Multi-omics analysis of mucosal and systemic immunity to SARS-CoV-2 after birth.

The dynamics of immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in infants and young children by analyzing blood samples and weekly nasal swabs collected before, during, and after infection with Omicron and non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, showed no sign of decay for up to 300 days. Infants mounted a robust mucosal immune response characterized by inflammatory cytokines, interferon (IFN) α, and T helper (Th) 17 and neutrophil markers (interleukin [IL]-17, IL-8, and CXCL1). The immune response in blood was characterized by upregulation of activation markers on innate cells, no inflammatory cytokines, but several chemokines and IFNα. The latter correlated with viral load and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell multi-omics. Together, these data provide a snapshot of immunity to infection during the initial weeks and months of life.

Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections.

Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A(4) hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B(4). We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.

Spatial Analysis of Drug-Susceptible and Multidrug-Resistant Cases of Tuberculosis, Ho Chi Minh City, Vietnam, 2020-2023.

We characterized the spatial distribution of drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) cases in Ho Chi Minh City, Vietnam, a major metropolis in southeastern Asia, and explored demographic and socioeconomic factors associated with local TB burden. Hot spots of DS and MDR TB incidence were observed in the central parts of Ho Chi Minh City, and substantial heterogeneity was observed across wards. Positive spatial autocorrelation was observed for both DS TB and MDR TB. Ward-level TB incidence was associated with HIV prevalence and the male proportion of the population. No ward-level demographic and socioeconomic indicators were associated with MDR TB case count relative to total TB case count. Our findings might inform spatially targeted TB control strategies and provide insights for generating hypotheses about the nature of the relationship between DS and MDR TB in Ho Chi Minh City and the wider southeastern region of Asia.

Correction: Recombinant Lloviu virus as a tool to study viral replication and host responses.

[This corrects the article DOI: 10.1371/journal.ppat.1010268.].

Recombinant Lloviu virus as a tool to study viral replication and host responses.

Next generation sequencing has revealed the presence of numerous RNA viruses in animal reservoir hosts, including many closely related to known human pathogens. Despite their zoonotic potential, most of these viruses remain understudied due to not yet being cultured. While reverse genetic systems can facilitate virus rescue, this is often hindered by missing viral genome ends. A prime example is Lloviu virus (LLOV), an uncultured filovirus that is closely related to the highly pathogenic Ebola virus. Using minigenome systems, we complemented the missing LLOV genomic ends and identified cis-acting elements required for LLOV replication that were lacking in the published sequence. We leveraged these data to generate recombinant full-length LLOV clones and rescue infectious virus. Similar to other filoviruses, recombinant LLOV (rLLOV) forms filamentous virions and induces the formation of characteristic inclusions in the cytoplasm of the infected cells, as shown by electron microscopy. Known target cells of Ebola virus, including macrophages and hepatocytes, are permissive to rLLOV infection, suggesting that humans could be potential hosts. However, inflammatory responses in human macrophages, a hallmark of Ebola virus disease, are not induced by rLLOV. Additional tropism testing identified pneumocytes as capable of robust rLLOV and Ebola virus infection. We also used rLLOV to test antivirals targeting multiple facets of the replication cycle. Rescue of uncultured viruses of pathogenic concern represents a valuable tool in our arsenal for pandemic preparedness.

REL and BHLHE40 Variants Are Associated with IL-12 and IL-10 Responses and Tuberculosis Risk.

The major human genes regulating Mycobacterium tuberculosis-induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression in humans are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling. We hypothesized that common variants in CNBP, REL, and BHLHE40 were associated with IL-12 and IL-10 production from dendritic cells, and that these variants also influence adaptive immune responses to bacillus Calmette-Guérin (BCG) vaccination and TB susceptibility. We characterized the association between common variants in CNBP, REL, and BHLHE40, innate immune responses in dendritic cells and monocyte-derived macrophages, BCG-specific T cell responses, and susceptibility to pediatric and adult TB in human populations. BHLHE40 single-nucleotide polymorphism (SNP) rs4496464 was associated with increased BHLHE40 expression in monocyte-derived macrophages and increased IL-10 from peripheral blood dendritic cells and monocyte-derived macrophages after LPS and TB whole-cell lysate stimulation. SNP BHLHE40 rs11130215, in linkage disequilibrium with rs4496464, was associated with increased BCG-specific IL-2+CD4+ T cell responses and decreased risk for pediatric TB in South Africa. SNPs REL rs842634 and rs842618 were associated with increased IL-12 production from dendritic cells, and SNP REL rs842618 was associated with increased risk for TB meningitis. In summary, we found that genetic variations in REL and BHLHE40 are associated with IL-12 and IL-10 cytokine responses and TB clinical outcomes. Common human genetic regulation of well-defined intermediate cellular traits provides insights into mechanisms of TB pathogenesis.

