Respiratory carriage of hypervirulent Klebsiella pneumoniae by indigenous populations of Malaysia.

Klebsiella pneumoniae is a Gram-negative Enterobacteriaceae that is classified by the World Health Organisation (WHO) as a Priority One ESKAPE pathogen. South and Southeast Asian countries are regions where both healthcare associated infections (HAI) and community acquired infections (CAI) due to extended-spectrum ß-lactamase (ESBL)-producing and carbapenem-resistant K. pneumoniae (CRKp) are of concern. As K. pneumoniae can also exist as a harmless commensal, the spread of resistance genotypes requires epidemiological vigilance. However there has been no significant study of carriage isolates from healthy individuals, particularly in Southeast Asia, and specially Malaysia. Here we describe the genomic analysis of respiratory isolates of K. pneumoniae obtained from Orang Ulu and Orang Asli communities in Malaysian Borneo and Peninsular Malaysia respectively. The majority of isolates were K. pneumoniae species complex (KpSC) 1 K. pneumoniae (n = 53, 89.8%). Four Klebsiella variicola subsp. variicola (KpSC3) and two Klebsiella quasipneumoniae subsp. similipneumoniae (KpSC4) were also found. It was discovered that 30.2% (n = 16) of the KpSC1 isolates were ST23, 11.3% (n = 6) were of ST65, 7.5% (n = 4) were ST13, and 13.2% (n = 7) were ST86. Only eight of the KpSC1 isolates encoded ESBL, but importantly not carbapenemase. Thirteen of the KpSC1 isolates carried yersiniabactin, colibactin and aerobactin, all of which harboured the rmpADC locus and are therefore characterised as hypervirulent. Co-carriage of multiple strains was minimal. In conclusion, most isolates were KpSC1, ST23, one of the most common sequence types and previously found in cases of K. pneumoniae infection. A proportion were hypervirulent (hvKp) however antibiotic resistance was low.

A pilot feasibility and acceptability trial of an internet indicated prevention program for perfectionism to reduce eating disorder symptoms in adolescents.

PURPOSE: Perfectionism is a transdiagnostic risk factor for eating disorders. Treating perfectionism can reduce symptoms of eating disorders. No research has examined an indicated prevention trial using internet-based Cognitive-Behavioural Therapy for Perfectionism (ICBT-P) in adolescent girls at elevated risk for eating disorders. Our aim was to conduct a preliminary feasibility trial using a co-designed ICBT-P intervention. It was hypothesised that a higher proportion of participants in the ICBT-P condition would achieve reliable and clinically significant change on perfectionism, eating disorders, anxiety and depression, compared to waitlist control. METHODS: Twenty-one adolescent girls with elevated symptoms of eating disorders (M age = 16.14 years) were randomised to a 4-week online feasibility trial of a co-designed ICBT-P prevention program or waitlist control. Qualitative surveys were used to gain participant perspectives. RESULTS: The ICBT-P condition had a higher proportion of participants achieve reliable change and classified as recovered on perfectionism and symptoms of eating disorders and anxiety, compared to waitlist control. Qualitative findings indicated that 100% of participants found the program helpful. CONCLUSION: The results indicate ICBT-P is a feasible and acceptable program for adolescent girls with elevated eating disorder symptoms. Future research is required to examine outcomes in a randomised controlled trial. LEVEL OF EVIDENCE: Level III: Evidence obtained from well-designed cohort or case-control analytic studies. TRIAL REGISTRATION NUMBER: This trial was prospectively registered with Australian and New Zealand Clinical Trials Registry (ACTRN12620000951954P) on 23/09/2020.

Risk factors and outcomes of bloodstream infection from a urinary source in kidney transplant recipients.

