during deployments is common and represents an independent risk factor for past-year PTSD and MDD. Improved training that targets moral-ethical dilemmas and treatment interventions that address moral injury expressions is warranted.