Clinical and research laboratories extensively use exome sequencing due to its high diagnostic rates, cost savings, impact on clinical management, and efficacy for disease gene discovery. While the rates of disease gene discovery have steadily increased, only ~16% of genes in the genome have confirmed disease associations. Here we describe our diagnostic laboratory’s disease gene discovery and ongoing data-sharing efforts with GeneMatcher. In total, we submitted 246 candidates from 243 unique genes to GeneMatcher, of which 45.93% are now clinically characterized. Submissions with at least one case meeting our candidate genes reporting criteria were significantly more likely to be characterized as of October 2021 compared to genes with no candidates meeting our reporting criteria (p=0.025). We reported relevant findings related to these gene-disease associations for 480 probands. In 219 (45.63%) instances, these results were reclassifications after an initial candidate gene (uncertain) or negative report. Since 2013, we have co-authored 105 publications focused on delineating gene-disease associations. Diagnostic laboratories are pivotal for disease gene discovery efforts and can screen phenotypes based on genotype matches, contact clinicians of relevant cases, and issue proactive reclassification reports. GeneMatcher is a critical resource in these efforts.

The development and evaluation of DNA metabarcoding protocols for haplotype-level resolution require attention, specifically for population genetic analysis, i.e., parallel estimation of genetic diversity and dispersal patterns among multiple species present in a bulk sample. Further exploration and assessment of the laboratory and bioinformatics strategies are warranted to unlock the potential of metabarcoding-inferred population genetic analysis. Here, we assessed the inference of freshwater macroinvertebrate haplotypes from DNA metabarcoding data using mock samples with known Sanger-sequenced haplotypes. We also examined the influence of different DNA template concentrations and PCR cycles on detecting true haplotypes and the reduction of spurious haplotypes obtained from DNA metabarcoding. We tested our haplotyping strategy on a mock sample containing 20 specimens from four species with known haplotypes based on the 658-bp Folmer region of the mitochondrial cytochrome c oxidase gene. The read processing and denoising step resulted in 14 zero-radius operational taxonomic units (ZOTUs) of 421-bp length, with 12 ZOTUs having 100% match with 12 of the Sanger haplotype sequences. Quality passing reads relatively increased with increasing PCR cycles, and the relative abundance of each ZOTUs was consistent for each cycle number. This suggests that increasing the cycle number from 24 to 64 did not affect the relative abundance of quality passing filter reads of each ZOTUs. Our study demonstrated the ability of DNA metabarcoding to infer intraspecific variability while highlighting the challenges that need to be addressed before its possible applications to population genetic studies.

Background and Purpose: Isoleucine is a branched-chain amino acid serving as an essential nutrient resource and metabolic. However， its role in cerebral ischemic stroke remains unknown. Experimental Approach: Middle cerebral artery occlusion (MCAO) was used to mimic in vivo model of stroke. Oxygen-glucose deprivation insult (OGD) was used to injure cultured cortical neurons. High-Performance Liquid Chromatography (HPLC) was used to measure the level of isoleucine. A western blot assay and immunofluorescent staining were used to measure the level of CBFB and PTEN. TTC staining was used to measure the infarct size. Cell death and viability were assessed by LDH and CCK8 assays. DCS was used to stimulate cortical neurons. tDCS was used to stimulate the cortex. Key Results: Extraneuronal isoleucine is decreased and intraneuronal isoleucine is increased after rat cerebral I/R injury. Reducing intraneuronal isoleucine via inhibition of its transporter, LAT1 promotes neuronal survival whereas supplementing isoleucine aggravates neuronal damage. Isoleucine downregulates the expression of CBFB, and that acts upstream of PTEN to mediate isoleucine-induced neuronal damage after OGD insult. To identify the therapeutic approach that suppresses the ischemia-induced increase of intraneuronal isoleucine, we tested the effect of tDCS on isoleucine. Our data suggest that Cathodal tDCS can reduce cerebral infarct size. And such neuroprotection is mediated through reducing LAT1-dependent increase of intraneuronal isoleucine. Conclusions and Implications: This study identifies LAT1- dependent increase of intraneuronal isoleucine promotes neuronal death after rat cerebral I/R injury. Our results indicate that tDCS protects against rat cerebral I/R injury through regulating LAT1-isoleucine-CBFB-PTEN signaling.

