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The spread of performance and image enhancing drugs (PIEDs) often requires forensic toxicology laboratories to identify unknown compounds without reference standards. We characterized the PIEDs melanotan II and bremelanotide, not legally marketed, in eight unknown samples confiscated by police together with anabolic steroids, hormone modulators, sexual enhancers and stimulants, intended for the black market of bodybuilders, using liquid chromatography-high resolution/high accuracy Orbitrap mass spectrometry (LC-HRMS). The characterization was carried out by the accurate mass measurements of MH+ ionic species, the study of their isotopic patterns and the associated relative isotopic abundance (RIA) values, as well as the accurate mass measurements of collision-induced product ions obtained in fragmentation experiments. LC-HRMS confirmed itself as a powerful analytical tool to elucidate the elemental composition and structural characteristics of unknown compounds.The human nose has been used as a detector in gas chromatography analysis to evaluate odoriferous compounds related to aroma and quality of wine. Several olfactometric techniques are available to access the description, intensity, and/or duration of the odor of each compound. Olfactometry can be associated with one-dimensional gas chromatography or multidimensional gas chromatography, including heart-cut gas chromatography and comprehensive two-dimensional gas chromatography. Multidimensional gas chromatography may help to resolve coeluted compounds and detect important trace components for the aroma. The identification of odor-active compounds may help to differentiate wines according to terroir, grapes cultivars used in winemaking or types of aging, understand the role of fungal infection of grapes for wine quality, find the best management practices in vineyard and vinification to obtain the greatest quality. In addition, when the instrumental techniques are combined with sensory analysis, even more accurate information may be obtained regarding the overall wine aroma. This review discloses the state of the art of olfactometric methods and the analytical techniques used to investigate odor-active compounds such as one-dimensional gas chromatography, multidimensional gas chromatography, and comprehensive two-dimensional gas chromatography. The advances in knowledge of wine aroma achieved with the use of these techniques in the target and profiling approaches were also discussed.The phase 2 placebo-controlled, double-blind PLUTO trial characterized the pharmacokinetics of belimumab plus standard systemic lupus erythematosus (SLE) therapy in patients with childhood-onset SLE (cSLE) and demonstrated similar efficacy and safety to that in adult SLE. Patients with active cSLE aged 5-17 years were randomized to intravenous belimumab 10 mg/kg every 4 weeks (n = 53). A linear 2-compartment population pharmacokinetics (popPK) model with first-order elimination was developed, and an exploratory exposure-response analysis assessed the impact of between-patient exposure variability on clinical response (SLE Responder Index 4 [SRI4]) in week 52, and occurrence of serious adverse events during the study. The popPK model estimated clearance of 158 mL/day, steady-state volume of distribution of 3.5 L, terminal half-life of 16.3 days, and distribution half-life of 0.8 days in the overall population. Fat-free mass (FFM) better characterized the pharmacokinetics than total body weight and was more consistent with allometric scaling theory; belimumab pharmacokinetics were largely determined by FFM. Age, sex, disease activity, and concomitant medication had no impact on pediatric belimumab exposure after accounting for body size. Individual and median steady-state pediatric pharmacokinetic profiles were similar to known adult profiles and pediatric exposure estimates for belimumab 10 mg/kg intravenously were consistent with adult exposures. Exposures were similar between SRI4 responders and nonresponders, and patients who did or did not experience a serious adverse event. There was no clinically relevant correlation between exposure and efficacy or safety, confirming belimumab 10 mg/kg intravenous dose every 4 weeks as appropriate for pediatric patients with cSLE.

Nonrestorative low anterior resection (n-rLAR) (also known as low Hartmann's) is performed for rectal cancer when a poor functional outcome is anticipated or there have been problems when constructing the anastomosis. Compared with restorative LAR (rLAR), little oncological outcome data are available for n-rLAR. The aim of this study was to compare oncological outcomes between rLAR and n-rLAR for primary rectal cancer.

This was a nationwide cross-sectional comparative study including all elective sphincter-saving LAR procedures for nonmetastatic primary rectal cancer performed in 2011 in 71 Dutch hospitals. Oncological outcomes of patients undergoing rLAR and n-rLAR were collected in 2015; the data were evaluated using Kaplan-Meier survival analysis and the results compared using log-rank testing. Uni- and multivariable Cox regression analysis was used to evaluate the association between the type of LAR and oncological outcome measures.

A total of 1197 patients were analysed, of whom 892 (75%) underwent rLAR and 305 (25%) underwent n-rLAR. The 3-year local recurrence (LR) rate was 3% after rLAR and 8% after n-rLAR (P<0.001). The 3-year disease-free survival and overall survival rates were 77% (rLAR) vs 62% (n-rLAR) (P<0.001) and 90% (rLAR) vs 75% (n-rLAR) (P<0.001), respectively. In multivariable Cox analysis, n-rLAR was independently associated with a higher risk of LR (OR=2.95) and worse overall survival (OR=1.72).

