Early-life nasal microbiota dynamics relate to longitudinal respiratory phenotypes in urban children.

BACKGROUND: Five distinct respiratory phenotypes based on latent classes of longitudinal patterns of wheezing, allergic sensitization. and pulmonary function measured in urban children from ages from 0 to 7 years have previously been described. OBJECTIVE: Our aim was to determine whether distinct respiratory phenotypes are associated with early-life upper respiratory microbiota development and environmental microbial exposures. METHODS: Microbiota profiling was performed using 16S ribosomal RNA-based sequencing of nasal samples collected at age 12 months (n = 120) or age 36 months (n = 142) and paired house dust samples collected at 3 months (12-month, n = 73; 36-month, n = 90) from all 4 centers in the Urban Environment and Childhood Asthma (URECA) cohort. RESULTS: In these high-risk urban children, nasal microbiota increased in diversity between ages 12 and 36 months (ß = 2.04; P = .006). Age-related changes in microbiota evenness differed significantly by respiratory phenotypes (interaction P = .0007), increasing most in the transient wheeze group. At age 12 months, respiratory illness (R2 = 0.055; P = .0001) and dominant bacterial genus (R2 = 0.59; P = .0001) explained variance in nasal microbiota composition, and enrichment of Moraxella and Haemophilus members was associated with both transient and high-wheeze respiratory phenotypes. By age 36 months, nasal microbiota was significantly associated with respiratory phenotypes (R2 = 0.019; P = .0376), and Moraxella-dominated microbiota was associated specifically with atopy-associated phenotypes. Analysis of paired house dust and nasal samples indicated that 12 month olds with low wheeze and atopy incidence exhibited the largest number of shared bacterial taxa with their environment. CONCLUSION: Nasal microbiota development over the course of early childhood and composition at age 3 years are associated with longitudinal respiratory phenotypes. These data provide evidence supporting an early-life window of airway microbiota development that is influenced by environmental microbial exposures in infancy and associates with wheeze- and atopy-associated respiratory phenotypes through age 7 years.

In Search of a Gold Standard Tool for Assessing Knowledge of Stroke: A Systematic Review.

BACKGROUND: Knowledge of stroke is essential to empower people to reduce their risk of these events. However, valid tools are required for accurate and reliable measurement of stroke knowledge. We aimed to systematically review contemporary stroke knowledge assessment tools and appraise their content validity, feasibility, and measurement properties. METHODS: The protocol was registered in PROSPERO (CRD42023403566). Electronic databases (MEDLINE, PsycInfo, CINAHL, Embase, Scopus, Web of Science) were searched to identify published articles (1 January 2015-1 March 2023), in which stroke knowledge was assessed using a validated tool. Two reviewers independently screened titles and abstracts prior to undertaking full-text review. COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methods guided the appraisal of content validity (relevance, comprehensiveness, comprehensibility), feasibility, and measurement properties. RESULTS: After removing duplicates, the titles and abstracts of 718 articles were screened; 323 reviewed in full; with 42 included (N = 23 unique stroke knowledge tools). For content validity, all tools were relevant, two were comprehensive, and seven were comprehensible. Validation metrics were reported for internal consistency (n = 20 tools), construct validity (n = 17 tools), cross-cultural validity (n = 15 tools), responsiveness (n = 9 tools), reliability (n = 7 tools), structural validity (n = 3 tools), and measurement error (n = 1 tool). The Stroke Knowledge Test met all content validity criteria, with validation data for six measurement properties (n = 3 rated "Sufficient"). CONCLUSION: Assessment of stroke knowledge is not standardised and many tools lacked validated content or measurement properties. The Stroke Knowledge Test was the most comprehensive but requires updating and further validation for endorsement as a gold standard.

MUC5AC Genetic Variation Is Associated With Tuberculous Meningitis Cerebral Spinal Fluid Cytokine Responses and Mortality.