BACKGROUND: Bacteriuria is common among kidney transplant recipients (KTR). Risk factors and outcomes associated with bloodstream infection due to a urinary source (BSIU) in KTR are poorly understood. METHODS: This single center case-control study from 2010 to 2022 compared KTR with BSIU to those with bacteria without bloodstream infection (BU). Multivariable logistic regression identified BSIU risk factors, and Cox models assessed its impact on graft failure. RESULTS: Among 3435 patients, who underwent kidney transplantation at Emory Hospital, 757 (22%) developed bacteriuria, among whom 142 (18.8%) were BSIU. Male sex, presence of Escherichia coli, Klebsiella pneumoniae, or Pseudomonas species in urine culture, urethral stricture, neuromuscular bladder disorder, and history of diabetes-induced renal failure were independently associated with increased odds of BSIU (Male sex: aOR 2.29, 95% CI 1.52, 3.47, E. coli: aOR 5.14, 95% CI 3.02, 9.13; K. pneumoniae aOR 3.19, 95% CI 1.65, 6.27, Pseudomonas spp aOR 3.06, 95% CI 1.25, 7.18; urethral stricture: 4.10, 95% CI 1.63, 10.3, neuromuscular bladder disorder aOR 1.98, 95% CI 1.09, 3.53, diabetes: aOR 1.64, 95% CI 1.08, 2.49). BSIU was associated with increased hazard of graft failure (HR 1.52, 95% CI 1.05, 2.20). CONCLUSION: Close monitoring is warranted for male KTR with bacteriuria, those with urine cultures positive for Pseudomonas spp, K. pneumoniae, or E. coli, as well as KTR with a history of diabetes-induced renal failure, urethral stricture, or neuromuscular bladder disorder due to their risk for developing BSIU. Future research should explore strategies to mitigate BSIU risk in these high-risk KTR and reduce the associated risk of long-term graft failure.

Screening asthmatics for atopic status using the ALergy EXplorer (ALEX2) macroarray.

BACKGROUND: Screening asthma patients for atopy facilitates management. Since 2010, the core biomarker for screening asthma subjects for atopic status has been the qualitative Phadiatop. multi-aeroallergen screen. A more quantitative macroarray, the Allergy Explorer (ALEX2), shows promise as an alternative. OBJECTIVE: The study's goal was to examine the pros and cons of the use of ALEX2 in the screening of asthma patients for atopic status. METHODS: We evaluated the atopic (IgE-sensitization) status in asthmatic Amish and Hutterite farm children using the ImmunoCAP and ALEX2 assays in Phadiatop equivocal and positive subjects. RESULTS: All 42 asthmatic children were analyzed by Phadiatop and total serum IgE. Of these, 22 had a negative Phadiatop (<0.1 kUa/L) and total IgE <100 kU/L which defined them as non-atopic and they were excluded from ALEX2 testing. Of six children with equivocal Phadiatops (0.1-0.2 kUa/L-Group 1) and three children with a negative Phadiatop but total IgE >100 kUa/L (group 3), 44% (n = 4) had detectable IgE antibody by ALEX2 to mite, tree pollen, and other allergens not detected by Phadiatop, but confirmed by allergen-specific ImmunoCAP testing. In 11 Phadiatop positive subjects (>0.2 kUa/L-group 2), all but one were positive by ALEX2. IgE antibody specific for mold and rabbit aeroallergens matched their agricultural and pet exposure history. Three children were positive for IgE antibody to allergens in the profilin, nsLTP, or PR-10 cross-reactive protein families. CONCLUSION: Judicious use of ALEX2's enhanced specificity data not provided by the Phadiatop can aid in the interpretation of sensitization patterns and planning management of atopic asthmatics, but sensitization relevance must be confirmed by the patient's clinical history.

Comparison of Empirically Derived and Model-Based Estimates of Key Population HIV Incidence and the Distribution of New Infections by Population Group in Sub-Saharan Africa.

