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PURPOSE: Many countries recommend human papillomavirus (HPV) vaccination in female adolescents at an age when other vaccines are routinely administered. This open, randomized, multicenter study (108464/NCT00426361) evaluated coadministration of HPV-16/18 AS04-adjuvanted vaccine with diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine (dTpa-IPV). METHODS: Healthy females aged 10-18 years were randomized to receive HPV vaccine at months 0, 1, and 6 (n = 248), HPV vaccine coadministered with dTpa-IPV at month 0 and HPV vaccine at months 1 and 6 (n = 255), or dTpa-IPV at month 0 followed by HPV vaccine at months 1, 2, and 7 (n = 248). Immunogenicity was evaluated at months 0, 1, and 7 or 8 (depending on group). Vaccine reactogenicity and safety were also assessed. RESULTS: Coadministered dTpa-IPV and HPV vaccine was noninferior to dTpa-IPV alone in terms of seroprotection against diphtheria (99.2% and 100%), tetanus (100% and 100%) and poliovirus types 1, 2, and 3 (> or = 99.6%), and geometric mean antibody concentrations (ELISA Units/mL) for pertussis toxoid (84 vs. 75), filamentous hemagglutinin (612 and 615) and pertactin (426 and 360) at month 1. Coadministered dTpa-IPV and HPV vaccine was noninferior to HPV vaccine alone in terms of seroconversion rates for HPV-16 (99.5% and 100%) and HPV-18 (99.5% and 100%) and geometric mean antibody titers (ELISA Units/mL) for HPV-16 (15,608 and 18,965) and HPV-18 (6,597 and 6,902) at month 7. Coadministration was generally well tolerated. The reactogenicity of dTpa-IPV and the first dose of HPV vaccine was similar. CONCLUSIONS: Results from this study support coadministration of the HPV-16/18 AS04-adjuvanted vaccine with dTpa-IPV vaccine in females aged 10-18 years. [ABSTRACT FROM AUTHOR]

Infected macrophages transition into aerobic glycolysis, a metabolic program crucial for control of bacterial infection. However, antimicrobial mechanisms supported by aerobic glycolysis are unclear. Methylglyoxal is a highly toxic aldehyde that modifies proteins and DNA and is produced as a side-product of glycolysis. Here we show that despite the toxicity of this aldehyde, infected macrophages generate high levels of methylglyoxal during aerobic glycolysis while downregulating the detoxification system. We use targeted mutations in mice to modulate methylglyoxal generation and show that reducing methylglyoxal production by the host promotes survival of Listeria monocytogenes and Mycobacterium tuberculosis , whereas increasing methylglyoxal levels improves control of bacterial infection. Furthermore, we show that bacteria that are unable to detoxify methylglyoxal are avirulent and experience up to 1000-fold greater genomic mutation frequency during infection. Taken together, these results suggest that methylglyoxal is an antimicrobial innate immune effector that defends the host against bacterial pathogens.

Terminal nucleotidyltransferases add nucleotides to the 3' end of RNA to modify their stability and function. In Caenorhabditis elegans, the terminal uridyltransferases/poly(U) polymerases PUP-1 (aka CID-1, CDE-1), PUP-2, and PUP-3 affect germline identity, survival, and development. Here, we identify small RNA (sRNA) and mRNA targets of these PUPs and of a fourth predicted poly(U) polymerase, F43E2.1/PUP-4. Using genetic and RNA sequencing approaches, we identify RNA targets of each PUP and the U-tail frequency and length of those targets. At the whole organism level, PUP-1 is responsible for most sRNA U-tailing, and other PUPs contribute to modifying discrete subsets of sRNAs. Moreover, the expression of PUP-2, PUP-3, and especially PUP-4 limits uridylation on some sRNAs. The relationship between uridylation status and sRNA abundance suggests that U-tailing can have a negative or positive effect on abundance depending on context. sRNAs modified by PUP activity primarily target mRNAs that are ubiquitously expressed or most highly expressed in the germline. mRNA data obtained with a Nanopore-based method reveal that the addition of U-tails to nonadenylated mRNA is substantially reduced in the absence of PUP-3. Overall, this work identifies PUP RNA targets, defines the effect of uridylation loss on RNA abundance, and reveals the complexity of PUP regulation in C. elegans development., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Purpose: Great travel distances and long travel times can be barriers to outpatient stroke rehabilitation services (OSR) receipt, but there is limited information on differences in proximity to specific OSR services between urban and potentially medically underserved rural areas. Accordingly, we compared travel distance and time to the nearest service for different OSR services between rural and urban counties in Tennessee., Methods: We conducted data scraping on Google Maps to locate Tennessee facilities offering any of the 13 American Heart Association recognized OSR services. We conducted manual validation by calling located facilities and visiting facility websites. We used the Wilcoxon rank sum test to examine if mean travel distance and time to a specific OSR service differed significantly between rural and urban counties., Results: All OSR services but audiology were available in Tennessee. In rural counties, social work had the highest median of mean travel distance (135.2 km), chaplaincy the highest median of mean travel time (113.5 min), and physical therapy the lowest distance (37.7 km) and time (36.3 min). Except for social work, rural counties had significantly higher travel distance and time than urban counties (P < .01) for all OSR services., Conclusions: Rural Tennessee counties had significantly higher travel distance and time for almost all OSR services compared to urban areas. These findings from a largely rural state with high stroke risk factor prevalence suggest that additional focus on establishing maximum travel limits for OSR are warranted to overcome transportation barriers to enhance post-stroke services access in similar areas., Competing Interests: All authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc.)

Background: The standard treatment for de novo metastatic hormone-sensitive prostate cancer (mHSPC) involves androgen deprivation therapy (ADT) combined with next-generation hormonal agents and/or docetaxel. While the standard dose (STD) of abiraterone is 1,000 mg administered while fasting, recent evidence suggests that a low dose (LOW) of 250 mg taken with a low-fat meal may achieve comparable pharmacokinetic outcomes., Objectives: This study aimed to evaluate the failure-free survival (FFS) and safety of LOW and STD in de novo high-risk mHSPC patients., Materials and Methods: We conducted a retrospective analysis of males with de novo high-risk mHSPC treated with ADT plus abiraterone (250 mg with a low-fat meal or 1000 mg fasting) at the Vietnam National Cancer Hospital from January 2019 to May 2024. The primary endpoint was FFS, assessed using Kaplan-Meier and multivariate Cox regression analyses., Results: The study included 183 patients, with 91 in the LOW group and 92 in the STD group. The rates of patients who achieved undetectable PSA (PSA < 0.2 ng/ml) were 52.7% in the LOW group and 47.8% in the STD group. The median time to undetectable PSA was 6.9 months in the LOW group and 6.4 months in the STD group. The median overall FFS was 28.1 months (95% CI: 21.1 to 35.0) in the LOW group and 25.4 months (95% CI: 15.5 to 35.3) in the STD group (P = .286). Multivariate analysis indicated that visceral metastases and detectable PSA (PSA ≥ 0.2 ng/ml) were significant negative predictors of FFS in both groups. The incidence of grade 3 and grade 4 adverse events was similar between the LOW group and the STD group., Conclusions: The LOW group and STD group showed effectiveness and safety in de novo high-risk mHSPC. The use of low-dose abiraterone in de novo mHSPC can significantly reduce treatment costs., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A stable aluminum tris(dithiolene) triradical ( 3 ) was experimentally realized through a low-temperature reaction of the sterically demanding lithium dithiolene radical ( 2 ) with aluminum iodide. Compound 3 was characterized by single-crystal X-ray diffraction, UV-vis and EPR spectroscopy, SQUID magnetometry, and theoretical computations. The quartet ground state of triradical 3 has been unambiguously confirmed by variable-temperature continuous wave EPR experiments and SQUID magnetometry. Both SQUID magnetometry and broken-symmetry DFT computations reveal a small doublet-quartet energy gap [Δ E DQ = 0.18 kcal mol -1 (SQUID); Δ E DQ = 0.14 kcal mol -1 (DFT)]. The pulsed EPR experiment (electron spin echo envelop modulation) provides further evidence for the interaction of these dithiolene-based radicals with the central aluminum nucleus of 3 .