BACKGROUND: The purpose of this study was to assess if single nucleotide polymorphisms (SNPs) in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis outcomes. METHODS: Independent SNPs in MUC5B and MUC5AC (genotyped by Illumina HumanOmniExpress array) were assessed for associations with tumor necrosis factor (TNF) concentrations (measured by immunoassay) in cerebral spinal fluid (CSF) from tuberculous meningitis (TBM) patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal tuberculosis susceptibility and TBM mortality. RESULTS: MUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF (P = 1.8 × 10-8) and IFN-γ (P = 2.3 × 10-6). In an additive genetic model, rs28737416 T/T genotype was associated with higher susceptibility to TBM (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.03-1.49; P = .02), but not pulmonary tuberculosis (OR, 1.11, 95% CI, .98-1.25; P = .10). TBM mortality was higher among participants with the rs28737416 T/T and T/C genotypes (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank P = .005) in a Vietnam discovery cohort (n = 210), an independent Vietnam validation cohort (n = 87; 9/87, 19.1% vs 1/20, 2.5%; log-rank P = .02), and an Indonesia validation cohort (n = 468, 127/287, 44.3% vs 65/181, 35.9%; log-rank P = .06). CONCLUSIONS: MUC5AC variants may contribute to immune changes that influence TBM outcomes.

EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity.

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.

Enhanced laser-induced damage performance of all-glass metasurfaces for energetic pulsed laser applications.

To fabricate optical components with surface layers compatible with high-power laser applications that may operate as antireflective coatings, polarization rotators, or harness physical anisotropy for other uses, metasurfaces are becoming an appealing candidate. In this study, large-beam (1.05 cm diameter) 351-nm laser-induced damage testing was performed on an all-glass metasurface structure composed of cone-like features with a subwavelength spacing of adjacent features. These structures were fabricated on untreated fused silica glass and damage tested, as were structures that were fabricated on fused silica glass that experienced a preliminary etching process to remove the surface Beilby layer that is characteristic of polished fused silica. The laser-induced damage onset for structures on untreated fused silica glass was 19.3J⋅c m -2, while the sample that saw an initial pretreatment etch exhibited an improved damage onset of 20.4J⋅c m -2, only 6% short of the reference pretreated glass damage onset of 21.7J⋅c m -2. For perspective, the National Ignition Facility operational average fluence at this wavelength and pulse length is about 10J/c m 2. At a fluence of 25.5J⋅c m -2, the reference (pretreated) fused silica initiated 5.2 damage sites per m m 2, while the antireflective metasurface sample with a preliminary etching process treatment initiated 9.8 damage sites per m m 2. These findings demonstrate that substrate-engraved metasurfaces are compatible with high energy and power laser applications, further broadening their application space.

Is sex a predictor for delayed cerebral ischaemia (DCI) and hydrocephalus after aneurysmal subarachnoid haemorrhage (aSAH)? A systematic review and meta-analysis.

OBJECTIVES: DCI and hydrocephalus are the most common complications that predict poor outcomes after aSAH. The relationship between sex, DCI and hydrocephalus are not well established; thus, we aimed to examine sex differences in DCI and hydrocephalus following aSAH in a systematic review and meta-analysis. METHODS: A systematic search was conducted using the PubMed, Scopus and Medline databases from inception to August 2022 to identify cohort, case control, case series and clinical studies reporting sex and DCI, acute and chronic shunt-dependent hydrocephalus (SDHC). Random-effects meta-analysis was used to pool estimates for available studies. RESULTS: There were 56 studies with crude estimates for DCI and meta-analysis showed that women had a greater risk for DCI than men (OR 1.24, 95% CI 1.11-1.39). The meta-analysis for adjusted estimates for 9 studies also showed an association between sex and DCI (OR 1.61, 95% CI 1.27-2.05). For acute hydrocephalus, only 9 studies were included, and meta-analysis of unadjusted estimates showed no association with sex (OR 0.95, 95%CI 0.78-1.16). For SDHC, a meta-analysis of crude estimates from 53 studies showed that women had a somewhat greater risk of developing chronic hydrocephalus compared to men (OR 1.14, 95% CI 0.99-1.31). In meta-analysis for adjusted estimates from 5 studies, no association of sex with SDHC was observed (OR 0.87, 95% CI 0.57-1.33). CONCLUSIONS: Female sex is associated with the development of DCI; however, an association between sex and hydrocephalus was not detected. Strategies to target females to reduce the development of DCI may decrease overall morbidity and mortality after aSAH.