BACKGROUND: The distribution of new HIV infections among key populations, including female sex workers (FSWs), gay men and other men who have sex with men (MSM), and people who inject drugs (PWID) are essential information to guide an HIV response, but data are limited in sub-Saharan Africa (SSA). We analyzed empirically derived and mathematical model-based estimates of HIV incidence among key populations and compared with the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates. METHODS: We estimated HIV incidence among FSW and MSM in SSA by combining meta-analyses of empirical key population HIV incidence relative to the total population incidence with key population size estimates (KPSE) and HIV prevalence. Dynamic HIV transmission model estimates of HIV incidence and percentage of new infections among key populations were extracted from 94 country applications of 9 mathematical models. We compared these with UNAIDS-reported distribution of new infections, implied key population HIV incidence and incidence-to-prevalence ratios. RESULTS: Across SSA, empirical FSW HIV incidence was 8.6-fold (95% confidence interval: 5.7 to 12.9) higher than total population female 15-39 year incidence, and MSM HIV incidence was 41.8-fold (95% confidence interval: 21.9 to 79.6) male 15-29 year incidence. Combined with KPSE, these implied 12% of new HIV infections in 2021 were among FSW and MSM (5% and 7% respectively). In sensitivity analysis varying KPSE proportions within 95% uncertainty range, the proportion of new infections among FSW and MSM was between 9% and 19%. Insufficient data were available to estimate PWID incidence rate ratios. Across 94 models, median proportion of new infections among FSW, MSM, and PWID was 6.4% (interquartile range 3.2%-11.7%), both much lower than the 25% reported by UNAIDS. CONCLUSION: Empirically derived and model-based estimates of HIV incidence confirm dramatically higher HIV risk among key populations in SSA. Estimated proportions of new infections among key populations in 2021 were sensitive to population size assumptions and were substantially lower than estimates reported by UNAIDS.

Measuring HIV Acquisitions Among Partners of Key Populations: Estimates From HIV Transmission Dynamic Models.

BACKGROUND: Key populations (KPs), including female sex workers (FSWs), gay men and other men who have sex with men (MSM), people who inject drugs (PWID), and transgender women (TGW) experience disproportionate risks of HIV acquisition. The UNAIDS Global AIDS 2022 Update reported that one-quarter of all new HIV infections occurred among their non-KP sexual partners. However, this fraction relied on heuristics regarding the ratio of new infections that KPs transmitted to their non-KP partners to the new infections acquired among KPs (herein referred to as "infection ratios"). We recalculated these ratios using dynamic transmission models. SETTING: One hundred seventy-eight settings (106 countries). METHODS: Infection ratios for FSW, MSM, PWID, TGW, and clients of FSW were estimated from 12 models for 2020. RESULTS: Median model estimates of infection ratios were 0.7 (interquartile range: 0.5-1.0; n = 172 estimates) and 1.2 (0.8-1.8; n = 127) for acquisitions from FSW clients and transmissions from FSW to all their non-KP partners, respectively, which were comparable with the previous UNAIDS assumptions (0.2-1.5 across regions). Model estimates for female partners of MSM were 0.5 (0.2-0.8; n = 20) and 0.3 (0.2-0.4; n = 10) for partners of PWID across settings in Eastern and Southern Africa, lower than the corresponding UNAIDS assumptions (0.9 and 0.8, respectively). The few available model estimates for TGW were higher [5.1 (1.2-7.0; n = 8)] than the UNAIDS assumptions (0.1-0.3). Model estimates for non-FSW partners of FSW clients in Western and Central Africa were high (1.7; 1.0-2.3; n = 29). CONCLUSIONS: Ratios of new infections among non-KP partners relative to KP were high, confirming the importance of better addressing prevention and treatment needs among KP as central to reducing overall HIV incidence.

Natural reversion promotes LPS elongation in an attenuated Coxiella burnetii strain.

Lipopolysaccharide (LPS) phase variation is a critical aspect of virulence in many Gram-negative bacteria. It is of particular importance to Coxiella burnetii, the biothreat pathogen that causes Q fever, as in vitro propagation of this organism leads to LPS truncation, which is associated with an attenuated and exempted from select agent status (Nine Mile II, NMII). Here, we demonstrate that NMII was recovered from the spleens of infected guinea pigs. Moreover, these strains exhibit a previously unrecognized form of elongated LPS and display increased virulence in comparison with the initial NMII strain. The reversion of a 3-bp mutation in the gene cbu0533 directly leads to LPS elongation. To address potential safety concerns, we introduce a modified NMII strain unable to produce elongated LPS.

HIV prevalence in transgender populations and cisgender men who have sex with men in sub-Saharan Africa 2010-2022: a meta-analysis.