While the dithiolene-based N-heterocyclic silane (4) reacts with two equivalents of BX 3 (X = Br, I) to give zwitterionic Lewis adducts 5 and 8, respectively, the parallel reaction of 4 with BCl 3 results in 10, a dithiolene-substituted N-heterocyclic silane, via the Si-S bond cleavage. Unlike 5, the labile 8 may be readily converted to 9 via BI 3 -mediated cleavage of the Si-N bond. The formation of 5 and 8 confirms that 4 uniquely possesses dual nucleophilic sites: (a) the terminal sulphur atom of the dithiolene moiety; and (b) the backbone carbon of the N-heterocyclic silane unit.

Polarons and spin-orbit (SO) coupling are distinct quantum effects that play a critical role in charge transport and spin-orbitronics. Polarons originate from strong electron-phonon interaction and are ubiquitous in polarizable materials featuring electron localization, in particular 3d transition metal oxides (TMOs). On the other hand, the relativistic coupling between the spin and orbital angular momentum is notable in lattices with heavy atoms and develops in 5d TMOs, where electrons are spatially delocalized. Here we combine ab initio calculations and magnetic measurements to show that these two seemingly mutually exclusive interactions are entangled in the electron-doped SO-coupled Mott insulator Ba 2 Na 1-x Ca x OsO 6 (0 < x < 1), unveiling the formation of spin-orbital bipolarons. Polaron charge trapping, favoured by the Jahn-Teller lattice activity, converts the Os 5d 1 spin-orbital J eff  = 3/2 levels, characteristic of the parent compound Ba 2 NaOsO 6 (BNOO), into a bipolaron 5d 2 J eff  = 2 manifold, leading to the coexistence of different J-effective states in a single-phase material. The gradual increase of bipolarons with increasing doping creates robust in-gap states that prevents the transition to a metal phase even at ultrahigh doping, thus preserving the Mott gap across the entire doping range from d 1 BNOO to d 2 Ba 2 CaOsO 6 (BCOO)., (© 2024. The Author(s).)

Background: While over half of US stroke patients were discharged to home, estimates of geographic access to outpatient stroke rehab facilities are unavailable. The objective of our study was to assess distance and travel time to the nearest outpatient stroke rehab facility in Tennessee, a high stroke prevalence state., Methods: We systematically scraped Google Maps with the terms "stroke", "rehabilitation", and "outpatient" to identify Tennessee stroke rehab facilities. We then averaged/aggregated Census block-level travel distance and travel time to determine the mean travel distance/time to a facility for each of the 95 Tennessee counties and the overall state. Comparisons of mean travel time/distance were made between rural and urban counties and between low, medium, and high stroke prevalence counties., Results: We found that 79% of facilities were in urban areas. Significantly higher median of mean travel times and distances (p values both <0.001) were observed in rural (22.0 miles, 31.6 min) versus urban counties (10.5 miles, 18.4 min). High (21.5 miles, 32.5 min) and medium (18.7 miles, 28.3 minutes) stroke prevalence counties, which often overlap with rural counties, had significantly higher median of mean travel times and distance than low stroke prevalence counties (7.3 miles, 14.5 min)., Conclusions: Rural Tennessee counties were faced with high stroke prevalence, inadequate facilities, and significantly greater travel distance and time to access care. Additional efforts to address transportation barriers and accelerate telerehabilitation implementation are crucial for improving equal access to stroke aftercare in these areas., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: William T. Harris II owns stock in Eli Lilly and Company. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Insufficient data exists regarding the relationship between body mass index (BMI) and the prognosis of chronic heart failure (CHF) specifically within low- and middle-income Asian countries. The objective of this study was to evaluate the impact of BMI on adverse outcomes of ambulatory patients with CHF in Vietnam., Methods: Between 2018 and 2020, we prospectively enrolled consecutive outpatients with clinically stable CHF in an observational cohort, single-center study. The participants were stratified according to Asian-specific BMI thresholds. The relationships between BMI and adverse outcomes (all-cause death and all-cause hospitalization) were analyzed by Kaplan-Meier survival curves and Cox proportional-hazards model., Results: Among 320 participants (age 63.5 ± 13.3 years, 57.9% male), the median BMI was 21.4 kg/m 2 (IQR 19.5-23.6), and 10.9% were underweight (BMI <18.50 kg/m 2 ). Over a median follow-up time of 32 months, the cumulative incidence of all-cause mortality and hospitalization were 5.6% and 19.1%, respectively. After multivariable adjustment, underweight patients had a significantly higher risk of all-cause mortality than patients with normal BMI (adjusted hazard ratios = 3.03 [95% CI: 1.07-8.55]). Lower BMI remained significantly associated with a worse prognosis when analyzed as a continuous variable (adjusted hazard ratios = 1.27 [95% CI: 1.03-1.55] per 1 kg/m 2 decrease for all-cause mortality). However, BMI was not found to be significantly associated with the risk of all-cause hospitalization ( p  > 0.05)., Conclusion: In ambulatory patients with CHF in Vietnam, lower BMI, especially underweight status (BMI < 18.5 kg/m 2 ), was associated with a higher risk of all-cause mortality. These findings suggest that BMI should be considered for use in risk classification, and underweight patients should be managed by a team consisting of cardiologists, nutritionists, and geriatricians., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nguyen, Ha, Tran, Nguyen, Pham, Tran, Pham, Allison, Reid and Kirkpatrick.)