Electric Monopole Transition from the Superdeformed Band in

The electric monopole (E0) transition strength ρ^{2} for the transition connecting the third 0^{+} level, a "superdeformed" band head, to the "spherical" 0^{+} ground state in doubly magic ^{40}Ca is determined via e^{+}e^{-} pair-conversion spectroscopy. The measured value ρ^{2}(E0;0_{3}^{+}→0_{1}^{+})=2.3(5)×10^{-3} is the smallest ρ^{2}(E0;0^{+}→0^{+}) found in A<50 nuclei. In contrast, the E0 transition strength to the ground state observed from the second 0^{+} state, a band head of "normal" deformation, is an order of magnitude larger ρ^{2}(E0;0_{2}^{+}→0_{1}^{+})=25.9(16)×10^{-3}, which shows significant mixing between these two states. Large-scale shell-model (LSSM) calculations are performed to understand the microscopic structure of the excited states and the configuration mixing between them; experimental ρ^{2} values in ^{40}Ca and neighboring isotopes are well reproduced by the LSSM calculations. The unusually small ρ^{2}(E0;0_{3}^{+}→0_{1}^{+}) value is due to destructive interference in the mixing of shape-coexisting structures, which are based on several different multiparticle-multihole excitations. This observation goes beyond the usual treatment of E0 strengths, where two-state shape mixing cannot result in destructive interference.

Impact of dementia literacy interventions for non-health-professionals: systematic review and meta-analysis.

OBJECTIVES: To assess evidence regarding the effects of interventions aimed at improving dementia literacy for different groups of non-health-professionals. METHODS: A systematic search for relevant interventions was conducted using a range of online databases (e.g. CINAHL, Embase, Medline, ProQuest, and PsycINFO) and hand-searching of reference lists. Eligible interventions were identified based on predefined inclusion/exclusion criteria and methodological quality criteria. Meta analyses were performed using a random-effects model. RESULTS: The final review included 14 interventions, which were either randomised controlled trials or non-randomised controlled trials. The interventions had varied contents, approaches, settings, and outcome measures. Evidence of improved dementia literacy in various aspects was found, and the intervention effects were strongest on knowledge of dementia. DISCUSSION: There is evidence for the positive impact of dementia literacy interventions on different groups of non-health-professionals. Best practices in intervention contents, approaches, and outcome measures should be examined to guide future interventions.

Organisational survey for acute stroke care in Vietnam: Regional Collaboration Programme.

OBJECTIVES: Low-middle income countries, such as Vietnam have a greater burden from stroke than high-income countries. Few health professionals have stroke specialist training, and the quality of care may vary between hospitals. To support improvements to stroke care, we aimed to gain a better understanding of the resources available in hospitals in Vietnam to manage acute stroke. MATERIALS AND METHODS: The survey questions were adapted from the Australian Organisational Survey of Stroke Services (Stroke Foundation). The final 65 questions covered the topics: hospital size and admissions for stroke; use of clinical protocols and assessments conducted; team structure and coordination; communication and team roles. The survey was distributed electronically or via paper form in Vietnamese to clinical leaders of 91 eligible hospitals (November-December 2020). Data were summarised descriptively. RESULTS: Sixty-six (73%) hospitals responded, and doctors predominately completed the survey (98%). Approximately 70% of hospitals had a stroke unit; median 630 acute strokes/year (IQR: 250-1200) and >90% used stroke clinical protocols. The daytime nurse-patient ratio was 1:4. There was a perceived lack of access to allied health staff, including psychologists/neuropsychologists, occupational therapists, and speech pathologists. Only 50% reported having a standardised rehabilitation assessment process. CONCLUSIONS: This is the first large-scale cross-sectional, national overview of stroke services in Vietnam. Future research should include a systematic clinical audit of stroke care to confirm aspects of the data from these hospitals. Repeating the survey in future years will enable the tracking of progress and may influence capacity building for stroke care in Vietnam.