A 16-year-old female presented to our ED with fever and coughing of blood for 3 days. She is known to have SLE for 5 months and takes oral prednisone. She was tested positive for COVID19. She developed hypocalcemia with clinically-diagnosed massive pulmonary embolism. She was treated with heparin and recovered.

We report the case of a 48-year-old woman, a teacher, with recurrent severe dysphonia and multiple and different lesions at the same time in her vocal folds.

The relativistic properties of Hydrogen-like atoms (HLAs) are here investigated in the Heisenberg picture for the first time. The relativistic vibrational Hamiltonian (RVH) is first defined as a power series of harmonic oscillator Hamiltonian by using the relativistic energy eigenvalue . By applying the first-order RVH (proportional to ) to the Heisenberg equation, a pair of coupled equations is turned out for the relativistic motion of the electron’s position and linear momentum. A simple comparison of the first-order relativistic and nonrelativistic equations reveals this reality that the natural (fundamental) frequency of HLA (like entropy) is slowly raised by increasing the atomic number from . The second-order RVH (proportional to ) has then been implemented to determine an exact expression for the electron relativistic frequency in the different atomic energy levels. In general, the physical role of RVH is fundamental because it not only specifies the temporal relativistic variations of position, velocity, and linear momentum of the oscillating electron, but also identifies the corresponding relativistic potential, kinetic, and mechanical energies. The results will finally be testified by demonstrating energy conservation.

We report a rare case of cervical epidural abscess at the C5-C6 levels. The patient underwent surgery with complete abscess removal through C6 vertebral body corpectomy. The result of bacteriological culture was Brucella melitensis. Brucellosis must be considered as a possible cause of epidural abscess in patients from endemic area.

Aim: To establish a population pharmacokinetic model and optimise tacrolimus dosing regimens in Chinese Han lung transplant recipients. Methods: Tacrolimus trough concentrations and clinical data of 70 adult lung transplant recipients were collected. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model. A Monte Carlo simulation was conducted to determine the optimal dosing regimen. Results: The pharmacokinetics of tacrolimus could be best described by a one-compartment model, with the CYP3A5 genotype, haematocrit (HCT), and alanine transaminase (ALT) as significant covariates. The clearance of tacrolimus in the CYP3A5 rapid and intermediate metabolisers were 3.03 and 1.99 times higher than those of CYP3A5 poor metaboliser, respectively. When HCT decreased from 0.30 to 0.20, the clearance of tacrolimus increased by 31.14%, and the apparent volume of distribution increased by 28.58%. The clearance of tacrolimus decreased by 8.67% when ALT increased from 20 IU·L-1 to 40 IU·L-1. Monte Carlo simulation indicated that recipients with CYP3A5*1/*1 receiving 3.5 mg twice daily, recipients with HCT < 0.2 receiving 5 mg twice daily, and recipients with ALT < 4IU·L-1 received 3 mg twice daily, could achieve the target concentrations of 10–15 ng·mL-1. Conclusions: A population pharmacokinetic model of tacrolimus in Chinese Han lung transplant recipients was successfully constructed. Recipients with the CYP3A5*1/*1 genotype, low HCT value, and low ALT value after surgery needed a higher maintenance dose to reach the therapeutic window, which provided a reference for the formulation of individualised tacrolimus regimen.

In this paper, we mainly consider the well-posedness and long-time behavior of solutions for the nonlocal diffusion porous medium equations with nonlinear term. Firstly, we obtain the well-posedness of the solutions in L1(Ω) for the equations. Secondly, we prove the existence of a global attractor by proving there exists a compact absorbing set. Finally, we apply index theory to consider the dimension of the attractor and prove that there exists an infinite dimensional attractor of the equations under proper conditions.