The 1 : 2 reaction of the imidazole-based dithiolate (2) with GeCl 2  • dioxane in THF/TMEDA gives 3, a TMEDA-complexed dithiolene-based germylene. Compound 3 is converted to monothiolate-complexed (5) and N-heterocyclic carbene-complexed (7) germanium(II) dithiolene complexes via Lewis base ligand exchange. A bis-dithiolene-based germylene (8), involving a 3c-4e S-Ge-S bond, has also been synthesized through controlled hydrolysis of 7. The bonding nature of 3, 5, and 8 was investigated by both experimental and theoretical methods., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The 1:1 reaction of the carbene-stabilized dithiolene zwitterion 1 with BH 3 ·SMe 2 gave the dithiolene-based hydroborane 2 and the doubly hydrogen-capped CAAC species 3 via hydride-coupled reverse electron transfer processes. The mechanism of this transformation was probed computationally using density functional theory. The subsequent 2:1 reaction of 2 with 1 resulted in 4 and 3 , suggesting that 1 can mediate the B-H bond activation not only for BH 3 but also for monohydroboranes. In the presence of BH 3 ·SMe 2 , 2 was unexpectedly converted to the corresponding diborane(4) complex 5 through a dehydrocoupling reaction at an elevated temperature., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: Long-term exposure to air pollutants is associated with increased stroke incidence, morbidity, and mortality; however, research on the association of pollutant exposure with poststroke hospital readmissions is lacking., Methods: We assessed associations between average annual carbon monoxide (CO), nitrogen dioxide (NO 2 ), ozone (O 3 ), particulate matter 2.5, and sulfur dioxide (SO 2 ) exposure and 30-day all-cause hospital readmission in US fee-for-service Medicare beneficiaries age ≥65 years hospitalized for ischemic stroke in 2014 to 2015. We fit Cox models to assess 30-day readmissions as a function of these pollutants, adjusted for patient and hospital characteristics and ambient temperature. Analyses were then stratified by treating hospital performance on the Centers for Medicare and Medicaid Services risk-standardized 30-day poststroke all-cause readmission measure to determine if the results were independent of performance: low (Centers for Medicare and Medicaid Services rate for hospital <25th percentile of national rate), high (>75th percentile), and intermediate (all others)., Results: Of 448 148 patients with stroke, 12.5% were readmitted within 30 days. Except for tropospheric NO 2 (no national standard), average 2-year CO, O 3 , particulate matter 2.5, and SO 2 values were below national limits. Each one SD increase in average annual CO, NO 2 , particulate matter 2.5, and SO 2 exposure was associated with an adjusted 1.1% (95% CI, 0.4-1.9%), 3.6% (95% CI, 2.9%-4.4%), 1.2% (95% CI, 0.2%-2.3%), and 2.0% (95% CI, 1.1%-3.0%) increased risk of 30-day readmission, respectively, and O 3 with a 0.7% (95% CI, 0.0%-1.5%) decrease. Associations between long-term air pollutant exposure and increased readmissions persisted across hospital performance categories., Conclusions: Long-term air pollutant exposure below national limits was associated with increased 30-day readmissions after stroke, regardless of hospital performance category. Whether air quality improvements lead to reductions in poststroke readmissions requires further research.

Aims: Little is known about the relationship between marital/partner status and patient-reported outcome measures (PROMs) following myocardial infarction (MI). We conducted a systematic review/meta-analysis and explored potential sex differences., Methods and Results: We searched five databases (Medline, Web of Science, Scopus, EMBASE, and PsycINFO) from inception to 27 July 2022. Peer-reviewed studies of MI patients that evaluated marital/partner status as an independent variable and reported its associations with defined PROMs were eligible for inclusion. Results for eligible studies were classified into four pre-specified outcome domains [health-related quality of life (HRQoL), functional status, symptoms, and personal recovery (i.e. self-efficacy, adherence, and purpose/hope)]. Study quality was appraised using Newcastle-Ottawa Scale, and data were synthesized by outcome domains. We conducted subgroup analysis by sex. We included 34 studies ( n = 16 712), of which 11 were included in meta-analyses. Being married/partnered was significantly associated with higher HRQoL {six studies [ n = 2734]; pooled standardized mean difference, 0.37 [95% confidence interval (CI), 0.12-0.63], I 2 = 51%} but not depression [three studies ( n = 2005); pooled odds ratio, 0.72 (95% CI, 0.32-1.64); I 2 = 65%] or self-efficacy [two studies ( n = 356); pooled β , 0.03 (95% CI, -0.09 to 0.14); I 2 = 0%]. The associations of marital/partner status with functional status, personal recovery outcomes, and symptoms of anxiety and fatigue were mixed. Sex differences were not evident due to mixed results from the available studies., Conclusions: Married/partnered MI patients had higher HRQoL than unpartnered patients, but the associations with functional, symptom, and personal recovery outcomes and sex differences were less clear. Our findings inform better methodological approaches and standardized reporting to facilitate future research on these relationships., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Marital/Partner support is associated with lower mortality and morbidity following acute myocardial infarction (AMI) and stroke. Despite an increasing focus on the effect of patient-centered factors on health outcomes, little is known about the impact of marital/partner status on patient-reported outcome measures (PROMs)., Objective: To synthesize evidence of the association between marital/partner status and PROMs after AMI and stroke and to determine whether associations differ by sex., Methods and Analysis: We will search MEDLINE (via Ovid), Web of Science Core Collection (as licensed by Yale University), Scopus, EMBASE (via Ovid), and PsycINFO (via Ovid) from inception to July 15, 2022. Two authors will independently screen titles, abstracts, and then full texts as appropriate, extract data, and assess risk of bias. Conflicts will be resolved by discussion with a third reviewer. The primary outcomes will be the associations between marital/partner status and PROMs. An outcome framework was designed to classify PROMs into four domains (health-related quality of life, functional status, symptoms, and personal recovery). Meta-analysis will be conducted if appropriate. Subgroup analysis by sex and meta-regression with a covariate for the proportion of male participants will be performed to explore differences by sex., Ethics and Dissemination: This research is exempt from ethics approval because the study will be conducted using published data. We will disseminate the results of the analysis in a related peer-reviewed journal., Trial Registration: PROSPERO registration number: CRD42022295975., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A carbene-stabilized dithiolene zwitterion ( 3 ) activates ammonia, affording 4 • and 5 , through both single-electron transfer (SET) and hydrogen atom transfer (HAT). Reaction products were characterized spectroscopically and by single-crystal X-ray diffraction. The mechanism of the formation of 4 • and 5 was probed by experimental and computational methods. This discovery is the first example of metal-free ammonia activation via HAT.