Case-Fatality and Functional Outcome after Subarachnoid Hemorrhage (SAH) in INternational STRoke oUtComes sTudy (INSTRUCT).

BACKGROUND: There are few large population-based studies of outcomes after subarachnoid hemorrhage (SAH) than other stroke types. METHODS: We pooled data from 13 population-based stroke incidence studies (10 studies from the INternational STRroke oUtComes sTudy (INSTRUCT) and 3 new studies; N=657). Primary outcomes were case-fatality and functional outcome (modified Rankin scale score 3-5 [poor] vs. 0-2 [good]). Harmonized patient-level factors included age, sex, health behaviours (e.g. current smoking at baseline), comorbidities (e.g.history of hypertension), baseline stroke severity (e.g. NIHSS >7) and year of stroke. We estimated predictors of case-fatality and functional outcome using Poisson regression and generalized estimating equations using log-binomial models respectively at multiple timepoints. RESULTS: Case-fatality rate was 33% at 1 month, 43% at 1 year, and 47% at 5 years. Poor functional outcome was present in 27% of survivors at 1 month and 15% at 1 year. In multivariable analysis, predictors of death at 1-month were age (per decade increase MRR 1.14 [1.07-1.22]) and SAH severity (MRR 1.87 [1.50-2.33]); at 1 year were age (MRR 1.53 [1.34-1.56]), current smoking (MRR 1.82 [1.20-2.72]) and SAH severity (MRR 3.00 [2.06-4.33]) and; at 5 years were age (MRR 1.63 [1.45-1.84]), current smoking (MRR 2.29 [1.54-3.46]) and severity of SAH (MRR 2.10 [1.44-3.05]). Predictors of poor functional outcome at 1 month were age (per decade increase RR 1.32 [1.11-1.56]) and SAH severity (RR 1.85 [1.06-3.23]), and SAH severity (RR 7.09 [3.17-15.85]) at 1 year. CONCLUSION: Although age is a non-modifiable risk factor for poor outcomes after SAH, however, severity of SAH and smoking are potential targets to improve the outcomes.

Utility of the Hospital Frailty Risk Score Derived From Administrative Data and the Association With Stroke Outcomes.

Background and Purpose: Conditions associated with frailty are common in people experiencing stroke and may explain differences in outcomes. We assessed associations between a published, generic frailty risk score, derived from administrative data, and patient outcomes following stroke/transient ischemic attack; and its accuracy for stroke in predicting mortality compared with other measures of clinical status using coded data. Methods: Patient-level data from the Australian Stroke Clinical Registry (2009­2013) were linked with hospital admissions data. We used International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes with a 5-year look-back period to calculate the Hospital Frailty Risk Score (termed Frailty Score hereafter) and summarized results into 4 groups: no-risk (0), low-risk (1­5), intermediate-risk (5­15), and high-risk (>15). Multilevel models, accounting for hospital clustering, were used to assess associations between the Frailty Score and outcomes, including mortality (Cox regression) and readmissions up to 90 days, prolonged acute length of stay (>20 days; logistic regression), and health-related quality of life at 90 to 180 days (quantile regression). The performance of the Frailty Score was then compared with the Charlson and Elixhauser Indices using multiple tests (eg, C statistics) for predicting 30-day mortality. Models were adjusted for covariates including sociodemographics and stroke-related factors. Results: Among 15 468 adult patients, 15% died ≤90 days. The frailty scores were 9% no risk; 23% low, 45% intermediate, and 22% high. A 1-point increase in frailty (continuous variable) was associated with greater length of stay (ORadjusted, 1.05 [95% CI, 1.04 to 1.06), 90-day mortality (HRadjusted, 1.04 [95% CI, 1.03 to 1.05]), readmissions (ORadjusted, 1.02 [95% CI, 1.02 to 1.03]; and worse health-related quality of life (median difference, −0.010 [95% CI −0.012 to −0.010]). Adjusting for the Frailty Score provided a slightly better explanation of 30-day mortality (eg, larger C statistics) compared with other indices. Conclusions: Greater frailty was associated with worse outcomes following stroke/transient ischemic attack. The Frailty Score provides equivalent precision compared with the Charlson and Elixhauser indices for assessing risk-adjusted outcomes following stroke/transient ischemic attack.