Video Grading of Pancreatic Anastomoses During Robotic Pancreatoduodenectomy to Assess Both Learning Curve and the Risk of Pancreatic Fistula: A Post Hoc Analysis of the LAELAPS-3 Training Program.

OBJECTIVE: To assess the learning curve of pancreaticojejunostomy during robotic pancreatoduodenectomy (RPD) and to predict the risk of postoperative pancreatic fistula (POPF) by using the objective structured assessment of technical skills (OSATS), taking the fistula risk into account. BACKGROUND: RPD is a challenging procedure that requires extensive training and confirmation of adequate surgical performance. Video grading, modified for RPD, of the pancreatic anastomosis could assess the learning curve of RPD and predict the risk of POPF. METHODS: Post hoc assessment of patients prospectively included in 4 Dutch centers in a nationwide LAELAPS-3 training program for RPD. Video grading of the pancreaticojejunostomy was performed by 2 graders using OSATS (attainable score: 12-60). The main outcomes were the combined OSATS of the 2 graders and POPF (grade B/C). Cumulative sum analyzed a turning point in the learning curve for surgical skill. Logistic regression determined the cutoff for OSATS. Patients were categorized for POPF risk (ie, low, intermediate, and high) based on the updated alternative fistula risk scores. RESULTS: Videos from 153 pancreatic anastomoses were included. Median OSATS score was 48 (interquartile range: 41-52) points and with a turning point at 33 procedures. POPF occurred in 39 patients (25.5%). An OSATS score below 49, present in 77 patients (50.3%), was associated with an increased risk of POPF (odds ratio: 4.01, P =0.004). The POPF rate was 43.6% with OSATS < 49 versus 15.8% with OSATS ≥49. The updated alternative fistula risk scores category "soft pancreatic texture" was the second strongest prognostic factor of POPF (odds ratio: 3.37, P =0.040). Median cumulative surgical experience was 17 years (interquartile range: 8-21). CONCLUSIONS: Video grading of the pancreatic anastomosis in RPD using OSATS identified a learning curve and a reduced risk of POPF in case of better surgical performance. Video grading may provide a valid method to surgical training, quality control, and improvement.

Severe falciparum malaria in pregnancy in Southeast Asia: a multi-centre retrospective cohort study.

BACKGROUND: Severe malaria in pregnancy causes maternal mortality, morbidity, and adverse foetal outcomes. The factors contributing to adverse maternal and foetal outcomes are not well defined. We aimed to identify the factors predicting higher maternal mortality and to describe the foetal mortality and morbidity associated with severe falciparum malaria in pregnancy. METHODS: A retrospective cohort study was conducted of severe falciparum malaria in pregnancy, as defined by the World Health Organization severe malaria criteria. The patients were managed prospectively by the Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border or were included in hospital-based clinical trials in six Southeast Asian countries. Fixed-effects multivariable penalised logistic regression was used for analysing maternal mortality. RESULTS: We included 213 (123 SMRU and 90 hospital-based) episodes of severe falciparum malaria in pregnancy managed between 1980 and 2020. The mean maternal age was 25.7 (SD 6.8) years, and the mean gestational age was 25.6 (SD 8.9) weeks. The overall maternal mortality was 12.2% (26/213). Coma (adjusted odds ratio [aOR], 7.18, 95% CI 2.01-25.57, p = 0.0002), hypotension (aOR 11.21, 95%CI 1.27-98.92, p = 0.03) and respiratory failure (aOR 4.98, 95%CI 1.13-22.01, p = 0.03) were associated with maternal mortality. Pregnant women with one or more of these three criteria had a mortality of 29.1% (25/86) (95%CI 19.5 to 38.7%) whereas there were no deaths in 88 pregnant women with hyperparasitaemia (> 10% parasitised erythrocytes) only or severe anaemia (haematocrit < 20%) only. In the SMRU prospective cohort, in which the pregnant women were followed up until delivery, the risks of foetal loss (23.3% by Kaplan-Meier estimator, 25/117) and small-for-gestational-age (38.3%, 23/60) after severe malaria were high. Maternal death, foetal loss and preterm birth occurred commonly within a week of diagnosis of severe malaria. CONCLUSIONS: Vital organ dysfunction in pregnant women with severe malaria was associated with a very high maternal and foetal mortality whereas severe anaemia or hyperparasitaemia alone were not associated with poor prognosis, which may explain the variation of reported mortality from severe malaria in pregnancy. Access to antenatal care must be promoted to reduce barriers to early diagnosis and treatment of both malaria and anaemia.