Background Relatively greater increases in hypertension prevalence among US rural residents may contribute to geographic disparities in recurrent stroke. There is limited US information on poststroke antihypertensive medication use by rural/urban residence. We assessed antihypertensive use and lifestyle characteristics for US rural compared with urban stroke survivors and residence-based trends in use between 2005 and 2019. Methods and Results US stroke survivors with hypertension were identified in the 2005 to 2019 national Behavioral Risk Factor Surveillance System surveys. We ascertained the survey-weighted prevalence of reported antihypertensive use and lifestyle characteristics (ie, physical activity, diabetes, cholesterol, body mass index, and smoking) among respondents with hypertension in odd years over this period by rural/urban residence. Separate trend analyses were used to detect changes in use over time. Survey-weighted logistic regression was used to calculate unadjusted and adjusted (sociodemographic and lifestyle factors) odds ratios for antihypertensive use by year. Our study included 82 175 individuals (36.4% rural residents). Lifestyle characteristics were similar between rural and urban residents except for higher smoking prevalence among rural residents. Antihypertensive use was similar between rural and urban stroke survivors in unadjusted and adjusted analyses (>90% in both populations). Trend analyses showed a small but significant increase in antihypertensive use over time among urban ( P =0.033) but not rural stroke survivors ( P =0.587). Conclusions Our findings indicate that poststroke antihypertensive use is comparable in rural and urban residents with a reported history of hypertension, but additional work is merited to identify reasons for a trend for increased use of these drugs among urban residents.

Background: Nanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminium hydroxide adjuvant., Methods: We conducted a dose-escalation, open label trial (phase 1) and a randomized, double-blind, placebo-controlled trial (phase 2) to evaluate the safety and immunogenicity of the Nanocovax vaccine (in 25 mcg, 50 mcg, and 75 mcg doses, aluminium hydroxide adjuvanted (0·5 mg/dose) in 2-dose regime, 28 days apart (ClinicalTrials.gov number, NCT04683484). In phase 1, 60 participants received two intramuscular injection of the vaccine following dose-escalation procedure. The primary outcomes were reactogenicity and laboratory tests to evaluate the vaccine safety. In phase 2, 560 healthy adults received either vaccine doses similar in phase 1 (25 or 50 or 75 mcg S antigen in 0·5 mg aluminium per dose) or adjuvant (0·5 mg aluminium) in a ratio of 2:2:2:1. One primary outcome was the vaccine safety, including solicited adverse events for 7 day and unsolicited adverse events for 28 days after each injection as well as serious adverse event or adverse events of special interest throughout the study period. Another primary outcome was anti-S IgG antibody response (Index unit/ml). Secondary outcomes were surrogate virus neutralisation (inhibition percentage), wild-type SARS-CoV-2 neutralisation (dilution fold), and T-cell responses by intracellular staining for interferon gamma (IFNg). Anti-S IgG and neutralising antibody levels were compared with convalescent serum samples from symptomatic Covid-19 patients., Findings: For phase 1 study, no serious adverse events were observed for all 60 participants. Most adverse events were grade 1 and disappeared shortly after injection. For phase 2 study, after randomisation, 480 participants were assigned to receive the vaccine with adjuvant, and 80 participants were assigned to receive the placebo (adjuvant only). Reactogenicity was absent or mild in the majority of participants and of short duration (mean ≤3 days). Unsolicited adverse events were mild in most participants. There were no serious adverse events related to Nanocovax. Regarding the immunogenicity, Nanocovax induced robust anti-S antibody responses. In general, there humoral responses were similar among vaccine groups which reached their peaks at day 42 and declined afterward. At day 42, IgG levels of vaccine groups were 60·48 [CI95%: 51·12-71·55], 49·11 [41·26-58·46], 57·18 [48·4-67·5] compared to 7·10 [6·32-13·92] of convalescent samples. IgG levels reported here can be converted to WHO international standard binding antibody unit (BAU/ml) by multiplying them to a conversion factor of 21·8. Neutralising antibody titre of vaccine groups at day 42 were 89·2 [52·2-152·3], 80·0 [50·8-125.9] and 95·1 [63·1-143·6], compared to 55·1 [33·4-91·0] of the convalescent group., Interpretation: Up to day 90, Nanocovax was found to be safe, well tolerated, and induced robust immune responses., Funding: This work was funded by the Coalition for Epidemic Preparedness Innovations (CEPI), the Ministry of Science and Technology of Vietnam, and Nanogen Pharmaceutical Biotechnology JSC., Competing Interests: TPN, HK, TML, TTNT, TTD, TVV, TTTV, QBPN, VTP, VTT, MTNT, TTTN, PTH, HTH, KDN, CCD, TTU, SMD are employees of Nanogen Pharmaceutical Biotechnology JSC. MTNT, and SMD are authors of a pending patent for Nanocovax., (© 2022 The Author(s).)

The superantigen staphylococcal enterotoxin C (SEC) is critical for Staphylococcus aureus infective endocarditis (SAIE) in rabbits. Superantigenicity, its hallmark function, was proposed to be a major underlying mechanism driving SAIE but was not directly tested. With the use of S. aureus MW2 expressing SEC toxoids, we show that superantigenicity does not sufficiently account for vegetation growth, myocardial inflammation, and acute kidney injury in the rabbit model of native valve SAIE. These results highlight the critical contribution of an alternative function of superantigens to SAIE. In support of this, we provide evidence that SEC exerts antiangiogenic effects by inhibiting branching microvessel formation in an ex vivo rabbit aortic ring model and by inhibiting endothelial cell expression of one of the most potent mediators of angiogenesis, VEGF-A. SEC's ability to interfere with tissue revascularization and remodeling after injury serves as a mechanism to promote SAIE and its life-threatening systemic pathologies.

Staphylococcus aureus causes severe, life-threatening infections that often are complicated by severe local and systemic pathologies with non-healing lesions. A classic example is S. aureus infective endocarditis (IE), where the secreted hemolysin β-toxin potentiates the disease via its sphingomyelinase and biofilm ligase activities. Although these activities dysregulate human aortic endothelial cell activation, β-toxin effect on endothelial cell function in wound healing has not been addressed. With the use of the ex vivo rabbit aortic ring model, we provide evidence that β-toxin prevents branching microvessel formation, highlighting its ability to interfere with tissue re-vascularization and vascular repair. We show that β-toxin specifically targets both human aortic endothelial cell proliferation and cell migration and inhibits human umbilical vein endothelial cell rearrangement into capillary-like networks in vitro . Proteome arrays specific for angiogenesis-related molecules provided evidence that β-toxin promotes an inhibitory profile in endothelial cell monolayers, specifically targeting production of TIMP-1, TIMP-4, and IGFBP-3 to counter the effect of a pro-angiogenic environment. Dysregulation in the production of these molecules is known to result in sprouting defects (including deficient cell proliferation, migration, and survival), vessel instability and/or vascular regression. When endothelial cells are grown under re-endothelialization/wound healing conditions, β-toxin decreases the pro-angiogenic molecule MMP-8 and increases the anti-angiogenic molecule endostatin. Altogether, the data indicate that β-toxin is an anti-angiogenic virulence factor and highlight a mechanism where β-toxin exacerbates S. aureus invasive infections by interfering with tissue re-vascularization and vascular repair., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tran, Tang and Salgado-Pabón.)