We describe an adult patient who presented with purulent pericarditis in whom two-dimensional transthoracic echocardiography demonstrated a marked decrease in the area of the right ventricular wall together with the overlying fibrin following intrapericardial administration of a fibrinolytic agent. Documentation of this decrease by measurements performed and illustrated on two-dimensional images have not been reported previously in an adult patient with purulent pericarditis, to the best of our knowledge.

Background: Candida auris is an emerging fungal pathogen of worldwide interest. It is associated with high mortality rates and exhibits increased resistance to antifungals. Ultraviolet-C (UVC) light can be used to disinfect surfaces to mitigate its spread. In this study, we analyzed the performance of different UVC wavelengths against C. auris to determine its wavelength sensitivity and UVC dose requirements and evaluated biofilm prevention dose requirements on most used materials in healthcare settings. Objectives: 1. To investigate UVC disinfection performances and wavelength sensitivity of C. auris; 2. To evaluate the UVC dose required for prevention of biofilm prevention on stainless steel. Methods: C. auris was grown following standard procedures. The study utilized six different UVC LED arrays with wavelengths between 252 and 280 nm. Arrays were set at similar intensities, to obtain doses of 5-40 mJcm-2 and similar irradiation time. Disinfection performance for each array was determined using log reduction value (LRV) and percentage reduction by comparing the controls against the irradiated treatments. Evaluation of the ability of 267 nm UVC LEDs to prevent C. auris biofilm formation was investigated using stainless steel, plastic coupons, and poly-cotton fabric. Results: Peak sensitivity to UVC disinfection was between 267 and 270 nm. With 20 mJcm-2, the study obtained LRV 3. On steel coupons, 30 mJcm-2 was sufficient to prevent biofilm formation, on plastic only 10 mJcm-2. A dose of 60 mJcm-2 reduced biofilms on poly-cotton fabric significantly. Conclusions: Results revealed that C. auris was most susceptible at 267-270 nm. Additional highlights from the study allow for the design and implementation of disinfection systems.

Fluctuating light (FL) and drought stress usually occur concomitantly. However, whether drought stress affects photosynthetic performance under FL remains unknown. Here, we measured gas exchange, chlorophyll fluorescence, and P700 redox state under FL in drought-stressed tomato (Solanum lycopersicum) seedlings. Drought stress significantly affected stomatal opening and mesophyll conductance after transition from low to high light and thus delayed photosynthetic induction under FL. Therefore, drought stress exacerbated the loss of carbon gain under FL. Furthermore, restriction of CO2 fixation under drought stress aggravated the over-reduction of photosystem I (PSI) upon transition from low to high light. The resulting stronger FL-induced PSI photoinhibition significantly supressed linear electron flow and PSI photoprotection. These results indicated that drought stress not only affected gas exchange under FL but also accelerated FL-induced photoinhibition of PSI. Furthermore, drought stress enhanced relative cyclic electron flow in FL, which partially compensated for restricted CO2 fixation and thus favored PSI photoprotection under FL. Therefore, drought stress has large effects on photosynthetic dark and light reactions under FL.

Objective: To assess the association between gestational age at delivery and postpartum severe acute maternal morbidity (SAMM) in twin pregnancies. Design: Population-based, national, prospective, cohort study Setting: From 02/2014 to 03/2015 in France Population: Women with twin pregnancies who gave birth after 32 weeks of gestation. We excluded women with fetal death or medical termination of either twin, with antepartum SAMM, with antepartum conditions responsible for postpartum SAMM. Methods: Gestational age at delivery was studied as the number of completed weeks of gestation. We assessed the association between gestational age at delivery and postpartum SAMM by using multivariable multilevel modified Poisson regression modelling. Main Outcome Measures: Composite criteria of postpartum severe acute maternal morbidity Results: Among the 7,713 women included, 410 (5.3%) developed postpartum SAMM, mainly (88.5%) postpartum haemorrhage. Compared with the reference category of 37 weeks, the risk of postpartum SAMM was significantly lower for all categories of earlier gestational age at delivery (from aRR=0.34, 95% CI 0.17-0.68 at 32 weeks to aRR=0.71, 95% CI 0.54-0.94 at 36 weeks), and did not differ for later categories. Conclusion: In twin pregnancies, compared with delivery at 37 weeks, delivery at earlier gestational ages is associated with a lower risk of postpartum SAMM. Continuing pregnancy beyond 37 weeks is not associated with an increased risk of postpartum SAMM. Funding: Supported by a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique, AOM2012) and a grant from Université Toulouse III. Keywords: severe acute maternal morbidity, twin pregnancy, timing of delivery