Click Chemistry and Radiochemistry: An Update.

The term "click chemistry" describes a class of organic transformations that were developed to make chemical synthesis simpler and easier, in essence allowing chemists to combine molecular subunits as if they were puzzle pieces. Over the last 25 years, the click chemistry toolbox has swelled from the canonical copper-catalyzed azide-alkyne cycloaddition to encompass an array of ligations, including bioorthogonal variants, such as the strain-promoted azide-alkyne cycloaddition and the inverse electron-demand Diels-Alder reaction. Without question, the rise of click chemistry has impacted all areas of chemical and biological science. Yet the unique traits of radiopharmaceutical chemistry have made it particularly fertile ground for this technology. In this update, we seek to provide a comprehensive guide to recent developments at the intersection of click chemistry and radiopharmaceutical chemistry and to illuminate several exciting trends in the field, including the use of emergent click transformations in radiosynthesis, the clinical translation of novel probes synthesized using click chemistry, and the advent of click-based in vivo pretargeting.

Preferences and experiences of pediatricians on implementing national guidelines on universal routine screening of adolescents for major depressive disorder: A qualitative study.

BACKGROUND: To explore the preferences of pediatricians for key factors around the implementation of universal routine screening guidelines for major depressive disorder in adolescent patients in a primary care setting. METHOD: Semi-structured qualitative interviews were conducted with U.S. pediatricians. Participants were recruited by convenience sampling and snowball sampling. Qualitive data were summarized using thematic analysis to identify themes relevant to preferences around implementing screening strategies for adolescent patients. Recruitment ended upon reaching thematic saturation when no new themes were revealed. RESULTS: Of the 14 participants, 11 identified as female, 3 male, 10 white, and 4 Asian. Top themes among pediatrician participants were around the screening modality (14/14 participants), screening validity (14/14), time barriers (14/14), and confidentiality barriers (12/14). Less frequently mentioned themes by pediatricians were workplace coordination and logistics (7/14), alternative starting ages for screening (7/14), more frequent screenings than annual screenings (3/14), and additional clinical training regarding depression diagnosis and treatment (2/14). LIMITATIONS: Pool of interviewed participants was limited by diversity in terms of geography, race/ethnicity, or practice settings. CONCLUSIONS: To promote the uptake of universal routine screening of adolescent major depression, pediatricians expressed it was important to address key implementation factors regarding the screening modality, screening validity, time constraints, and confidential care concerns in a primary care delivery context. Findings could be used to inform the development of implementation strategies to facilitate depression screening in primary care. Future research is needed to quantitively assess decisions and tradeoffs that pediatricians make when implementing universal screening to support adolescent mental health.

Financial toxicity among cancer patients, survivors and their families in the United Kingdom: a scoping review.