Multiple cross-sectional and longitudinal studies have shown that serum levels of the chemokine ligand 2 (CCL-2) are associated with type 1 diabetes (T1D), although the direction of effect differs. We assessed CCL-2 serum levels in a longitudinal cohort to clarify this association, combined with genetic data to elucidate the regulatory role of CCL-2 in T1D pathogenesis. The Diabetes Autoimmunity Study in the Young (DAISY) followed 310 subjects with high risk of developing T1D. Of these, 42 became persistently seropositive for islet autoantibodies but did not develop T1D (non-progressors); 48 did develop T1D (progressors). CCL-2 serum levels among the three study groups were compared using linear mixed models adjusting for age, sex, HLA genotype, and family history of T1D. Summary statistics were obtained from the CCL-2 protein quantitative trait loci (pQTL) and CCR2 expression QTL (eQTL) studies. The T1D fine mapping association data were provided by the Type 1 Diabetes Genetics Consortium (T1DGC). Serum CCL-2 levels were significantly lower in both progressors (p = 0.004) and non-progressors (p = 0.005), compared to controls. Two SNPs (rs1799988 and rs746492) in the 3p21.31 genetic locus, which includes the CCL-2 receptor, CCR2 , were associated with increased CCR2 expression (p = 8.2e-5 and 5.2e-5, respectively), decreased CCL-2 serum level (p = 2.41e-9 and 6.21e-9, respectively), and increased risk of T1D (p = 7.9e-5 and 7.9e-5, respectively). The 3p21.31 genetic region is associated with developing T1D through regulatory control of the CCR2/CCL2 immune pathway., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

A series of reactions between Lewis bases and an imidazole-based dithione dimer (1) has been investigated. Both cyclic(alkyl)(amino)carbene (CAAC) (2) and N-heterocyclic carbene (NHC) (4), in addition to N-heterocyclic silylene (NHSi) (6), demonstrate the capability to cleave the sulphur-sulphur bonds in 1, giving carbene-stabilized dithiolene (L 0 ) zwitterions (3 and 5) and a spirocyclic silicon-dithiolene compound (7), respectively. The bonding nature of 3, 5, and 7 are probed by both experimental and theoretical methods., (© 2021 Wiley-VCH GmbH.)

Glycerol monolaurate (GML), a naturally occurring monoglyceride, is widely used commercially for its antimicrobial properties. Interestingly, several studies have shown that GML not only has antimicrobial properties but is also an anti-inflammatory agent. GML inhibits peripheral blood mononuclear cell proliferation and inhibits T cell receptor (TCR)-induced signaling events. In this study, we perform an extensive structure activity relationship analysis to investigate the structural components of GML necessary for its suppression of human T cell activation. Human T cells were treated with analogs of GML, differing in acyl chain length, head group, linkage of acyl chain, and number of laurate groups. Treated cells were then tested for changes in membrane dynamics, LAT clustering, calcium signaling, and cytokine production. We found that an acyl chain with 12-14 carbons, a polar head group, an ester linkage, and a single laurate group at any position are all necessary for GML to inhibit protein clustering, calcium signaling, and cytokine production. Removing the glycerol head group or replacing the ester linkage with a nitrogen prevented derivative-mediated inhibition of protein cluster formation and calcium signaling, while still inhibiting TCR-induced cytokine production. These findings expand our current understanding of the mechanisms of action of GML and the of GML needed to function as a novel immunosuppressant.

The first Sustainable Development Goals (SDGs) of The United Nations aims to "end poverty in all its forms everywhere". Its seven associated targets aim, among others, to eradicate extreme poverty for all people everywhere. In Vietnam, poverty eradication in ethnic minorities and mountainous areas are among the top priorities. This study aims to learn about farmers' livelihoods associated with perceived difficulties in Chau Thai Commune, Nghe An Province, a rural mountainous area in Vietnam. A random sampling technique and a face-to-face interview method were employed to conduct a field survey in the region in 2018. The dataset collected from 215 households shows that Chau Thai Commune's livelihood largely depends on agriculture and forestry. Plantation forest and livestock are major sources of farmers' income while forestland accounts for over 90% of households' land. Besides, the disparity in livelihood in areas such as forestland, labor and income between the poor and non-poor households is reported. This primary data could be useful for scholars who want to conduct a further in-depth study and or experts, policymakers who work in Vietnam's 'New Rural Development' program to devise a better rural livelihood -improvement policy for farmers, particularly the poor in the uplands of Vietnam and beyond., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (© 2021 The Author(s).)

While the 1 : 1 reaction of 3 with an N-heterocyclic carbene ({(Me)CN(i-Pr)}2C:) in THF resulted in ligand-substituted product 4, the corresponding 1 : 2 reaction (in the presence of H2O) gives the first structurally characterized germanium tris(dithiolene)dianion 5 as the major product and the "naked" dithiolene radical 6˙ as a minor by-product. The structure and bonding of 4 and 5 were probed by experimental and theoretical methods. Our study suggests that carbene-mediated partial hydrolysis may represent a new method to access tris(dithiolene) complexes of main-group elements.

Active surveillance for zoonotic respiratory viruses is essential to inform the development of appropriate interventions and outbreak responses. Here we target individuals with a high frequency of animal exposure in Vietnam. Three-year community-based surveillance was conducted in Vietnam during 2013-2016. We enrolled a total of 581 individuals (animal-raising farmers, slaughterers, animal-health workers, and rat traders), and utilized reverse transcription-polymerase chain reaction to detect 15 common respiratory viruses in pooled nasal-throat swabs collected at baseline or acute respiratory disease episodes. A respiratory virus was detected in 7.9% (58 of 732) of baseline samples, and 17.7% (136 of 770) of disease episode samples (P < .001), with enteroviruses (EVs), rhinoviruses and influenza A virus being the predominant viruses detected. There were temporal and spatial fluctuations in the frequencies of the detected viruses over the study period, for example, EVs and influenza A viruses were more often detected during rainy seasons. We reported the detection of common respiratory viruses in individuals with a high frequency of animal exposure in Vietnam, an emerging infectious disease hotspot. The results show the value of baseline/control sampling in delineating the causative relationships and have revealed important insights into the ecological aspects of EVs, rhinoviruses and influenza A and their contributions to the burden posed by respiratory infections in Vietnam., (© 2019 Oxford University Clinical Research Unit. Journal of Medical Virology published by Wiley Periodicals, Inc.)

We present a combined experimental and computational study of the effect of charge doping in the osmium based double perovskite Ba 2 Na 1- x Ca x OsO 6 for 0 ≤ x ≤ 1 in order to provide a structural and electronic basis for understanding this complex Dirac-Mott insulator material. Specifically, we investigate the effects of the substitution of monovalent Na with divalent Ca, a form of charge doping or alloying that nominally tunes the system from Os 7+ with a 5d 1 configuration to Os 6+ with 5d 2 configuration. After an X-ray diffraction characterization, the local atomic and electronic structure has been experimentally probed by X-ray absorption fine structure at all the cation absorption edges at room temperature; the simulations have been performed using ab initio density functional methods. We find that the substitution of Na by Ca induces a linear volume expansion of the crystal structure which indicates an effective alloying due to the substitution process in the whole doping range. The local structure corresponds to the expected double perovskite one with rock-salt arrangement of Na/Ca in the B site and Os in the B' one for all the compositions. X-ray absorption near edge structure measurements show a smooth decrease of the oxidation state of Os from 7+ (5d 1 ) to 6+ (5d 2 ) with increasing Ca concentration, while the oxidation states of Ba, Na, and Ca are constant. This indicates that the substitution of Na by Ca gives rise to an effective electron transfer from the B to the B' site. The comparison between X-ray absorption measurements and ab initio simulations reveals that the expansion of the Os-O bond length induces a reduction of the crystal field splitting of unoccupied Os derived d states., Competing Interests: The authors declare no competing financial interest.