NEK5 activity regulates the mesenchymal and migratory phenotype in breast cancer cells.

PURPOSE: Breast cancer remains a prominent global disease affecting women worldwide despite the emergence of novel therapeutic regimens. Metastasis is responsible for most cancer-related deaths, and acquisition of a mesenchymal and migratory cancer cell phenotypes contributes to this devastating disease. The utilization of kinase targets in drug discovery have revolutionized the field of cancer research but despite impressive advancements in kinase-targeting drugs, a large portion of the human kinome remains understudied in cancer. NEK5, a member of the Never-in-mitosis kinase family, is an example of such an understudied kinase. Here, we characterized the function of NEK5 in breast cancer. METHODS: Stably overexpressing NEK5 cell lines (MCF7) and shRNA knockdown cell lines (MDA-MB-231, TU-BcX-4IC) were utilized. Cell morphology changes were evaluated using immunofluorescence and quantification of cytoskeletal components. Cell proliferation was assessed by Ki-67 staining and transwell migration assays tested cell migration capabilities. In vivo experiments with murine models were necessary to demonstrate NEK5 function in breast cancer tumor growth and metastasis. RESULTS: NEK5 activation altered breast cancer cell morphology and promoted cell migration independent of effects on cell proliferation. NEK5 overexpression or knockdown does not alter tumor growth kinetics but promotes or suppresses metastatic potential in a cell type-specific manner, respectively. CONCLUSION: While NEK5 activity modulated cytoskeletal changes and cell motility, NEK5 activity affected cell seeding capabilities but not metastatic colonization or proliferation in vivo. Here we characterized NEK5 function in breast cancer systems and we implicate NEK5 in regulating specific steps of metastatic progression.

Femtosecond damage experiments and modeling of broadband mid-infrared dielectric diffraction gratings.

High peak and average power lasers with high wall-plug efficiency, like the Big Aperture Thulium (BAT) laser, have garnered tremendous attention in laser technology. To meet the requirements of the BAT laser, we have developed low-dispersion reflection multilayer dielectric (MLD) gratings suitable for compression of high-energy pulses for operations at 2 micron wavelength. We carried out 10000-on-1 damage tests to investigate the fluence damage thresholds of the designed MLD gratings and mirrors, which were found between 100-230 mJ/cm2. An ultrashort pulsed laser (FWHM = 53 fs, λ = 1.9 µm) operating at 500 Hz was used in the serpentine raster scans. The atomic force microscope images of the damage sites show blister formation of the underlying layers at lower fluences but ablation of the grating pillars at higher fluences. We simulated the dynamic electronic excitation in the MLD optics with a finite-difference in the time domain approach in 2D. The simulation results agree well with the LIDT measurements and the observed blister formation. This model is able to evaluate the absolute LIDT of MLD gratings.

Direct radical functionalization methods to access substituted adamantanes and diamondoids.