High temperature stress inhibits wheat photosynthetic processes and threatens wheat production. Photosynthetic heat tolerance (commonly measured as Tcrit – the critical temperature at which incipient damage to photosystem II occurs) in wheat genotypes could be improved by exploiting genetic variation and genotype-by-environment interaction (GEI) for this trait. Flag leaf Tcrit of a total of 54 wheat genotypes were evaluated in 12 thermal environments over three years in Australia using linear mixed models for assessing GEI effects. Nine of the 12 environments had significant genotypic effect and highly variable broad-sense heritability (H2 ranged from 0.15 to 0.75). Tcrit GEI was variable, with 55.6% of the genetic variance across environments accounted for by the factor analytic model. Mean daily growth temperature preceding anthesis was the most influential environmental driver of Tcrit GEI, suggesting varied scales of biochemical, physiological, and structural adaptations to temperature requiring different durations to manifest at the thylakoid membrane and leaf levels. These changes help protect or repair photosystem II upon exposure to heat stress. To support current wheat breeding, we identified genotypes superior to commercial cultivars commonly grown by farmers, and showed that there is potential for developing genotypes with greater photosynthetic heat tolerance.

Novel cocoa butter equivalents were designed using dry fractionated Pequi oil and solvent fractionated Kpangnan butter. Static crystallization of binary mixtures of these two fractions into the triclinic form (β2) was achieved after 12 days for all mixtures and after 4 days for the 80:20 w/w and 90:10 w/w fractionated Kpangnan:Pequi oil mixtures. Moreover, after 60 days of storage at 22oC, all binary blends (except 100% fractionated pequi oil and 100% fractionated Kpangnan butter) were crystallized in the most stable triclinic crystal form (β1). Here we also discovered an unusual melting behavior for the fractionaled 30:70 w/w and 20:80 w/w fractionated Kpangnan:Pequi oil mixtures, where after 4 days of static crystallization at room 22oC, these mixtures displayed higher than predicted melting points, 41.89 oC and 33.32 oC, respectively. This suggested a faster kinetics of transformation to the triclinic β2 form for those mixtures. Our results suggest that the 30:70 w/w fractionated Kpangnan:Pequi oil mixture with a melting point of 34oC after 60 days storage at 22oC, a stable triclinic β2 form, and a triglyceride composition of 28% POP, 4.6% POS and 33% SOS displayed solid state characteristics, melting point and crystal structure, of a commercial cocoa butter equivalent.

Staphylococcus saprophyticus is the second most frequent causative microorganism in acute uncomplicated urinary tract infections in young women. However, it is potentially capable of causing more invasive infections including bacteremia, particularly secondary to pyelonephritis.

Saphenous vein graft (SVG) aneurysms are rare complications after coronary artery bypass grafting which may lead to major complications. We report a patient with SVG aneurysm, it’s treatment by percutaneous intervention using peripheral vascular plug. Procedure was complicated by an ACS of unclear cause, which was urgently diagnosed and treated.