Staphylococcus aureus infections can lead to diseases that range from localized skin abscess to life-threatening toxic shock syndrome. The SrrAB two-component system (TCS) is a global regulator of S. aureus virulence and critical for survival under environmental conditions such as hypoxic, oxidative, and nitrosative stress found at sites of infection. Despite the critical role of SrrAB in S. aureus pathogenicity, the mechanism by which the SrrAB TCS senses and responds to these environmental signals remains unknown. Bioinformatics analysis showed that the SrrB histidine kinase contains several domains, including an extracellular Cache domain and a cytoplasmic HAMP-PAS-DHp-CA region. Here, we show that the PAS domain regulates both kinase and phosphatase enzyme activity of SrrB and present the structure of the DHp-CA catalytic core. Importantly, this structure shows a unique intramolecular cysteine disulfide bond in the ATP-binding domain that significantly affects autophosphorylation kinetics. In vitro data show that the redox state of the disulfide bond affects S. aureus biofilm formation and toxic shock syndrome toxin-1 production. Moreover, with the use of the rabbit infective endocarditis model, we demonstrate that the disulfide bond is a critical regulatory element of SrrB function during S. aureus infection. Our data support a model whereby the disulfide bond and PAS domain of SrrB sense and respond to the cellular redox environment to regulate S. aureus survival and pathogenesis., Competing Interests: The authors declare no competing interest.

Survival for patients with newly diagnosed cervical cancer has not significantly improved over the past several decades. We sought to identify a clinically relevant set of prognostic genes for squamous cell carcinoma of the cervix (SCCC), the most common cervical cancer subtype. Using RNA-sequencing data and survival data from 203 patients in The Cancer Genome Atlas (TCGA), we conducted a series of analyses using different decile cutoffs for gene expression to identify genes that could indicate large and consistent survival differences across different decile cutoffs of gene expression. Those analyses identified 42 high-risk genes. A patient's survivability could be estimated by simply counting the number of high-risk genes with extremely high expression (above the 90 th percentile) or estimating a transcriptomic risk score (TRS) using a machine learning algorithm with 9 of the 42 genes. On multivariate analysis, the significant predictors of mortality included high TRS (HR = 44.8), stage IV (HR = 28.1), intermediate TRS (HR = 4.75), and positive lymph node status (HR = 2.92). Approximately 18% of earlier-stage patients were identified as a poor-prognosis subgroup with high TRS. In patients with SCCC, transcriptomic risk appears to better predict survival than clinical prognostic factors, including stage., Competing Interests: None., (AJCR Copyright © 2020.)

Streptococcus sanguinis ( S. sanguinis ) is an abundant oral commensal which can cause disseminated human infection if it gains access to the bloodstream. The most important among these diseases is infective endocarditis (IE). While virulence phenotypes of S. sanguinis have been correlated to disease severity, genetic factors mediating these phenotypes, and contributing to pathogenesis are largely uncharacterized. In this report, we investigate the roles of 128 genes in virulence-related phenotypes of S. sanguinis and characterize the pathogenic potential of two selected mutants in a left-sided, native valve IE rabbit model. Assays determining the ability of our mutant strains to produce a biofilm, bind to and aggregate platelets, and adhere to or invade endothelial cells identified sixteen genes with novel association to these phenotypes. These results suggest the presence of many uncharacterized genes involved in IE pathogenesis which may be relevant for disease progression. Two mutants identified by the above screening process - SSA&#95;1099 , encoding an RTX-like protein, and mur2 , encoding a peptidoglycan hydrolase - were subsequently evaluated in vivo . Wild type (WT) S. sanguinis reliably induced cardiac vegetations, while the SSA&#95;1099 and mur2 mutants produced either no vegetation or vegetations of small size. Splenomegaly was reduced in both mutant strains compared to WT, while pathology of other distal organs was indistinguishable. Histopathology analyses suggest the cardiac lesions and vegetations in this model resemble those observed in humans. These data indicate that SSA&#95;1099 and mur2 encode virulence factors in S. sanguinis which are integral to pathogenesis of IE., (Copyright © 2020 Martini, Moricz, Ripperger, Tran, Sharp, Forsythe, Kulhankova, Salgado-Pabón and Jones.)

Phage regulatory switches (phage-RSs) are a newly described form of active lysogeny where prophages function as regulatory mechanisms for expression of chromosomal bacterial genes. In Staphylococcus aureus , ϕSa3int is a widely distributed family of prophages that integrate into the β-toxin structural gene hlb , effectively inactivating it. However, β-toxin-producing strains often arise during infections and are more virulent in experimental infective endocarditis and pneumonia infections. We present evidence that in S. aureus MW2, ϕSa3mw excision is temporally and differentially responsive to growth conditions relevant to S. aureus pathogenesis. PCR analyses of ϕSa3mw (integrated and excised) and of intact hlb showed that ϕSa3mw preferentially excises in response to hydrogen peroxide-induced oxidative stress and during biofilm growth. ϕSa3mw remains as a prophage when in contact with human aortic endothelial cells in culture. A criterion for a prophage to be considered a phage-RS is the inability to lyse host cells. MW2 grown under phage-inducing conditions did not release infectious phage particles by plaque assay or transmission electron microscopy, indicating that ϕSa3mw does not carry out a productive lytic cycle. These studies highlight a dynamic, and perhaps more sophisticated, S. aureus -prophage interaction where ϕSa3int prophages provide a novel regulatory mechanism for the conditional expression of virulence factors. IMPORTANCE β-Toxin is a sphingomyelinase hemolysin that significantly contributes to Staphylococcus aureus pathogenesis. In most S. aureus isolates the prophage ϕSa3int inserts into the β-toxin gene hlb , inactivating it, but human and experimental infections give rise to β-toxin-producing variants. However, it remained to be established whether ϕSa3mw excises in response to specific environmental cues, restoring the β-toxin gene sequence. This is not only of fundamental interest but also critical when designing intervention strategies and therapeutics. We provide evidence that ϕSa3mw actively excises, allowing the conditional expression of β-toxin. ϕSa3int prophages may play a novel and largely uncharacterized role in S. aureus pathogenesis as molecular regulatory switches that promote bacterial fitness and adaptation to the challenges presented by the mammalian host., (Copyright © 2019 Tran et al.)

