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Gonorrhoea infection rates and the risk of infection from opportunistic pathogens including P. aeruginosa have both risen globally, in part due to increasing broad-spectrum antibiotic resistance. Development of new antimicrobial drugs is necessary and urgent to counter infections from drug resistant bacteria. Aspartate-semialdehyde dehydrogenase (ASADH) is a key enzyme in the aspartate biosynthetic pathway, which is critical for amino acid and metabolite biosynthesis in most microorganisms including important human pathogens. Here we present the first structures of two ASADH proteins from N. gonorrhoeae and P. aeruginosa solved by X-ray crystallography. These high-resolution structures present an ideal platform for in silico drug design, offering potential targets for antimicrobial drug development as emerging multidrug resistant strains of bacteria become more prevalent.

•All 3 doses of VAX-24 were well tolerated, with a safety profile similar to PCV20.•All treatment arms resulted in robust increases in OPA GMTs and IgG GMCs.•VAX-24 achieved higher serotype valency and enhanced immune responses versus PCV20. Despite current polysaccharide and conjugate vaccine use, pneumococcal diseases remain prevalent in older adults. VAX-24 is a 24-valent pneumococcal conjugate vaccine (PCV) containing eCRM, a proprietary carrier protein with non-native amino acids (para-azidomethyl-L-phenylalanine) that undergo site-specific conjugation to pneumococcal polysaccharides that have been activated with a small-molecule linker (dibenzocyclooctyne). Site-specific conjugation utilizing click chemistry enables consistent exposure of T-cell epitopes, reduction in carrier protein to pneumococcal polysaccharide ratio, and enhances manufacturing process consistency to improve PCVs by increasing serotype coverage while minimizing carrier suppression. Healthy adults aged 65 or older were randomized in a 1:1:1:1 ratio to receive a single injection of VAX-24 at 1 of 3 dose levels (1.1, 2.2, or a mixed dose of 2.2 or 4.4 mcg) or Prevnar 20® (PCV20) in a phase 2, blinded study. Primary outcome measures were solicited local and systemic events within 7 days post-vaccination, unsolicited adverse events (AEs) within 1 month, and serious AEs, medically attended AEs, or new onset of chronic disease within 6 months of vaccination. Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) were measured pre-vaccination and at 1 month post-vaccination. Of 207 participants enrolled, 200 completed the trial. Safety profiles were comparable across the three VAX-24 doses and PCV20. Robust OPA and IgG immune responses were seen for all 24 serotypes. On average, immune responses to VAX-24 2.2 mcg dose were similar or higher compared to PCV20. In adults ≥ 65 years, VAX-24 had a safety profile similar to PCV20 through six months post-vaccination and induced robust OPA and IgG responses to all 24 serotypes, supporting prior data showing that site-specific conjugation allows for increased serotype coverage with similar or higher immune response vs other PCVs. The outcome of this phase 2 study further supports use of VAX-24 2.2 mcg dose in phase 3 trials. Clinicaltrials.gov: NCT05297578.

Recent loosening of state and federal policy restrictions on marijuana, along with changes in social norms regarding marijuana use and decreases in prevalence of other types of substance use, may lead to increases in youth initiating marijuana before other types of substances such as alcohol and tobacco. We investigated predictors and potential consequences of initiating marijuana before other drugs for youth aged 12–21-years in the USA. Nationally representative, cross-sectional survey data from the US National Survey on Drug Use and Health supplied self-reported age of first marijuana, cigarettes, alcohol, other tobacco, and other illegal drug use among 12–21-year-old samples from 2004 to 2014 (n = 275,559). We first examined the degree to which initiating marijuana use first was associated with sex, age, race/ethnicity, and survey year. Then, we examined whether using marijuana first predicted heavy marijuana use, cannabis use disorder (CUD), alcohol use disorder (AUD), nicotine dependence (ND), or lifetime use of other illegal drugs. Among all survey youth (substance users and non-users), the proportion using marijuana first increased from 4.8 to 8.8% from 2004 to 2014. Those using marijuana first (vs. alcohol or cigarettes first) were more likely to be male and older and Black, American Indian/Alaskan Native, multiracial, or Hispanic than White or Asian. Among substance users and adjusting for age of onset and the number of substances used, using marijuana first was associated higher odds of heavy current marijuana use and CUD. In recent years, youth have been increasingly likely to use marijuana as their first drug and sequence of initiation is associated with race/ethnicity, gender, and age. Using marijuana first might increase the chance of heavy use and CUD.