Adamantane derivatives have diverse applications in the fields of medicinal chemistry, catalyst development and nanomaterials, owing to their unique structural, biological and stimulus-responsive properties, among others. The synthesis of substituted adamantanes and substituted higher diamondoids is frequently achieved via carbocation or radical intermediates that have unique stability and reactivity when compared to simple hydrocarbon derivatives. In this review, we discuss the wide range of radical-based functionalization reactions that directly convert diamondoid C-H bonds to C-C bonds, providing a variety of products incorporating diverse functional groups (alkenes, alkynes, arenes, carbonyl groups, etc.). Recent advances in the area of selective C-H functionalization are highlighted with an emphasis on the H-atom abstracting species and their ability to activate the particularly strong C-H bonds that are characteristic of these caged hydrocarbons, providing insights that can be applied to the C-H functionalization of other substrate classes.

Theoretical Investigation of the Mechanisms and Kinetics of the Bimolecular and Unimolecular Reactions Involving in the C4H6 Species.

A theoretical study of the mechanisms and kinetics for the C4H6 system was carried out using ab initio molecular orbital theory based on the CCSD(T)/CBS//B3LYP/6-311++G(3df,2p) method in conjunction with statistical theoretical variable reaction coordinate transition-state theory and RRKM/ME calculations. The calculated results indicate that buta-1,3-diene, but-1-yne, and C4H5 + H can be the major products of the C3 + C1 reaction, while CCH2 + C2H4 and C4H5 + H play an important role in the C2 + C2 reaction. In contrast, the C4H6 fragmentation giving rise to C3 + C1 and C4H5 + H becomes the key reaction paths under any temperature and pressure. The rate constants for the system have been calculated in the 300-2000 K temperature range at various pressures for which the C2 + C2 → C4H6 high-P limit rate constant, 10.24 × 1014T-0.51 cm3/mol/s, agrees well with the measured value of Hidaka et al., 9.64 × 1014T-0.5 cm3/mol/s. Also, the high-P limit rate constants of the channels but-2-yne → 2-C4H5 + H and C3 + C1 → C4H6, being 1.7 × 1014 exp(-351.5 kJ·mol-1/RT) s-1 and 5.07 × 1013 exp(0.694 kJ·mol-1/RT) cm3/mol/s, are in good agreement with the available literature data 5 × 1014 exp(-365.3 kJ·mol-1/RT) s-1 and 4.09 × 1013 exp(1.08 kJ·mol-1/RT) cm3/mol/s reported by Hidaka et al. and Knyazev and Slagle, respectively. Moreover, the 298 K/50 Torr branching ratios for the formation of buta-1,2-diene (0.43) and but-1-yne (0.57) as well as the total rate constant 5.18 × 1013 cm3/mol/s of the channels C3 + C1 → buta-1,2-diene and C3 + C1 → but-1-yne are in excellent accord with the laboratory values given by Fahr and Nayak, being 0.4, 0.6, and (9.03 ± 1.8) × 1013 cm3/mol/s, respectively. Last but not least, the rate constants and branching ratios for the C4H6 dissociation processes in the present study also agree closely with the theoretically and experimentally reported data.

Review on the Use of Artificial Intelligence to Predict Fire Performance of Construction Materials and Their Flame Retardancy.

The evaluation and interpretation of the behavior of construction materials under fire conditions have been complicated. Over the last few years, artificial intelligence (AI) has emerged as a reliable method to tackle this engineering problem. This review summarizes existing studies that applied AI to predict the fire performance of different construction materials (e.g., concrete, steel, timber, and composites). The prediction of the flame retardancy of some structural components such as beams, columns, slabs, and connections by utilizing AI-based models is also discussed. The end of this review offers insights on the advantages, existing challenges, and recommendations for the development of AI techniques used to evaluate the fire performance of construction materials and their flame retardancy. This review offers a comprehensive overview to researchers in the fields of fire engineering and material science, and it encourages them to explore and consider the use of AI in future research projects.

Predictors of Unlikely Bacterial Pneumonia and Adverse Pneumonia Outcome in Children Admitted to a Hospital in Central Vietnam.