BACKGROUND: The aim of this scoping review was to identify key research gaps and priorities in order to advance policy and practice for people living with cancer in the UK. METHODS: The review adhered to PRISMA guidelines for scoping review. We searched MEDLINE, EMBASE, Scopus, Web of Science and Google Scholar on 16 July 2022. There were no restrictions in terms of study design and publication time; gray literature was included. The key words, 'financial' or 'economic', were combined with each of the following words 'hardship/stress/burden/distress/strain/toxicity/catastrophe/consequence/impact.' RESULTS: 29/629 studies/reports published during 1982-2022 were eligible to be included in the review. No study conducted a comprehensive inquiry and reported all aspects of financial toxicity (FT) or used a validated measure of FT. The most three commonly reported outcomes related to financial hardship were financial well-being (24/29), benefit/welfare (17/29) and mental health status (16/29). CONCLUSIONS: It is evident that FT is experienced by UK cancer patients/survivors and that the issue is under-researched. There is an urgent need for further research including rigorous studies which contribute to a comprehensive understanding about the nature and extent of FT, disparities in experience, the impacts of FT on outcomes and potential solutions to alleviate FT and related problems.

Supporting the implementation of drinking water management systems in New South Wales, Australia.

Since 2010, New South Wales (NSW) Health has assisted local water utilities to develop and implement risk-based drinking water management systems based on the Australian Drinking Water Guidelines Framework for Management of Drinking Water Quality. This support has benefited regional communities, and especially smaller utilities, by helping to identify and control risks. NSW Health's support projects have resulted in statistically significant improvements across many elements of drinking water management system implementation. Through this program of support, NSW Health has identified possible infrastructure and operational needs and assessed implementation of drinking water management systems. In parallel, NSW Health has worked to assess the risk from Cryptosporidium in drinking water supplies and to develop a formal audit program. Findings from the NSW Health support program informed the development of two NSW Government programs and the commitment of more than $1 billion to help local water utilities address public health and other critical needs. The introduction of risk-based drinking water management systems has driven incremental improvement in drinking water quality management across the state of NSW.

Parent-Reported Use of Pediatric Primary Care Telemedicine: Survey Study.

BACKGROUND: Telemedicine delivered from primary care practices became widely available for children during the COVID-19 pandemic. OBJECTIVE: Focusing on children with a usual source of care, we aimed to examine factors associated with use of primary care telemedicine. METHODS: In February 2022, we surveyed parents of children aged ≤17 years on the AmeriSpeak panel, a probability-based panel of representative US households, about their children's telemedicine use. We first compared sociodemographic factors among respondents who did and did not report a usual source of care for their children. Among those reporting a usual source of care, we used Rao-Scott F tests to examine factors associated with parent-reported use versus nonuse of primary care telemedicine for their children. RESULTS: Of 1206 respondents, 1054 reported a usual source of care for their children. Of these respondents, 301 of 1054 (weighted percentage 28%) reported primary care telemedicine visits for their children. Factors associated with primary care telemedicine use versus nonuse included having a child with a chronic medical condition (87/301, weighted percentage 27% vs 113/753, 15%, respectively; P=.002), metropolitan residence (262/301, weighted percentage 88% vs 598/753, 78%, respectively; P=.004), greater internet connectivity concerns (60/301, weighted percentage 24% vs 116/753, 16%, respectively; P=.05), and greater health literacy (285/301, weighted percentage 96% vs 693/753, 91%, respectively; P=.005). CONCLUSIONS: In a national sample of respondents with a usual source of care for their children, approximately one-quarter reported use of primary care telemedicine for their children as of 2022. Equitable access to primary care telemedicine may be enhanced by promoting access to primary care, sustaining payment for primary care telemedicine, addressing barriers in nonmetropolitan practices, and designing for lower health-literacy populations.

Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria.

BACKGROUND: Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed "radical cure." METHODS: We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin. RESULTS: A protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, -4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96). CONCLUSIONS: Among patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123 .).

Panels of circulating microRNAs as potential diagnostic biomarkers for breast cancer: a systematic review and meta-analysis.

