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International audience; Background:Infectious purpura fulminans is a disabling disease often leading to amputations. Free flaps preserve limb length, covering exposed areas. We examined the efficacy of free flaps for lower limb salvage in infectious purpura fulminans survivors by evaluating surgical management, walking ability and quality of life.Methods:This single-center, observational, descriptive, retrospective study was conducted in from 2016 to 2019. Adult purpura fulminans survivors who received a free flap for lower limb salvage were included. Patient characteristics and data on surgical management and rehabilitation were collected. Quality of life (SF-36 questionnaire), limb function and walking ability were later evaluated post-surgically.Results:The 6 patients included, mean age 38 years, had all required amputations. Nine free flaps were performed to cover important structures in 7 cases and for stump resurfacing in 2. All flaps were successful. Patients resumed walking at a mean of 204 ± 108 days after the onset of purpura fulminans. Post-surgical evaluation was performed at a mean of 30 ± 9.3 months. Five patients required secondary revision. All were independent for the activities of daily living. Mean physical component score was 37.6 ± 9.4 and mental component score was 44.6 ± 13.2 (minimum 0, maximum 100).Conclusions:Use of the free flap in patients with infectious purpura fulminans, after multidisciplinary reflection, is an appropriate procedure that preserves limb length. In spite of secondary complications, preservation of limb length enables patients to resume walking, with relatively good independence and quality of life.; Introduction :Le purpura fulminans infectieux est une pathologie invalidante entraînant souvent des amputations. L’objectif est d’évaluer le sauvetage de membre inférieur par lambeaux libres dans le purpura fulminans infectieux : la prise en charge chirurgicale, la marche, et la qualité de vie des patients.Méthodes :Il s’agit d’une étude observationnelle, descriptive, rétrospective de 2016 à 2019. Les patients inclus étaient des adultes survivants au purpura fulminans, bénéficiant d’un lambeau libre pour sauvetage d’un membre inférieur. Les données recueillies étaient les caractéristiques des patients, la prise en charge chirurgicale et la rééducation. L’évaluation à distance portait sur les patients, la marche, leur qualité de vie.Résultats :Six patients ont été inclus, avec 38 ans de moyenne d’âge. Neuf lambeaux libres ont été réalisés, et se sont déroulés avec succès. La reprise de la marche s’est effectuée en moyenne 204 ± 108 jours après le purpura fulminans. L’évaluation à distance était en moyenne réalisée à 30 ± 9,3 mois. Cinq patients sur 6 ont nécessité des corrections secondaires. Tous les patients sont autonomes dans la vie quotidienne. Le score résumé physique était en moyenne de 37,6 ± 9,4, le score résumé psychique de 44,6 ± 13,2 (minimum 0, maximum 100).Conclusion :Le lambeau libre chez les patients atteints de purpura fulminans infectieux est une procédure adaptée, permettant de préserver la longueur de membre, avec un bénéfice pour le patient malgré les complications secondaires, permettant une reprise de la marche, une autonomie, et une qualité de vie relativement bonne.

Background Betel-nut consumption is the fourth most common addictive habit globally and there is good evidence linking the habit to obesity, type 2 diabetes (T2D) and the metabolic syndrome. The aim of our pilot study was to identify gene expression relevant to obesity, T2D and the metabolic syndrome using a genome-wide transcriptomic approach in a human monocyte cell line incubated with arecoline and its nitrosated products. Results The THP1 monocyte cell line was incubated separately with arecoline and 3-methylnitrosaminopropionaldehyde (MNPA) in triplicate for 24 h and pooled cDNA indexed paired-end libraries were sequenced (Illumina NextSeq 500). After incubation with arecoline and MNPA, 15 and 39 genes respectively had significant changes in their expression (q CLEC10A, MAPK8IP1, NEGR1, NQ01 and INHBE genes. Conclusions Our preliminary studies have identified a large number of genes relevant to obesity, T2D and metabolic syndrome whose expression was changed significantly in human TPH1 cells following incubation with betel-nut derived arecoline or with MNPA. These findings require validation by further cell-based work and investigation amongst betel-chewing communities.