Introduction: The Global AIDS Strategy 2021-2026 calls for equitable and equal access to HIV prevention and treatment programmes for all populations to reduce HIV incidence and end HIV/AIDS as a public health threat by 2030. Transgender populations (TGP), including transmen (TGM) and transwomen (TGW) are populations that have been marginalised and are at high risk of HIV infection in sub-Saharan Africa (SSA). Limited surveillance data on HIV among TGP are available in the region to guide programmatic responses and policymaking. Surveillance data on cisgender men who have sex with men (cis-MSM) are comparatively abundant and may be used to infer TGP HIV prevalence. Methods: Data from key population surveys conducted in SSA between 2010-2022 were identified from existing databases and survey reports. Studies that collected HIV prevalence on both TGP and cis-MSM populations were analysed in a random effect meta-analysis to estimate the ratio of cis-MSM:TGW HIV prevalence. Results: Eighteen studies were identified encompassing 8,052 TGW and 19,492 cis-MSM. TGW HIV prevalence ranged from 0-71.6% and cis-MSM HIV prevalence from 0.14-55.7%. HIV prevalence in TGW was 50% higher than in cis-MSM (prevalence ratio (PR) 1.50 95% CI 1.26-1.79). TGW HIV prevalence was highly correlated with year/province-matched cis-MSM HIV prevalence (R2 = 0.62), but poorly correlated with year/province-matched total population HIV prevalence (R2 = 0.1). Five TGM HIV prevalence estimates were identified ranging from 1-24%. Insufficient TGM data were available to estimate cis-MSM:TGM HIV prevalence ratios. Conclusion: Transgender women experience a significantly greater HIV burden than cis-MSM in SSA. Bio-behavioural surveys designed and powered to measure determinants of HIV infection, treatment coverage, and risk behaviours among transgender populations, distinct from cis-MSM, will improve understanding of HIV risk and vulnerabilities among TGP and support improved programmes.

HIV incidence among women engaging in sex work in sub-Saharan Africa: a systematic review and meta-analysis.

Introduction: HIV incidence among women in sub-Saharan Africa (SSA) has declined steadily, but it is unknown whether new infections among women who engage in sex work (WESW) have declined at a similar rate. We synthesised estimates of HIV incidence among WESW in SSA and compared these to the wider female population to understand levels and trends in incidence over time. Methods: We searched Medline, Embase, Global Health, Popline, Web of Science, and Google Scholar from January 1990 to October 2022, and grey literature for estimates of HIV incidence among WESW in SSA. We included studies reporting empirical estimates in any SSA country. We calculated incidence rate ratios (IRR) compared to age-district-year matched total female population incidence estimates. We conducted a meta-analysis of IRRs and used a continuous mixed-effects model to estimate changes in IRR over time. Results: From 32 studies between 1985 and 2020, 2,194 new HIV infections were observed in WESW over 51,000 person-years (py). Median HIV incidence was 4.3/100py (IQR 2.8-7.0/100py), declining from a median of 5.96/100py between 1985 and 1995 to a median of 3.2/100py between 2010 and 2020. Incidence among WESW was nine times higher than in matched total population women (RR 8.6, 95%CI: 5.7-12.9), and greater in Western and Central Africa (RR 22.4, 95%CI: 11.3-44.3) than in Eastern and Southern Africa (RR 5.3, 95%CI: 3.7-7.6). Annual changes in log IRRs were minimal (-0.1% 95%CI: -6.9 to +6.8%). Conclusions: Across SSA, HIV incidence among WESW remains disproportionately high compared to the total female population but showed similar rates of decline between 1990 and 2020. Improved surveillance and standardisation of approaches to obtain empirical estimates of sex worker incidence would enable a clearer understanding of whether we are on track to meet global targets for this population and better support data-driven HIV prevention programming.

Characterization of Proteus mirabilis and associated plasmids isolated from anaerobic dairy cattle manure digesters.

Proteus mirabilis is an opportunistic pathogen associated with a variety of human infections, including urinary tract infections. The prevalence of P. mirabilis in foods of animal origin and in the manure by-products created in animal production is not well documented. Further, the prevalence and persistence of extended-spectrum cephalosporin (ESC) resistant P. mirabilis is largely unknown. In this study, we characterized ESC-resistant P. mirabilis recovered from various stages of dairy manure anaerobic digestion. Isolates were screened by PCR for blaCTX-M, blaCMY and blaSHV, and antimicrobial susceptibility testing was performed. Fifty-six P. mirabilis carrying CTX-M were sequenced with short and long read sequencing technologies, and the assembled chromosomes and plasmids were compared. ESC-resistant Proteus was found in four of the six manure digesters, an indication that not all digesters were colonized with resistant strains. Both CTX-M-1 and CTX-M-15 plasmids were found in P. mirabilis isolates. Transfer of plasmid DNA by conjugation was also explored, with ESC-resistance plasmids able to transfer to Escherichia coli at high frequency. We concluded that P. mirabilis can harbour and transfer ESC-resistance genes and plasmids, and may be an overlooked reservoir of antimicrobial resistance.