PURPOSE: Circulating microRNAs (miRNAs) are potential diagnostic biomarkers for breast cancer (BC). The application of miRNA panels could improve the performance of screening tests. Here, we integrated bioinformatic tools and meta-analyses to select circulating miRNAs with high diagnostic accuracy and combined these markers to develop diagnostic panels for BC. METHODS: Analyses across databases were performed to identify potential BC-related circulating miRNAs. Next, a comprehensive meta-analysis was conducted for each miRNA following the PRISMA guidelines. An electronic and manual search for relevant literature was carried out by two reviewers through PubMed, ScienceDirect, Biomed Central, and Google Scholar. The quality of the included studies was assessed using the QUADAS-2, and the statistical analyses were performed using R software 4.1.1. Finally, the accurate biomarkers confirmed through meta-analyses were combined into diagnostic models for BC. RESULTS: Twenty-seven circulating miRNAs were identified as BC-related by bioinformatic tools. After screening, only 10 miRNAs presented in 45 studies were eligible for meta-analyses. By assessing pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio, 8 miRNAs (miR-21, miR-30b, miR-125b, miR-145, miR221 miR-222, and miR-335) were revealed as promising BC diagnostic biomarkers. Two panels constructed from these miRNAs showed excellent diagnostic accuracy for BC, with areas under the SROC curve of 0.917 and 0.944. CONCLUSION: We identified 8 potential circulating miRNAs and 2 diagnostic models that are useful for diagnosing BC. However, the established miRNA panels have not been tested in any experimental studies and thus should be validated in large case-control studies for clinical use.

Cardiopulmonary transit time: A novel PET imaging biomarker of in vivo physiology for risk stratification of heart transplant recipients.

BACKGROUND: Myocardial blood flow (MBF) can be quantified using dynamic PET studies. These studies also inherently contain tomographic images of early bolus displacement, which can provide cardiopulmonary transit times (CPTT) as measure of cardiopulmonary physiology. The aim of this study was to assess the incremental prognostic value of CPTT in heart transplant (OHT) recipients. METHODS: 94 patients (age 56 ± 16 years, 78% male) undergoing dynamic 13N-ammonia stress/rest studies were included, of which 68 underwent right-heart catherization. A recently validated cardiac allograft vasculopathy (CAV) score based on PET measures of regional perfusion, peak MBF and left-ventricular (LV) ejection fraction (LVEF) was used to identify patients with no, mild or moderate-severe CAV. Time-activity curves of the LV and right ventricular (RV) cavities were obtained and used to calculate the difference between the LV and RV bolus midpoint times, which represents the CPTT and is expressed in heartbeats. Patients were followed for a median of 2.5 years for the occurrence of major adverse cardiac events (MACE), including cardiovascular death, hospitalization for heart failure or acute coronary syndrome, or re-transplantation. RESULTS: CPTT was significantly correlated with cardiac filling pressures (r = .434, P = .0002 and r = .439, P = .0002 for right atrial and pulmonary wedge pressure), cardiac output (r = - .315, P = .01) and LVEF (r = - .513, P < .0001). CPTT was prolonged in patients with MACE (19.4 ± 6.0 vs 14.5 ± 3.0 heartbeats, P < .001, N = 15) with CPTT ≥ 17.75 beats showing optimal discriminatory value in ROC analysis. CPTT ≥ 17.75 heartbeats was associated with a 10.1-fold increased risk (P < .001) of MACE and a 7.3-fold increased risk (P < .001) after adjusting for PET-CAV, age, sex and time since transplant. CONCLUSION: Measurements of cardiopulmonary transit time provide incremental risk stratification in OHT recipients and enhance the value of multiparametric dynamic PET imaging, particularly in identifying high-risk patients.

A sustainable, low-cost carbonaceous hydrochar adsorbent for methylene blue adsorption derived from corncobs.

In this study, activated carbon from corncobs was successfully synthesized by hydrothermal carbonization and hydrochemical activation at low temperatures, followed by pyrolysis. A developed method of hydrochemical activation of hydrochar that uses only small amounts of chemicals is a promising approach. After activation, the activator residues in the hydrothermal product can constantly act as a chemical activator during pyrolysis to form corncob-activated carbon (AHC-KOH), which had specific surface area of 965.028 m2/g and oxygenated functional groups of 0.3780 mmol/g, 31.67 and 4 times, respectively, of those of the inactivated sample. AHC-KOH was used to study the adsorption characteristics of methylene blue (MB). The MB adsorption efficiency of AHC-KOH was the highest at 489.560 mg/g, which was considerably higher than that of activated carbons produced from other biomasses. The isotherm equilibrium and adsorbent kinetics parameters of MB adsorption on AHC-KOH were also determined using the Langmuir isotherm model (R2 = 0.99) and pseudo-second-order kinetic model (R2 > 0.99). Thus, the results indicate that an inexpensive adsorbent produced from corncobs using the above method is a promising material for wastewater treatment.