BACKGROUND: Pneumonia is the leading cause of antibiotic use and hospitalization in Vietnam. There is a need for better prediction of unlikely bacterial pneumonia and adverse pneumonia outcome in order to guide hospital admission and improve rational antibiotic use. METHODS: All children under 5 admitted with pneumonia (per clinician assessment) to the Da Nang Hospital for Women and Children were prospectively enrolled. Children were classified as having likely or unlikely bacterial pneumonia and followed for outcome assessment. A Bayesian model averaging approach was used to identify predictors of unlikely bacterial pneumonia and adverse pneumonia outcome, which guided the development of a pragmatic management algorithm. RESULTS: Of 3817 patients assessed, 2199 (57.6%) met World Health Organization (WHO) pneumonia criteria. In total, 1594 (41.7%) children were classified as having unlikely and 129 (3.4%) as having likely bacterial pneumonia. The remainder (2399; 62.9%) were considered to have disease of uncertain etiology. Factors predictive of unlikely bacterial pneumonia were no fever, no consolidation on chest radiograph, and absolute neutrophil count <5 × 109/L at presentation, which had a negative predictive value (NPV) for likely bacterial pneumonia of 99.0%. Among those who met WHO pneumonia criteria, 8.6% (189/2199) experienced an adverse outcome. Not having any WHO danger sign or consolidation on chest radiograph had an NPV of 96.8% for adverse pneumonia outcome. CONCLUSIONS: An algorithm that screens for predictors of likely bacterial pneumonia and adverse pneumonia outcome could reduce unnecessary antibiotic use and hospital admission, but its clinical utility requires validation in a prospective study.

Sources of Multidrug Resistance in Patients With Previous Isoniazid-Resistant Tuberculosis Identified Using Whole Genome Sequencing: A Longitudinal Cohort Study.

BACKGROUND: Meta-analysis of patients with isoniazid-resistant tuberculosis (TB) given standard first-line anti-TB treatment indicated an increased risk of multidrug-resistant TB (MDR-TB) emerging (8%), compared to drug-sensitive TB (0.3%). Here we use whole genome sequencing (WGS) to investigate whether treatment of patients with preexisting isoniazid-resistant disease with first-line anti-TB therapy risks selecting for rifampicin resistance, and hence MDR-TB. METHODS: Patients with isoniazid-resistant pulmonary TB were recruited and followed up for 24 months. Drug susceptibility testing was performed by microscopic observation drug susceptibility assay, mycobacterial growth indicator tube, and by WGS on isolates at first presentation and in the case of re-presentation. Where MDR-TB was diagnosed, WGS was used to determine the genomic relatedness between initial and subsequent isolates. De novo emergence of MDR-TB was assumed where the genomic distance was 5 or fewer single-nucleotide polymorphisms (SNPs), whereas reinfection with a different MDR-TB strain was assumed where the distance was 10 or more SNPs. RESULTS: Two hundred thirty-nine patients with isoniazid-resistant pulmonary TB were recruited. Fourteen (14/239 [5.9%]) patients were diagnosed with a second episode of TB that was multidrug resistant. Six (6/239 [2.5%]) were identified as having evolved MDR-TB de novo and 6 as having been reinfected with a different strain. In 2 cases, the genomic distance was between 5 and 10 SNPs and therefore indeterminate. CONCLUSIONS: In isoniazid-resistant TB, de novo emergence and reinfection of MDR-TB strains equally contributed to MDR development. Early diagnosis and optimal treatment of isoniazid-resistant TB are urgently needed to avert the de novo emergence of MDR-TB during treatment.

Development of ligand-coated beads to measure macrophage antimicrobial activities.