A fast-growing, non-chromogenic, acid-fast-staining bacterium (DL90 T ) was isolated from a peat bog in northern Minnesota. On the basis of 16S rRNA gene sequence similarity (99.8 % identity with Mycolicibacterium septicum and 98 % with Mycolicibacterium peregrinum ) and chemotaxonomic data (fatty acid content), strain DL90 T represents a member of the genus Mycolicibacterium . Physiological tests (growth curves, biofilm formation, antibiotic sensitivity, colony morphologies and heat tolerance) and biochemical analysis (arylsulfatase activity and fatty acid profiles) distinguish DL90 T from its closest relative M. septicum . Phylogenomic reconstruction of the ' Fortuitium-Vaccae ' clade, digital DNA-DNA hybridization (DDH) values of 61 %, and average nucleotide identity (ANI) values of approximately 95 % indicate that DL90 T is likely to be diverged from M. septicum . Thus, we propose that DL90 T represents a novel species, given the name Mycolicibacterium nivoides with the type strain being isolate DL90 T (=JCM 32796 T =NCCB 100660 T ).

Clostridioides (formerly Clostridium) difficile produces two major toxins, TcdA and TcdB, upon entry into stationary phase. Transcription of tcdA and tcdB requires the specialized sigma factor, σ TcdR , which also directs RNA Polymerase to transcribe tcdR itself. We fused a gene for a red fluorescent protein to the tcdA promoter to study toxin gene expression at the level of individual C. difficile cells. Surprisingly, only a subset of cells became red fluorescent upon entry into stationary phase. Breaking the positive feedback loop that controls σ TcdR production by engineering cells to express tcdR from a tetracycline-inducible promoter resulted in uniform fluorescence across the population. Experiments with two regulators of tcdR expression, σ D and CodY, revealed neither is required for bimodal toxin gene expression. However, σ D biased cells toward the Toxin-ON state, while CodY biased cells toward the Toxin-OFF state. Finally, toxin gene expression was observed in sporulating cells. We conclude that (i) toxin production is regulated by a bistable switch governed by σ TcdR , which only accumulates to high enough levels to trigger toxin gene expression in a subset of cells, and (ii) toxin production and sporulation are not mutually exclusive developmental programs., (© 2018 John Wiley & Sons Ltd.)

Glycerol monolaurate (GML) is a monoglyceride with potent antimicrobial properties that suppresses T cell receptor (TCR)-induced signaling and T cell effector function. Actin rearrangement is needed for the interaction of T cells with antigen-presenting cells and for migration to sites of infection. Because of the critical role actin rearrangement plays in T cell effector function, we analyzed the effect of GML on the rearrangement of the actin cytoskeleton after TCR activation. We found that GML-treated human T cells were less adherent than untreated T cells and did not form actin ring structures but instead developed numerous inappropriate actin-mediated filopodia. The formation of these filopodia was not due to disruption of TCR-proximal regulators of actin or microtubule polymerization. Instead, total internal reflection fluorescence microscopy demonstrated mislocalization of actin nucleation protein Arp2 microclusters, but not those containing the adaptor proteins SLP-76 and WASp, or the actin nucleation protein ARPC3, which are necessary for TCR-induced actin rearrangement. Additionally, SLP-76 microclusters colocalized with WASp and WAVE microclusters but not with LAT. Together, our data suggest that GML alters actin cytoskeletal rearrangements and identify diverse functions for GML as a T cell-suppressive agent., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: GSK has modified the licensed monovalent bulk manufacturing process for its split-virion inactivated quadrivalent influenza vaccine (IIV4) to harmonize the process among different strains, resulting in an increased number of finished vaccine doses, while compensating for the change from inactivated trivalent influenza vaccine (IIV3) to IIV4. To confirm the manufacturing changes do not alter the profile of the vaccine, a clinical trial was conducted to compare IIV4 made by the currently licensed process with a vaccine made by the new (investigational) process (IIV4-I). The main objectives were to compare the reactogenicity and safety of IIV4-I versus IIV4 in all age groups, and to demonstrate the non-inferiority of the hemagglutination-inhibition (HI) antibody responses based on the geometric mean titer ratio of IIV4-I versus IIV4 in children., Methods: The Phase III, randomized, double-blind, multinational study included three cohorts: adults (18-49 years; N = 120), children (3-17 years; N = 821), and infants (6-35 months; N = 940). Eligible subjects in each cohort were randomized 1:1 to receive IIV4-I or IIV4. Both vaccines contained 15 μg of hemagglutinin antigen for each of the four seasonal virus strains. Adults and vaccine-primed children received one dose of vaccine, and vaccine-unprimed children received two doses of vaccine 28 days apart. All children aged ≥9 years were considered to be vaccine-primed and received one dose of vaccine., Results: The primary immunogenicity objective of the study was met in demonstrating immunogenic non-inferiority of IIV4-I versus IIV4 in children. The IIV4-I was immunogenic against all four vaccine strains in each age cohort. The reactogenicity and safety profile of IIV4-I was similar to IIV4 in each age cohort, and there was no increase in the relative risk of fever (≥38 °C) with IIV4-I versus IIV4 within the 7-day post-vaccination period in infants (1.06; 95% Confidence Interval: 0.75, 1.50; p = 0.786)., Conclusions: The study demonstrated that in adults, children, and infants, the IIV4-I made using an investigational manufacturing process was immunogenic with a reactogenicity and safety profile that was similar to licensed IIV4. These results support that the investigational process used to manufacture IIV4-I is suitable to replace the current licensed process., Trial Registration: ClinicalTrials.gov: NCT02207413 ; trial registration date: August 4, 2014.

Central nervous system infections (CNSI) are a leading cause of death and long-term disability in children. Using ICD-10 data from 2005 to 2015 from three central hospitals in Ho Chi Minh City (HCMC), Vietnam, we exploited generalized additive mixed models (GAMM) to examine the spatial-temporal distribution and spatial and climatic risk factors of paediatric CNSI, excluding tuberculous meningitis, in this setting. From 2005 to 2015, there were 9469 cases of paediatric CNSI; 33% were ⩽1 year old at admission and were mainly diagnosed with presumed bacterial CNSI (BI) (79%), the remainder were >1 year old and mainly diagnosed with presumed non-bacterial CNSI (non-BI) (59%). The urban districts of HCMC in proximity to the hospitals as well as some outer districts had the highest incidences of BI and non-BI; BI incidence was higher in the dry season. Monthly BI incidence exhibited a significant decreasing trend over the study. Both BI and non-BI were significantly associated with lags in monthly average temperature, rainfall, and river water level. Our findings add new insights into this important group of infections in Vietnam, and highlight where resources for the prevention and control of paediatric CNSI should be allocated.