PurposeSmoking is a modifiable lifestyle factor that has not been established as a prostate cancer risk factor, nor emphasized in prostate cancer prevention. Studies have shown that African American (AA) smokers have a poorer cancer prognosis than European Americans (EAs), while having a lower prevalence of heavy smoking. We examined the relationship between cigarette smoking and prostate cancer aggressiveness and assessed racial differences in smoking habits on the probability of high-aggressive prostate cancer.MethodsUsing data from the North Carolina-Louisiana Prostate Cancer Project (n = 1,279), prostate cancer aggressiveness was defined as high or low based on Gleason scores, serum prostate-specific antigen levels, and tumor stage. Cigarette smoking was categorized as current, former, or never smokers. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI).ResultsSelf-reported current (OR = 1.99; 95% CI 1.30–3.06) smoking was associated with high-aggressive prostate cancer relative to never smokers. When stratified by self-reported race, the odds of having high-aggressive cancer increased among AA current (OR = 3.58; 95% CI 2.04–6.28) and former smokers (OR = 2.21; 95% CI 1.38–3.53) compared to AA never smokers, but the odds were diminished among the EA stratum (Pself-reported race x smoking status = 0.003).ConclusionCigarette smoking is associated with prostate cancer aggressiveness, a relationship modulated by self-reported race. Future research is needed to investigate types of cigarettes smoked and metabolic differences that may be contributing to the racial disparities observed.

Abstract Introduction Among United States teens during the 1990s, increasing cigar use coincided with increasing use of tobacco cigar shells filled with cannabis, called “blunts.” Cigar smokers are more likely to use cannabis, and we hypothesized that starting to smoke cigars might be a probabilistic “trigger” of blunt smoking. We turned to the case-crossover approach to evaluate this hypothesis. Methods Within US National Surveys on Drug Use and Health, 2009–2013, we identified a nationally representative sample of newly incident blunt smokers aged 12- to 21-years-old (n = 4868) and compared month-of-onsets for smoking of cigars and blunts. Using the subjects-as-their-own-controls case-crossover design, we specified the first month prior to blunt use as a “hazard interval” and the second month prior to blunt use as a “control interval.” We used Mantel–Haenszel (MH) estimators to estimate the matched-pairs odds ratio (OR). Results The MH OR estimate was 1.7 (95% CI = 1.3, 2.3), with excess odds of cigar onsets during the hazard interval relative to the control interval. Two alternative control interval specifications yielded congruent estimates (OR = 2.7 and 2.9, respectively). Conclusions A short interval right after starting to smoke cigars may be one of increased risk of starting to smoke blunts. We discuss cigar, cigarillo, and “blunt wraps” control approaches that might reduce both tobacco and cannabis-related harms. Implications If this evidence is correct, increased market-targeting to promote youthful cigar and cigarillo smoking might be followed by increased rates of blunt smoking in a vulnerable population. As noted by others, enhanced risk of smoking-attributable harms might be a consequence of mixed tobacco-cannabis formulations.

Despite substantial reductions in pneumococcal disease with the availability of pneumococcal conjugate vaccines, a significant burden of pneumococcal disease remains due to the diversity of serotypes combined with serotype replacement. We developed a new vaccine candidate, VAX-24 (24-valent pneumococcal conjugate vaccine), using cell-free protein synthesis to produce a variant of cross-reactive material 197 (eCRM) as the carrier protein, increasing serotype coverage while minimising carrier suppression. The aim of this clinical trial was to assess the safety, tolerability, and immunogenicity of three different doses of VAX-24 compared to pneumococcal 20-valent conjugate vaccine (PCV20). This was a phase 1/2, randomised, double-masked study of VAX-24 versus PCV20 conducted in the USA. Key inclusion criteria included being a male or female aged 18 to 64 years in good health; key exclusion criteria included previous history of pneumococcal disease, receipt of a licensed or investigational pneumococcal vaccine, or immunosuppressive therapy. Participants were randomly allocated in a 1:1:1:1 ratio by permuted block to receive one dose of VAX-24 (1·1 μg of each antigen, 2·2 μg of each antigen, or 2·2 μg of 17 antigens mixed with 4·4 μg of seven antigens), or PCV20. The safety population included all participants with safety data. The immunogenicity population was as per-treatment in phase 2. Primary outcome measures included solicited and unsolicited adverse events. Secondary outcomes included serotype-specific opsonophagocytic activity (OPA) geometric mean titres (GMT), and IgG geometric mean concentrations (GMC) were measured 1 month postvaccination. Traditional non-inferiority criteria included OPA geometric mean ratio (GMR), with a lower bound of the two sided 95% CI of greater than 0·5 for shared serotypes. This completed trial is registered at ClinicalTrials.gov, NCT05266456. Safety profiles were comparable among the treatment groups, with 170 of 209 participants (81%, 95% CI 75·2–86·2) to 178 of 207 participants (86%, 80·5–90·4) reporting at least one solicited adverse event among the three VAX-24 groups. 24 of 207 participants (12%, 7·6–16·8) to 32 of 209 of participants (15%, 10·7–20·9) experiened an unsolicited treatment emergent adverse event within 1 month postvaccination. VAX-24 2·2 μg met traditional OPA GMR non-inferiority criteria for all 20 shared serotypes; 16 serotypes elicited GMR point estimates greater than 1·0, and four reached the lower bound of the two-sided 95% CI greater than 1·0. VAX-24 had a safety profile similar to PCV20 at all doses, with the 2·2 μg dose showing increased serotype coverage with decreased carrier suppression. Vaxcyte.