Stakeholder integration predicts better outcomes from groundwater sustainability policy.

Natural resources policies that promote sustainable management are critical for protecting diverse stakeholders against depletion. Although integrating diverse stakeholders into these policies has been theorized to improve protection, empirical evidence is lacking. Here, we evaluate 108 Sustainability Plans under California's Sustainable Groundwater Management Act to quantify how well stakeholders are integrated into plans and protected from groundwater depletion. We find that the majority of Sustainability Plans do not integrate or protect the majority of their stakeholders. Nevertheless, our results show that when stakeholders are more integrated into a Sustainability Plan, they are more likely to be protected, particularly for those that lack formal access to decision-making processes. Our findings provide strong empirical evidence that integrating diverse stakeholders into sustainability planning is beneficial for stakeholders who are vulnerable to the impacts of natural resource depletion.

Consensus recommendations for the assessment and treatment of perinatal obsessive-compulsive disorder (OCD): A Delphi study.

The perinatal period is one of increased vulnerability to parents experiencing the onset of, or an increase of existing, obsessive-compulsive disorder (OCD) symptoms. Existing OCD and perinatal mental health best practice guidelines do not detail specific considerations relevant to OCD in the perinatal period ('Perinatal OCD'). Perinatal OCD risks being undiagnosed or misdiagnosed, and subsequently untreated or mistreated, with potential negative impacts for individuals and families experiencing this problem, highlighting the importance of specific guidance. This study employed a modified Delphi survey methodology to establish recommended best practice for the assessment and treatment of perinatal OCD. A literature review identified 103 initial best practice recommendations, and participants suggested 18 further recommendations. These recommendations were rated for importance over three survey rounds by two expert panels, comprising of 15 professionals with clinical or research expertise in perinatal OCD and 14 consumers with lived experience of perinatal OCD. One-hundred and two statements were endorsed for inclusion in the final set of recommendations for clinical best practice with perinatal OCD. These recommendations inform practice across eight themes; psychoeducation, screening, assessment, differential diagnosis, case care considerations, treatment, partners & families, and culture & diversity. This novel study is the first to collate and outline a set of clinical best practice recommendations, developed using the consensus perspectives of both individuals with lived experience and professionals with relevant expertise, for supporting individuals with perinatal OCD and their families. Differences between panel perspectives, and directions for future research are also discussed.

Single cell profiling at the maternal-fetal interface reveals a deficiency of PD-L1+ non-immune cells in human spontaneous preterm labor.

The mechanisms that underlie the timing of labor in humans are largely unknown. In most pregnancies, labor is initiated at term (≥ 37 weeks gestation), but in a signifiicant number of women spontaneous labor occurs preterm and is associated with increased perinatal mortality and morbidity. The objective of this study was to characterize the cells at the maternal-fetal interface (MFI) in term and preterm pregnancies in both the laboring and non-laboring state in Black women, who have among the highest preterm birth rates in the U.S. Using mass cytometry to obtain high-dimensional single-cell resolution, we identified 31 cell populations at the MFI, including 25 immune cell types and six non-immune cell types. Among the immune cells, maternal PD1+ CD8 T cell subsets were less abundant in term laboring compared to term non-laboring women. Among the non-immune cells, PD-L1+ maternal (stromal) and fetal (extravillous trophoblast) cells were less abundant in preterm laboring compared to term laboring women. Consistent with these observations, the expression of CD274, the gene encoding PD-L1, was significantly depressed and less responsive to fetal signaling molecules in cultured mesenchymal stromal cells from the decidua of preterm compared to term women. Overall, these results suggest that the PD1/PD-L1 pathway at the MFI may perturb the delicate balance between immune tolerance and rejection and contribute to the onset of spontaneous preterm labor.

Draft Genome Sequence of Bacillus anthracis N1, Isolated from a Recreational Freshwater Kettle Lake in Ontario, Canada.