Several fast- to intermediate-growing, acid-fast, scotochromogenic bacteria were isolated from Sarracenia purpurea pitcher waters in Minnesota sphagnum peat bogs. Two strains (DL734T and DL739T) were among these isolates. On the basis of 16S rRNA gene sequences, the phylogenetic positions of both strains is in the genus Mycobacterium with no obvious relation to any characterized type strains of mycobacteria. Phenotypic characterization revealed that neither strain was similar to the type strains of known species of the genus Mycobacterium in the collective properties of growth, pigmentation or fatty acid composition. Strain DL734T grew at temperatures between 28 and 32 °C, was positive for 3-day arylsulfatase production, and was negative for Tween 80 hydrolysis, urease and nitrate reduction. Strain DL739T grew at temperatures between 28 and 37 °C, and was positive for Tween 80 hydrolysis, urea, nitrate reduction and 3-day arylsulfatase production. Both strains were catalase-negative while only DL739T grew with 5 % NaCl. Fatty acid methyl ester profiles were unique for each strain. DL739T showed an ability to survive at 8 °C with little to no cellular replication and is thus considered to be psychrotolerant. Therefore, strains DL734T and DL739T represent two novel species of the genus Mycobacterium with the proposed names Mycobacterium sarraceniae sp. nov. and Mycobacterium helvum sp. nov., respectively. The type strains are DL734T (=JCM 30395T=NCCB 100519T) and DL739T (=JCM 30396T=NCCB 100520T), respectively.

Lyme disease is the most frequently reported vector borne illness in the United States, and incidences are increasing steadily year after year. This study explores the influence of landscape (e.g., land use pattern and landscape fragmentation) and climatic factors (e.g., temperature and precipitation) at a regional scale on Lyme disease incidence. The study area includes thirteen states in the Northeastern United States. Lyme disease incidence at county level for the period of 2002-2006 was linked with several key landscape and climatic variables in a negative binomial regression model. Results show that Lyme disease incidence has a relatively clear connection with regional landscape fragmentation and temperature. For example, more fragmentation between forests and residential areas results in higher local Lyme disease incidence. This study also indicates that, for the same landscape, some landscape variables derived at a particular scale show a clearer connection to Lyme disease than do others. In general, the study sheds more light on connections between Lyme disease incidence and climate and landscape patterns at the regional scale. Integrating findings of this regional study with studies at a local scale will further refine understanding of the pattern of Lyme disease as well as increase our ability to predict, prevent, and respond to disease.

Unlabelled: In Europe, the introduction of monovalent meningococcal serogroup C (MenC) conjugate vaccines has resulted in a significant decline in MenC invasive disease. However, given the potential for strain evolution and increasing travel to areas of high endemicity, protection against additional serogroups is needed. In this study, the immunogenicity, measured by a serum bactericidal activity assay using rabbit complement (rSBA), and the safety of a quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) were compared to that of a licensed monovalent MenC conjugate vaccine (MenC-CRM₁₉₇) in children 2-10 years of age. Children were randomised (3:1) to receive a single dose of either MenACWY-TT or MenC-CRM₁₉₇. Non-inferiority of the immunogenicity of MenACWY-TT versus MenC-CRM₁₉₇ in terms of rSBA-MenC vaccine response was demonstrated. Exploratory analyses suggested that rSBA-MenC geometric mean titres adjusted for pre-vaccination titres were lower in children vaccinated with MenACWY-TT compared to MenC-CRM₁₉₇. Nevertheless, at 1 month post-vaccination, ≥99.3 % of the children who received MenACWY-TT had rSBA titres ≥1:128 for each of the four vaccine serogroups, which is the more conservative correlate of protection. The reactogenicity and safety profile of MenACWY-TT was clinically acceptable and no serious adverse events considered related to vaccination were reported throughout the study., Conclusion: When administered to European school-age children, MenACWY-TT has a clinically acceptable safety profile and, when compared with MenC-CRM₁₉₇, the potential to broaden protection against meningococcal disease caused by serogroups A, W-135 and Y while maintaining protection against MenC. This study has been registered at www.clinicaltrials.gov NCT00674583.

Background: Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder precipitated by exposure to extreme traumatic stress. Yet, most individuals exposed to traumatic stress do not develop PTSD and may be considered psychologically resilient. The neural circuits involved in susceptibility or resiliency to PTSD remain unclear, but clinical evidence implicates changes in the noradrenergic system., Methods: An animal model of PTSD called Traumatic Experience with Reminders of Stress (TERS) was developed by exposing C57BL/6 mice to a single shock (2 mA, 10 sec) followed by exposure to six contextual 1-minute reminders of the shock over a 25-day period. Acoustic startle response (ASR) testing before the shock and after the last reminder allowed experimenters to separate the shocked mice into two cohorts: mice that developed a greatly increased ASR (TERS-susceptible mice) and mice that did not (TERS-resilient mice)., Results: Aggressive and social behavioral correlates of PTSD increased in TERS-susceptible mice but not in TERS-resilient mice or control mice. Characterization of c-Fos expression in stress-related brain regions revealed that TERS-susceptible and TERS-resilient mice displayed divergent brain activation following swim stress compared with control mice. Pharmacological activation of noradrenergic inhibitory autoreceptors or blockade of postsynaptic α(1)-adrenoreceptors normalized ASR, aggression, and social interaction in TERS-susceptible mice. The TERS-resilient, but not TERS-susceptible, mice showed a trend toward decreased behavioral responsiveness to noradrenergic autoreceptor blockade compared with control mice., Conclusions: These data implicate the noradrenergic system as a possible site of pathological and perhaps also adaptive plasticity in response to traumatic stress., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

To characterize neuronal gene expression in amyotrophic lateral sclerosis (ALS), we quantitated one glial and three neuronal mRNAs in spinal cords of 7 subjects with ALS and 11 controls. The ALS cases showed no loss of mRNA for the neurofilament light subunit when assessed with in situ hybridization. Northern analysis, and RNase protection assay; and no loss of mRNA for amyloid precursor protein or a growth-associated protein (GAP-43/B-50) on Northern analysis. ALS cords also showed no significant change in glial mRNA. Our findings indicate that expression of these neuronal mRNAs is well maintained in ALS-afflicted spinal cord. They do not support the hypothesis of a generalized impairment of neuronal gene transcription in the pathogenesis of this disorder.

1. Aluminum administration to susceptible animal species results in neurofilament accumulation in neuronal perikarya and proximal axons. Pathogenetic studies in vivo have shown that aluminum rapidly associates with neuronal chromatin. Whether the effect of aluminum on DNA components plays a role in the production of the neurofibrillary lesion remains unclear. 2. In this study we used Northern analysis and in situ hybridization to evaluate mRNA levels of specific neuronal and glial components in the rabbit spinal cord at various times following aluminum administration. 3. Our results show that (a) all neuronal mRNAs evaluated (neurofilament triplet components, neuronal-specific enolase, and amyloid precursor protein) are markedly decreased, with no decrease in glial fibrillary acidic protein; (b) the effect on neuronal gene expression occurs early and concurrently with the development of the neurofibrillary lesion and reverses rapidly after a single dose of aluminum; and (c) there is a direct correlation between the severity of the neurofibrillary lesion and the decrease in neuronal mRNA levels. 4. We interpret our results to mean that the accumulation of neurofilaments in this model is not due to a selective effect on neurofilament gene expression but may be due to an inhibition of genes coding for components involved in processing of neurofilament proteins.