Abstract Objective: To analyze baseline clinical and laboratory characteristics and explore the possible predictors of lung necrosis severity in children with community-acquired necrotizing pneumonia (NP). Methodology: This retrospective observational study was performed in a tertiary referral center. A total of 104 patients aged <15 years with community-acquired pneumonia and radiologically confirmed NP were included. Patients were classified into the mild, moderate, or massive necrosis groups. Results: Among them, 29, 41, and 34 patients had mild, moderate, and massive necrosis, respectively. Moreover, 34.6% of the patients were admitted to the pediatric intensive care unit. Massive necrosis was more likely to occur during winter (p<0.05) and was associated with more severe clinical outcomes, such as longer duration of fever, longer hospitalization, increased mortality, and a higher risk of subsequent surgical intervention (p<0.05). Multivariate analysis demonstrated that the following were independent risk factors for massive necrosis: C-reactive protein (CRP) ≥ 122 mg/L (adjusted odds ratio [aOR], 8.780; 95% confidence interval [CI], 3.320–21.089; p=0.003), serum albumin ≤ 30.8 g/L (aOR, 11.608; 95% CI, 5.147–27.058; p=0.001), and immunoglobulin M (IgM) ≤ 95.7 mg/dL (aOR, 7.152; 95% CI, 2.240–17.692; p=0.021). Receiver operating characteristic analysis demonstrated that these variables showed good diagnostic performance for differentiating patients with massive necrosis from all patients with NP. Conclusion: NP is a potentially severe complication of pediatric community-acquired pneumonia. Different severities of lung necrosis can lead to different clinical outcomes. CRP, serum albumin, and IgM levels are independent predictors of the degree of lung necrosis.

Free phytosterols (PS) and phytosterol esters (PSE) usually coexist in natural oils, which significantly affect the crystallization behavior of oil. However, the phase behaviors of PS/PSE mixtures in oils and their roles on the crystallization behavior of oil are still unclear. In this study, the dissolution and crystallization behaviors of PS/PSE mixtures in medium chain triglyceride (MCT) were studied, and the synergistic mechanism of PS/PSE mixtures on the crystallization behaviors of MCT was further clarified. The results showed that when the mass ratio of PS: PSE was greater than 3: 7, PS/PSE mixtures recrystallized a new urchin-like crystal structure, which was different from PS spherical or PSE plate-like crystal structure, in MCT. The new urchin-like PS/PSE crystal had a larger surface area, and its melting point was between PS and PSE. It also showed the synergistic ability to promote the crystallization nucleation of MCT. When the total content of PS and PSE was 1 wt%, and the mass ratio of PS: PSE was 5: 5, the crystallization peak temperature of PS/PSE/MCT was 12 ºC higher than that of virgin MCT, 2.5 ºC higher than that of PSE/MCT, and 10.3 ºC higher than that of PS/MCT. These results not only provide a method for obtaining new crystal structure of phytosterols, but also have great significance for controlling the crystallization behaviors of oils by precisely adjusting the nutritional composition of oils.

Lymphangiomas are a common benign neoplasm, which can develop in the digestive tracts. Hemorrhagic jejunal tumors are relatively rare and diagnostic challenge. We report herein a case of hemorrhagic jejunal hemolymphangioma successfully diagnosed and treated by double-balloon enteroscopy.

Cutaneous manifestations are increasingly reported in patients with COVID-19 disease .A review of cutaneous manifestations of COVID-19 especially among health care workers (HCW) is thus required.

A 82 years old female presented with cellulitis with abscess of the left foot after 10 days. We are reporting a case report of complex wound healing with upto 70% skin loss over dorsum of foot with the application of Negative Pressure Wound Therapy and dressing with placental extract gel.

A 27-year-old presented a complete dislocation of the talus with a missing medial malleolus through a lateral wound after a motorcycle accident. Only extruded contaminated talus was found, debrided, and reimplanted, and pinned within two hours. The outcome was good at 14 months without infection and MRI-confirmed talus revascularization.

Management of bone metastases from renal cell carcinoma (RCC) has significantly changed after the era of targeted therapy that improved the overall survival (OS).Surgical decision-making remains a subject of controversy.We report a case of pelvic bone metastasis from RCC, 2 months after nephrectomy and surgery of a revealing clavicular metastasis