Cryptococcosis is an invasive infection that accounts for 15% of AIDS-related fatalities. Still, treating cryptococcosis remains a significant challenge due to the poor availability of effective antifungal therapies and emergence of drug resistance. Interestingly, protease inhibitor components of antiretroviral therapy regimens have shown some clinical benefits in these opportunistic infections. We investigated Major aspartyl peptidase 1 (May1), a secreted Cryptococcus neoformans protease, as a possible target for the development of drugs that act against both fungal and retroviral aspartyl proteases. Here, we describe the biochemical characterization of May1, present its high-resolution X-ray structure, and provide its substrate specificity analysis. Through combinatorial screening of 11,520 compounds, we identified a potent inhibitor of May1 and HIV protease. This dual-specificity inhibitor exhibits antifungal activity in yeast culture, low cytotoxicity, and low off-target activity against host proteases and could thus serve as a lead compound for further development of May1 and HIV protease inhibitors.

A frequency-domain approach is described for estimating parameters, such as stability and control derivatives, in aircraft flight dynamic models from measured input and output data. The approach uses orthogonal phase-optimized multisines for moving the aircraft control effectors, Fourier analysis for computing multiple-input multiple-output frequency responses, and a maximum likelihood estimator called frequency response error (FRE) for determining values and uncertainties for the model parameters. The approach is demonstrated using flight test data for two subscale airplanes: the T-2 generic transport model and the X-56A aeroelastic demonstrator. Results and comparisons with the output-error method indicated that the approach produced accurate estimates of stability and control derivatives and their uncertainties from flight test data.

A method is presented for estimating frequency responses of multiple-input multiple-output bare-airframe dynamics from flight test data containing feedback control and/or mixing of control effectors. Orthogonal phase-optimized multisines are used to simultaneously excite each input with unique harmonic frequencies, at which frequency responses are computed as ratios of output-to-input Fourier transform data. The confounding effects of feedback and mixing are resolved by interpolation of the frequency responses. The analysis can be run in batch for post-flight analysis, or in real time as the aircraft is flying. The effectiveness of the method was verified using simulations of the subscale T-2 generic transport airplane with rate feedback. The method was also demonstrated using flight test data from the X-56A MUTT aeroelastic airplane, which was flown with both feedback control and mixing.

Vitamin D supplementation can prevent and cure nutritional rickets in infants and children. Preclinical and observational data suggest that the vitamin D endocrine system has a wide spectrum of skeletal and extra-skeletal activities. There is consensus that severe vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) concentration 50 nmol/l for optimal bone health in older adults. However, the causal link between vitamin D and many extra-skeletal outcomes remains unclear. The VITAL, ViDA and D2d randomized clinical trials (combined number of participants >30,000) indicated that vitamin D supplementation of vitamin D-replete adults (baseline serum 25OHD >50 nmol/l) does not prevent cancer, cardiovascular events, falls or progression to type 2 diabetes mellitus. Post hoc analysis has suggested some extra-skeletal benefits for individuals with vitamin D deficiency. Over 60 Mendelian randomization studies, designed to minimize bias from confounding, have evaluated the consequences of lifelong genetically lowered serum 25OHD concentrations on various outcomes and most studies have found null effects. Four Mendelian randomization studies found an increased risk of multiple sclerosis in individuals with genetically lowered serum 25OHD concentrations. In conclusion, supplementation of vitamin D-replete individuals does not provide demonstrable health benefits. This conclusion does not contradict older guidelines that severe vitamin D deficiency should be prevented or corrected., This Review highlights results from large randomized clinical trials performed during the period 2017–2020 and Mendelian randomization studies on vitamin D levels. Together, findings indicate that vitamin D supplementation alone in vitamin D-replete adults does not provide health benefits; however, vitamin D deficiency should always be corrected., Key points Vitamin D and calcium supplementation can cure nutritional rickets and can modestly decrease the risk of major fractures in older adults with poor vitamin D status or calcium intake.Large supplementation trials recruiting vitamin D-replete adults (serum 25OHD concentration >50 nmol/l) have demonstrated no effects on the incidence of cancer, cardiovascular events or type 2 diabetes mellitus (T2DM) and no benefits in terms of bone density and the risk of falls.Post-hoc analysis of large supplementation trials has suggested that supplementation of individuals with vitamin D deficiency modestly delays age-related bone loss and progression to T2DM, and improves lung function.A meta-analysis suggested that vitamin D supplementation results in a modest decrease in cancer mortality.Over 60 Mendelian randomization studies have examined causal links between genetically lower vitamin D levels and health outcomes; most studies generated null effects except four studies that demonstrated an increased risk of multiple sclerosis.In conclusion, supplementation of vitamin D-replete individuals does not generate overall health benefits; however, correction of severe vitamin D deficiency remains essential.