BackgroundResidents of disadvantaged neighbourhoods report higher levels of depressive symptoms; however, few studies have employed prospective designs during adolescence, when depression tends to emerge. We examined associations of neighbourhood social fragmentation, income inequality and median household income with depressive symptoms in a nationally representative survey of adolescents.MethodsThe NEXT Generation Health Study enrolled 10th-grade students from 81 US high schools in the 2009–2010 school year. Depressive symptoms were assessed with the Modified Depression Scale (wave 1) and the paediatric Patient-Reported Outcome Measurement Information System (waves 2–6). Neighbourhood characteristics at waves 1, 3, 4, and 5 were measured at the census tract level using geolinked data from the American Community Survey 5-year estimates. We used linear mixed models to relate neighbourhood disadvantage to depressive symptoms controlling for neighbourhood and individual sociodemographic factors.ResultsNone of the models demonstrated evidence for associations of social fragmentation, income inequality or median household income with depressive symptoms.ConclusionDespite the prospective design, repeated measures and nationally representative sample, we detected no association between neighbourhood disadvantage and depressive symptoms. This association may not exist or may be too small to detect in a geographically dispersed sample. Given the public health significance of neighbourhood effects, future research should examine the developmental timing of neighbourhood effects across a wider range of ages than in the current sample, consider both objective and subjective measures of neighbourhood conditions, and use spatially informative techniques that account for conditions of nearby neighbourhoods.

The original version of this article contained a mistake: The first sentence in the Results section of the Abstract should read as follows: “The proportion who had initiated marijuana before other substances increased from 4.4% to 8.0%”.

Intravenous gene delivery using liposome–DNA complexes (LDC) has previously been shown to elicit antitumor activity, but only in rodent tumor models. Therefore, we conducted a study to determine in a large animal spontaneous tumor model whether intravenous infusions of LDC could target gene expression to cutaneous tumor tissues and whether repeated treatments had an effect on tumor growth or angiogenesis. A total of 13 dogs with cutaneous soft tissue sarcomas were enrolled in the study and were randomized to receive a series of 6 weekly infusions of LDC containing either canine endostatin DNA or DNA encoding an irrelevant gene (luciferase). Serial tumor biopsies were obtained to assess transgene expression, tumor microvessel density (MVD), and intratumoral leukocyte inflammatory responses. We found that intravenous infusion of LDC did not result in detectable gene expression in cutaneous tumor tissues. However, two of 13 treated dogs had objective tumor responses and eight dogs had stable disease during the treatment period. In addition, a significant decrease in tumor MVD was noted in six of 12 treated dogs at the completion of six treatments. These results suggest that intravenous infusions of LDC may elicit nonspecific antitumor activity and inhibit tumor angiogenesis.

Background. The decreased immune response among elderly individuals results in reduced influenza vaccine efficacy. Strategies to improve vaccine efficacy in elderly individuals are needed. The goal of this study was to determine whether a cationic lipid/DNA complex (CLDC) can improve the efficacy of the trivalent inactivated influenza vaccine Fluzone in elderly nonhuman primates. Methods. Elderly (age, > 18 years) rhesus macaques were vaccinated with Fluzone, with or without CLDC, and challenged with a human seasonal influenza virus isolate, A/Memphis/7/2001(HlNl). Results. We found that elderly macaques have significantly lower levels of circulating naive CD4⁺ T cells, naive CD8⁺ T cells, and B cells as compared to juvenile monkeys. Furthermore, on the day of challenge, recipients of Fluzone/CLDC had significantly higher plasma anti-influenza virus immunoglobulin G (P < .001) and immunoglobulin A (P<. 001) titers than recipients of Fluzone alone. After virus challenge, only the Fluzone/CLDC-vaccinated animals had a significantly lower level of virus replication (P < .01) relative to the unvaccinated control animals. Conclusions. These results demonstrate that CLDC can enhance the immunogenicity and efficacy of a licensed TIV in immunosenescent elderly monkeys.