BACKGROUND INFORMATION: After macrophage recognises and phagocytoses the microorganism, their phagosome undergoes a maturation process, which creates a hostile environment for the bacterium. The lumen is acidified, and proteolysis occurs to kill and degrade pathogen for further antigen presentation. It is important to understand the association between the macrophage intracellular activities and the outcome of infection. Different methods have been developed to measure the phagosome dynamics of macrophages, but there are still limitations. RESULTS: We used Mycobacterium tuberculosis (Mtb) antigens, the causative agent of tuberculosis (TB), as a model of infectious disease. Adopting a fluorescent bead-based assay, we developed beads coated with trehalose 6,6'dimycolate (TDM) from Mtb cell wall and ß-glucan from yeast cell wall to measure the macrophage phagosomal activities using a microplate reader. We examined the consistency of the assay using J774 cells and validated it using human monocyte-derived macrophages (hMDM) from healthy volunteers and TB patients. There was a decreased pH and increased proteolysis in the lumen of J774 cells after phagocytosing the ligand-coated beads. J774 macrophage showed no difference in the acidification and proteolysis in response to control IgG beads, TDM and ß-glucan beads. hMDM from healthy volunteers or TB patients showed heterogeneity in the intracellular activities when treated with ligand-coated beads. CONCLUSIONS AND SIGNIFICANCE: The beads coated with specific ligands from Mtb worked well in both macrophage cell line and human primary macrophages, which can be exploited to further study the phagosomal function of macrophage in TB. Our bead model can be applied to different ligands from other pathogens, which could extend the understanding of the associations between macrophage antimicrobial functions and outcomes of infectious diseases and the possible cellular mechanisms involved.

Combination Reactions of Propargyl Radical with Hydroxyl Radical and the Isomerization and Dissociation of trans-Propenal.

Ab initio investigation for the ground-electronic potential energy surface (PES) of the CH2CCH + OH combination and the trans-CH2CHCHO isomerization and decomposition has been performed at the UCCSD(T)/CBS(TQ5)//M06-2X/aug-cc-pVTZ level of theory. Thermal and microcanonical rate constants, as well as branching ratios in the 300-2000 K temperature range have been predicted based on optimized structures and vibrational frequencies of species involved using statistical theoretical VRC-TST and RRKM master equation computations. The calculated results are in good agreement with the prior reported data, particularly as an accurate scaling of the energy barriers was carried out. Based on the view of PES and kinetic-predicted values, the reaction paths leading to C2H2 + CO + H2, CH3CH + CO, C2H4 + CO, C2H3 + HCO, and C3H3O + H are the prevailing product channels for the C3H3 + OH bimolecular reaction under the considered 300-2000 K temperature range. Among those products, CH3CH + CO is the most dominant one in the low-temperature condition; however, C2H2 + CO + H2 becomes the most favorable product in the high-temperature region. Alternatively, the C3H4O dissociation processes leading to C2H2 + CO + H2, C2H3 + HCO, C2H4 + CO, and CH2C + CH2O constitute the major paths, in which, C2H2 + CO + H2 is the most critical one with the ∼62% and ∼59% branching ratios at E = 148 and 182 kcal/mol, respectively. The overall second-order rate constants of the bimolecular reaction C3H3 + OH → products obtained at the pressure 760 Torr (Ar) can be illustrated by the modified Arrhenius expression of k(T) = 1.36 × 10-13T1.26 exp[(-1.12 ± 0.43 kcal mol-1)/RT] and/or k(T) = 3.77 × 1017T-7.58 exp[(-18.82 ± 0.20 kcal mol-1)/RT] cm3 molecule-1 s-1, covering the temperature range of 300-1300 and/or 1300-2000 K, respectively. The total high-pressure limit rate constant for the C3H3 + OH → CH2CCHOH barrierless processes is in good agreement with the k(T) = 8.30 × 10-10 T-0.1 cm3 molecule-1 s-1 literature data. Moreover, microcanonical rate constants for the C3H4O isomerization and dissociation are in excellent accordance with the previously predicted values given by Chin and Lee. The present study supplies a thorough insight into the mechanisms and kinetics of the C3H3 + OH combination as well as the C3H4O multistep isomerization/dissociation pathways.