Vitamin D3 has many important health benefits. Unfortunately, these benefits are not widely known among health care personnel and the general public. As a result, most of the world’s population has serum 25-hydroxyvitamin D (25(OH)D) concentrations far below optimal values. This narrative review examines the evidence for the major causes of death including cardiovascular disease, hypertension, cancer, type 2 diabetes mellitus, and COVID-19 with regard to sub-optimal 25(OH)D concentrations. Evidence for the beneficial effects comes from a variety of approaches including ecological and observational studies, studies of mechanisms, and Mendelian randomization studies. Although randomized controlled trials (RCTs) are generally considered the strongest form of evidence for pharmaceutical drugs, the study designs and the conduct of RCTs performed for vitamin D have mostly been flawed for the following reasons: they have been based on vitamin D dose rather than on baseline and achieved 25(OH)D concentrations; they have involved participants with 25(OH)D concentrations above the population mean; they have given low vitamin D doses; and they have permitted other sources of vitamin D. Thus, the strongest evidence generally comes from the other types of studies. The general finding is that optimal 25(OH)D concentrations to support health and wellbeing are above 30 ng/mL (75 nmol/L) for cardiovascular disease and all-cause mortality rate, whereas the thresholds for several other outcomes appear to range up to 40 or 50 ng/mL. The most efficient way to achieve these concentrations is through vitamin D supplementation. Although additional studies are warranted, raising serum 25(OH)D concentrations to optimal concentrations will result in a significant reduction in preventable illness and death.

Discrepancies between current guidance from NICE on the treatment of vitamin D deficiency and the recommended daily amounts [RDAs] for its prevention in the UK

The thermal scattering laws (TSL) take into account the crystalline structure and atomic motions of isotopes bound in materials. This paper presents the CINEL code, which was developed to generate temperature-dependent TSL for solid, liquid and free gas materials of interest for nuclear reactors. CINEL is able to calculate TSL from the phonon density of states (PDOS) of materials under the Gaussian-Incoherent approximations. The PDOS can be obtained by using theoretical approaches (e.g., ab initio density functional theory and molecular dynamics) or experimental results. In this work, the PDOS presented in the ENDF/BVIII.0 and NJOY-NCrystal libraries were used for numerical validation purposes. The CINEL results are in good agreement with those reported in these databases, even in the specific cases of TSL with the newly mixed elastic format. The coding flexibility offered by Python using the JupyterLab interface allowed to investigate limits of physical models reported in the literature, such as a four-site model for UO2, anharmonic behaviors of oxygen atoms bound in a Fm3m structure, texture in Zry4 samples and jump corrections in a roto-translational diffusion model for liquid water. The use of graphic processing units (GPU) is a necessity to perform calculations in a few minutes. The performances of the CINEL code is illustrated with the results obtained on actinide oxides having a Fm3m structure (UO2, ThO2, NpO2 and PuO2), low enriched fuel (UMo), cladding (Zry4) and moderators (H2O with a specific emphasis on ice).