This nationwide study revealed that n-rLAR for rectal cancer was associated with poorer oncological outcome than r-LAR. This is probably a noncausal relationship, and might reflect technical difficulties during low pelvic dissection in a subset of those patients, with oncological implications.

This nationwide study revealed that n-rLAR for rectal cancer was associated with poorer oncological outcome than r-LAR. This is probably a noncausal relationship, and might reflect technical difficulties during low pelvic dissection in a subset of those patients, with oncological implications.Bone morphogenetic protein 2 (BMP2)-induced heterotopic bone formation (HBF) starts synchronously from zero upon BMP2 induction, which is advantageous for lineage tracking. The studies reported here in GLAST-CreErt2 tdTomato red (TR)floxSTOPflox mice during BMP2-induced HBF show 78.8 ± 11.6% of chondrocytes and 86.5 ± 1.9% of osteoblasts are TR+ after approximately 1 week. Clustering after single-cell RNAseq resulted in nine cell types, and analysis revealed one as a highly replicating stem-like cell (RSC). Pitstop2 Pseudotiming suggested that the RSC transitions to a mesenchymal stem-like cell that simultaneously expresses multiple osteoblast and chondrocyte transcripts (chondro-osseous progenitor [COP]). RSCs and COPs were isolated using flow cytometry for unique surface markers. Isolated RSCs (GLAST-TR+ Hmmr+ Cd200- ) and COPs (GLAST-TR+ Cd200+ Hmmr- ) were injected into the muscle of mice undergoing HBF. Approximately 9% of the cells in heterotopic bone (HB) in mice receiving RSCs were GLAST-TR+ , compared with less than 0.5% of the cells in mice receiving COPs, suggesting that RSCs are many times more potent than COPs. Analysis of donor-derived TR+ RSCs isolated from the engrafted HB showed approximately 50% were COPs and 45% were other cells, presumably mature bone cells, confirming the early nature of the RSCs. We next isolated RSCs from these mice (approximately 300) and injected them into a second animal, with similar findings upon analysis of HBF. Unlike other methodology, single cell RNAseq has the ability to detect rare cell populations such as RSCs. The fact that RSCs can be injected into mice and differentiate suggests their potential utility for tissue regeneration.The scope of the impact of the Coronavirus disease 19 (COVID-19) pandemic on living donor kidney transplantation (LDKT) practices across the world is not well-defined. We received survey responses from 204 transplant centers internationally from May to June 2020 regarding the impact of the COVID-19 pandemic on LDKT practices. Respondents represented 16 countries on five continents. Overall, 75% of responding centers reported that LDKT surgery was on hold (from 67% of North American centers to 91% of European centers). The majority (59%) of centers reported that new donor evaluations were stopped (from 46% of North American centers to 86% of European centers), with additional 23% of centers reporting important decrease in evaluations. Only 10% of centers reported slight variations on their evaluations. For the centers that continued donor evaluations, 40% performed in-person visits, 68% by video, and 42% by telephone. Center concerns for donor (82%) and recipient (76%) safety were the leading barriers to LDKT during the pandemic, followed by patients concerns (48%), and government restrictions (46%). European centers reported more barriers related to staff limitations while North and Latin American centers were more concerned with testing capacity and insufficient resources including protective equipment. As LDKT resumes, 96% of the programs intend to screen donor and recipient pairs for coronavirus infection, most of them with polymerase chain reaction testing of nasopharyngeal swab samples. The COVID-19 pandemic has had broad impact on all aspects of LDKT practice. Ongoing research and consensus-building are needed to guide safe reopening of LDKT programs.A Ca2+ -activated Cl- channel protein, ANO1, is expressed in vascular smooth muscle cells where Cl- current is thought to potentiate contraction by contributing to membrane depolarization. However, there is an inconsistency between previous knockout and knockdown studies on ANO1's role in small arteries. In this study, we assessed cardiovascular function of heterozygous mice with global deletion of exon 7 in the ANO1 gene. We found decreased expression of ANO1 in aorta, saphenous and tail arteries from heterozygous ANO1 knockout mice in comparison with wild type. Accordingly, ANO1 knockdown reduced the Ca2+ -activated Cl- current in smooth muscle cells. Consistent with conventional hypothesis, the contractility of aorta from ANO1 heterozygous mice was reduced. Surprisingly, we found an enhanced contractility of tail and saphenous arteries from ANO1 heterozygous mice when stimulated with noradrenaline, vasopressin, and K+ -induced depolarization. This difference was endothelium-independent. The increased contractility of ANO1 downregulated small arteries was due to increased Ca2+ influx. The expression of L-type Ca2+ channels was not affected but expression of the plasma membrane Ca2+ ATPase 1 and the Piezo1 channel was increased. Expressional analysis of tail arteries further suggested changes of ANO1 knockdown smooth muscle cells toward a pro-contractile phenotype. We did not find any difference between genotypes in blood pressure, heart rate, pressor response, and vasorelaxation in vivo. Our findings in tail and saphenous arteries contrast with the conventional hypothesis and suggest additional roles for ANO1 as a multifunctional protein in the vascular wall that regulates Ca2+ homeostasis and smooth muscle cell phenotype.