Discovery of inhibitors against mycobacterium branched-chain amino acid aminotransferases through in silico screening and experimental evaluation.

Tuberculosis (TB) is one of the most dangerous infectious diseases and is caused by Mycobacterium bovis (Mb) and Mycobacterium tuberculosis (Mt). Branched-chain amino acid aminotransferases (BCATs) were reported to be the key enzyme for methionine synthesis in Mycobacterium. Blocking the methionine synthesis in Mycobacterium can inhibit the growth of Mycobacterium. Therefore, in silico screening of inhibitors can be a good way to develop a potential drug for treating TB. A pyridoxal 5'-phosphate (PLP)-form of Mycobacterium bovis branched-chain amino acid aminotransferases (MbBCAT), an active form of MbBCAT, was constructed manually for docking approximately 150 000 compounds and the free energy was calculated in Autodock Vina. The 10 compounds which had the highest affinity to MbBCAT were further evaluated for their inhibitory effects against MbBCAT. Within the selected compounds, compound 4 (ZINC12359007) was found to be the best inhibitor against MbBCAT with the inhibitory constant Ki of 0·45 µmol l-1 and IC50 of 2·37 µmol l-1 . Our work provides potential candidates to develop effective drugs to prevent TB since the well-known structural information would be beneficial in the structure-based modification and design.

Single-incision endoscopic-assisted temporoparietal fascia harvest for single stage auricular reconstruction.

INTRODUCTION: The temporoparietal fascia flaps (TPFF) have been widely used to cover the framework in auricular reconstructions. However, flap harvesting is mostly done by open surgery which may be easier but often results in bad scarring and hair loss. We would like to present a series of cases using endoscopic-assisted flap harvesting techniques with only one single cosmetic auricular incision. PATIENTS AND METHODS: Prospective studies from June 2018 to September 2021 on patients who underwent single-stage total auricular reconstruction using autologous costal cartilage and porous polyethylene (PPE) framework. Variables include age, gender, flap survivability as well as visual results and complications. RESULTS: A total of 61 TPFFs were harvested to cover 15 autologous costal cartilages and 46 PPE frameworks in 60 patients (one patient had operation on both sides). TPFF harvests are performed by endoscopic techniques with one single auricular incision. There was no flap necrosis, no bleeding and no cases required framework removal. Only 7/61 (11.5%) ears had small framework exposure which resolved on their own or only required local skin flap coverage and 1 ear had frontal nerve injury. CONCLUSION: Single-stage auricular reconstruction is a difficult surgery, yet greatly beneficial to young children. Through a single-incision endoscopic technique, we can obtain sufficiently large high-survivability TPFFs ensuring full coverage of the autologous costal cartilage or PPE framework. This method is reliable, and reproducible with advanced training. After reviewing the literature, we can state that our report probably includes the largest endoscopic-assisted TPFF harvesting series and the first to implement single-incision endoscopic technique in auricular reconstructions.

Behavior problems reduce academic outcomes among primary students: A moderated mediation of parental burnout and parents' self-compassion.

The present study examines the mediating role of parental burnout in the relationship between students' behavior problems and academic outcomes and whether this mediating process is moderated by parents' self-compassion (PSC). This study was designed according to a cross-sectional study model, and includes 821 Vietnamese primary students (Mage = 9.98, SD = 0.889) completing behavior problems questionnaires. The parents completed parental burnout and the PSC questionnaires. The school office reported academic outcomes. Main findings include: (1) Student's behavior problems have a direct negative influence on academic outcomes; (2) the mediating role of parental burnout was significant; (3) the moderating role of PSC was also significant. This study suggests that students' behavior problems increase parental burnout, reducing academic outcomes. Next, higher self-compassion protected parents from the negative effect of children's behavior problems. The results of this study are meaningful for developing interventions, which help improve parents' mental health and children's positive outcomes.