IntroductionSeveral studies have reported the importance of vitamin D status to musculoskeletal health in populations of older adults. Here we report relationships between circulating serum 25(OH)D and musculoskeletal health in a community cohort of UK adults in midlife and investigate whether environmental (dietary intake, use of supplements) and/or genetic factors (4 SNPs previously related to vitamin D status) play more significant roles in determining vitamin D status in this population.MethodsParticipants were recruited from the Hertfordshire Cohort Study, an established longitudinal cohort study of community dwelling adults and were seen at baseline and follow up 9–12 years later. Lumbar spine and total femur BMD were measured at baseline using a Hologic QDR 4500 instrument. Osteoarthritis (OA) was defined by radiographs of the knees graded according to Kellgren & Lawrence at both time points. Serum 25(OH)D concentrations were measured using a DiaSorin Liaison chemiluminescent assay. Genotyping of 4 SNPs previously associated with 25(OH)D values were assessed: (rs12785878 (DHCR7), rs10741657 (CYP2R1) and rs6013897 (CYP24A1)) and a fourth SNP (rs4588), described as “a near-perfect proxy (i.e. substitute) for rs2282679 on the GC gene”.Results820 subjects (397 men, 423 women) participated at baseline, and 339 of these 820 subjects (164 men; 175 women) participated in a follow up study of OA progression. The median (IQR) age of participants at baseline was 64.0 (61.8–66.5) and 65.5 (63.3–67.6) for men and women respectively. Median circulating levels of 25(OH)D were 44.6 (35.0–63.0) nmol/L and 41.3 (29.8–53.5) nmol/L in men and women respectively. Circulating 25(OH)D was strongly associated with season of blood testing (p ConclusionCirculating 25(OH)D levels were generally lower than is recommended in community dwelling adults in midlife, with marked seasonal variation observed, but relationships with reported vitamin D supplementation were weaker. Circulating 25(OH)D was directly associated with hip BMD in men but relationships with BMD in women and radiographic OA were not seen in this sample.

Cryptococcus neoformans, the most common cause of fungal meningitis, is a basidiomycete haploid budding yeast with a complete sexual cycle. Genome modification by homologous recombination is feasible using biolistic transformation and long homology arms, but the method is arduous and unreliable. Recently, multiple groups have reported the use of CRISPR-Cas9 as an alternative to biolistics, but long homology arms are still necessary, limiting the utility of this method. Since the S. pyogenes Cas9 derivatives used in prior studies were not optimized for expression in C. neoformans, we designed, synthesized, and tested a fully C. neoformans-optimized Cas9. We found that a Cas9 harboring only common C. neoformans codons and a consensus C. neoformans intron together with a TEF1 promoter and terminator and a nuclear localization signal (C. neoformans-optimized CAS9 or “CnoCAS9”) reliably enabled genome editing in the widely-used KN99α C. neoformans strain. Furthermore, editing was accomplished using donors harboring short (50 bp) homology arms attached to marker DNAs produced with synthetic oligonucleotides and PCR amplification. We also demonstrated that prior stable integration of CnoCAS9 further enhances both transformation and homologous recombination efficiency; importantly, this manipulation does not impact virulence in animals. We also implemented a universal tagging module harboring a codon-optimized fluorescent protein (mNeonGreen) and a tandem Calmodulin Binding Peptide-2X FLAG Tag that allows for both localization and purification studies of proteins for which the corresponding genes are modified by short homology-directed recombination. These tools enable short-homology genome engineering in C. neoformans.

Although observational studies of health outcomes generally suggest beneficial effects with, or following, higher serum 25-hydroxyvitamin D [25(OH)D] concentrations, randomized controlled trials (RCTs) have generally not supported those findings. Here we review results from observational studies and RCTs regarding how vitamin D status affects several nonskeletal health outcomes, including Alzheimer’s disease and dementia, autoimmune diseases, cancers, cardiovascular disease, COVID-19, major depressive disorder, type 2 diabetes, arterial hypertension, all-cause mortality, respiratory tract infections, and pregnancy outcomes. We also consider relevant findings from ecological, Mendelian randomization, and mechanistic studies. Although clear discrepancies exist between findings of observational studies and RCTs on vitamin D and human health benefits these findings should be interpreted cautiously. Bias and confounding are seen in observational studies and vitamin D RCTs have several limitations, largely due to being designed like RCTs of therapeutic drugs, thereby neglecting vitamin D’s being a nutrient with a unique metabolism that requires specific consideration in trial design. Thus, RCTs of vitamin D can fail for several reasons: few participants’ having low baseline 25(OH)D concentrations, relatively small vitamin D doses, participants’ having other sources of vitamin D, and results being analyzed without consideration of achieved 25(OH)D concentrations. Vitamin D status and its relevance for health outcomes can usefully be examined using Hill’s criteria for causality in a biological system from results of observational and other types of studies before further RCTs are considered and those findings would be useful in developing medical and public health policy, as they were for nonsmoking policies. A promising approach for future RCT design is adjustable vitamin D supplementation based on interval serum 25(OH)D concentrations to achieve target 25(OH)D levels suggested by findings from observational studies.

