Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Functional MC1R-gene variants are associated with increased risk for severe photoaging of facial skin.

The objective of this study was to assess the association between melanocortin-1 receptor (MC1R) variants and the severity of facial skin photoaging. The study population comprised 530 middle-aged French women. A trained dermatologist graded the severity of facial skin photoaging from photographs using a global scale. Logistic regressions were performed to assess the influence of MC1R polymorphisms on severe photoaging with adjustment for possible confounders (demographic and phenotypic data and sun exposure intensity). Among the fifteen MC1R variants identified, the nine most common were V60L, V92M, R151C, R160W, R163Q, R142H, D294H, D84E, and I155T. One hundred and eighty-five individuals (35%) were WT homozygotes, 261 (49%) had one common variant, 78 (15%) had two common variants, and six (1%) had at least one rare variant. After adjustment for possible confounders, the presence of two common variants was already a risk factor for severe photoaging (AOR (95% confidence interval): 2.33 (1.17-4.63)). This risk reached 5.61 (1.43-21.96) when two major diminished-function variants were present. Surprisingly, the minor variant, V92M, was associated with increased risk of photoaging (2.57 (1.23-5.35)). Our results suggest that genetic variations of MC1R are important determinants for severe photoaging.

MC1R gene polymorphism affects skin color and phenotypic features related to sun sensitivity in a population of French adult women.

The melanocortin-1 receptor (MC1R) gene is known to play a major role in skin and hair pigmentation and to be highly polymorphic in Caucasians. This study was performed to investigate the relationships between MC1R gene polymorphisms and skin color in a large sample of French middle-aged Caucasian women. The codons 60 to 265 and the codon 294 of the MC1R gene were sequenced in 488 women. The skin color was measured on the inner side of the forearm using a spectrophotometric instrument. Fifteen variants were identified: Arg151Cys, Arg160Trp, Arg142His, Asp294His, Ile155Thr, Asp84Glu, Val60Leu, Val92Met, Arg163Gln, Ser83Pro, Thr95Met, Pro256Ser, Val265Ile, Ala166Ala and Gln233Gln. Women carrying Arg151Cys, Asp294His, Arg160Trp and Asp84Glu variants had a significantly higher reflectance in the red region, which indicates a lower level of functional melanin. This association was the most pronounced for women carrying Asp84Glu. In contrast, no significant difference was observed for other variants. Moreover, associations between MC1R polymorphisms and the risks of experiencing sunburn and of having freckles were found independently of skin color. Our findings support the hypothesis that MC1R polymorphisms do not necessarily alter the skin color but should sensitize the skin to UV-induced DNA damage.

Relationships between visual and tactile features and biophysical parameters in human facial skin.

BACKGROUND/PURPOSE: Skin properties, such as colour, hydration and texture, can be studied on a qualitative basis by a clinical assessment or on a quantitative basis using techniques that measure biophysical properties of the skin. The aim of this study was to explore the links between facial skin features and a range of skin biophysical parameters using multivariate methods. METHODS: A study was conducted on 256 female volunteers from Ile-de-France with apparent healthy skin, aged between 20 and 50, under controlled environmental conditions (mean+/-standard deviation: room temperature 22.9+/-0.3 degrees C; relative humidity 48.5+/-2.3%). The study included a medical questionnaire and a clinical examination of the skin performed by a dermatologist, and a biophysical evaluation of the skin properties. Seventy visual and tactile skin features were assessed on the forehead and the cheek using ordinal variables illustrated by photographic scales. Twenty-eight biophysical measurements were taken in the same areas using the following equipment: Chromameter, Evaporimeter, Corneometer, Skicon, Sebumeter, Sebutape, skin thermometer, skin pH-meter and Silflo. In order to group the variables illustrating a same unimodal phenomenon, a typology of the skin features and a typology of the biophysical parameters were carried out using a clustering method. Then, the relationships between each group of clinical features and each group of biophysical parameters were studied using a series of partial least squares (PLS) regressions. RESULTS: From eight groups of clinical features and three groups of biophysical parameters that were identified, 12 significant PLS regression models were built. Our findings suggest that differences in chromametric measurements express not only differences in skin colour but also differences in skin surface properties, such as skin vascularity status, thickness, and existence of wrinkles, and also demonstrate that the level of sebum excretion can affect other aspects of the skin surface. CONCLUSION: Some skin features assessed clinically do not appear to be linked to any biophysical parameter. This finding confirms that certain phenomena evaluated on the basis of visual or tactile skin features are not assessed on the basis of the biophysical properties of the skin measured by our bioengineering techniques. Indeed, visual skin features mainly appreciate the skin surface aspect, contrary to some biophysical surrogate markers known to provide information on underlying epidermal structures. Therefore, both clinical and biophysical assessments must be associated to supply a relevant and accurate approach for skin aspect characterisation.