Purpose: The management of pediatric concussions creates a clinical challenge due to unknown patient compliance with prescribed therapies and interventions. The purpose of this pilot study was to describe the logistical use of ecological momentary assessment (EMA) to track compliance to a physical therapy facilitated vestibular/ocular motor home exercise program (HEP) in patients diagnosed with concussion. Methods: A convenience sample of 20 concussed patients (aged 13–18 years [mdn = 14.5, IQR = 14.0–16.8]) was included in this initial pilot study. All participants were evaluated within seven days of injury. Participants were instructed to complete one daily HEP compliance log until medical clearance on their parent or guardians’ mobile device using an EMA application. Results: Participants were evaluated a median 3.5 (IQR = 1.3–6.5) days post injury, recovered in a median 15.5 (IQR = 11.0–25.0) days, and completed a mean 5.85 (SD = 3.9) total EMA logs representing a 47% completion rate. Participants reported completing a mean 1.21 (SD = 0.77) HEPs per day with a range of 0.0 to 3.0. Self-reported HEP compliance did not significantly correlate with recovery time in days (P = 0.26). Conclusions: The overall response rate for EMA logs was 47% and participants reported completing 1.2 HEPs per day. Analysis of this preliminary data did not reveal a correlation between HEP compliance and recovery time in days. Participants reported the primary barrier to completing daily questionnaires was access to their parent or guardians’ mobile device at the time of the prompt. Overall, the data derived from EMA appears useful for tracking the progression of this heterogenous injury.

The Goutallier and Warner Classification systems are useful in determining rotator cuff reparability. Data are limited on how accurately the scapular-Y view used in both systems reflects the 3-dimensional (3-D) changes in fatty infiltration (FI) and muscle atrophy (MA). Tendon retraction in the setting of a cuff tear may also influence the perception of these changes. This study's objectives were to (1) measure the 3-D volume of the supraspinatus muscle in intact rotator cuffs, and with varying magnitudes of retraction; (2) measure the 3-D volume of FI in the supraspinatus muscle in these conditions; and (3) determine the influence of tendon retraction on measured FI and MA using the Goutallier and Warner Classification Systems.Between August 2015 and February 2016, all shoulder magnetic resonance images (MRIs) at the Portland VA Medical Center were standardized to include the medial scapular border. MRIs and charts were reviewed for inclusion/exclusion criteria. Included MRIs were categorized into 4 groups based on rotator cuff retraction. Supraspinatus muscle and fossa were traced to create 3-D volumes. FI and MA were measured within the supraspinatus. The supraspinatus muscle was graded among 6 physicians using the Goutallier and Warner classification systems. These grades were compared to 3-D measured FI and MA. The influence of tendon retraction on the measured grades were also evaluated.One hundred nine patients met inclusion/exclusion criteria. Ten MRIs for each group (N = 40) were included for image analysis. Supraspinatus volume tracings were highly reproducible and consistent between tracers. Supraspinatus muscle volumes decreased while global FI and MA increased with greater degrees of tendon retraction. In muscles with less than 10% global fat, fat concentrated in the lateral third of the muscle. In muscle with more than 10% global fat content, it distributed more diffusely throughout the muscle from medial to lateral. In comparing the scapular-Y to a medial cut, there was no consistent trend in FI whereas MA was more accurate at the medial cut.Parasagittal imaging location did not significantly influence the Goutallier score; however, assessment of MA using the Warner score leads readers to perceive less MA medially regardless of the magnitude of tendon retraction. The pattern of FI within the supraspinatus muscle changes from a laterally based location around the muscle-tendon junction to a more diffuse, global infiltration pattern when the whole muscle fat content exceeds 10%.