Bacillus anthracis is widespread in soil and a causative agent of anthrax, primarily in herbivores. Here, we report the draft genome sequence of Bacillus anthracis strain N1, which was isolated from a recreational freshwater lake and found to carry multiple antibiotic resistance genes and biosynthetic gene clusters.

Draft Genome Sequence of Exiguobacterium sp. Strain N5, Isolated from a Recreational Freshwater Kettle Lake in Ontario.

Exiguobacterium spp. are facultative anaerobic, Gram-positive, non-spore-forming bacilli, reported to tolerate extreme environments. Here, we report the draft genome sequence of Exiguobacterium sp. strain N5, isolated from a recreational freshwater lake.

Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and therapy resistance. Devimistat is a novel agent that inhibits pyruvate dehydrogenase complex (PDH). A phase III clinical trial in AML patients combining devimistat and chemotherapy was terminated for futility, suggesting AML cells were able to circumvent the metabolic inhibition of devimistat. The means by which AML cells resist PDH inhibition is unknown. AML cell lines treated with devimistat or deleted for the essential PDH subunit, PDHA, showed a decrease in glycolysis and decreased glucose uptake due to a reduction of the glucose transporter GLUT1 and hexokinase II. Both devimistat-treated and PDHA knockout cells displayed increased sensitivity to 2-deoxyglucose, demonstrating reliance on residual glycolysis. The rate limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase 2 (PCK2) was significantly upregulated in devimistat-treated cells, and its inhibition increased sensitivity to devimistat. The gluconeogenic amino acids glutamine and asparagine protected AML cells from devimistat. Non-glycolytic sources of acetyl-CoA were also important with fatty acid oxidation, ATP citrate lyase (ACLY) and acyl-CoA synthetase short chain family member 2 (ACSS2) contributing to resistance. Finally, devimistat reduced fatty acid synthase (FASN) activity. Taken together, this suggests that AML cells compensate for PDH and glycolysis inhibition by gluconeogenesis for maintenance of essential glycolytic intermediates and fatty acid oxidation, ACLY and ACSS2 for non-glycolytic production of acetyl-CoA. Strategies to target these escape pathways should be explored in AML.

Characterization of Escherichia coli and Other Enterobacterales Resistant to Extended-Spectrum Cephalosporins Isolated from Dairy Manure in Ontario, Canada.

Extended-spectrum cephalosporins (ESCs) resistance genes, such as blaCTX-M, blaCMY, and blaSHV, have been found regularly in bacteria from livestock. However, information on their distribution in dairy cattle in Canada and on the associated genome sequences of ESC-resistant Enterobacterales is sparse. In this study, the diversity and distribution of ESC-resistant Escherichia coli throughout manure treatments in six farms in Southern Ontario were assessed over a one-year period, and their ESC-resistance plasmids were characterized. The manure samples were enriched using selective media. The resulting isolates were screened via polymerase chain reaction for blaCTX-M, blaCMY, and blaSHV. No E. coli carrying blaSHV were detected. Escherichia coli (n = 248) carrying blaCTX-M or blaCMY underwent whole-genome sequencing using an Illumina MiSeq/NextSeq. These isolates were typed using multilocus sequence typing (MLST) and their resistance gene profiles. A subset of E. coli (n = 28) were sequenced using Oxford Nanopore Technologies. Plasmids were assembled using Unicycler and characterized via the resistance genes pattern, replicon type, plasmid MLST, phylogenetic analysis, and Mauve alignments. The recovery of ESC-resistant Enterobacterales (18 species, 8 genera) was drastically reduced in manure outputs. However, multiple treatment stages were needed to attain a significant reduction. 62 sequence types were identified, with ST10, ST46, ST58, ST155, ST190, ST398, ST685, and ST8761 being detected throughout the treatment pipeline. These STs overlapped with those found on multiple farms. The ESC-resistance determinants included CTX-M-1, -14, -15, -17, -24, -32, -55, and CMY-2. The plasmids carrying blaCTX-M were more diverse than were the plasmids carrying blaCMY. Known "epidemic plasmids" were detected for both blaCTX-M and blaCMY. IMPORTANCE The increase in antimicrobial resistance is of concern for human and animal health, especially when resistance is conferred to extended-spectrum cephalosporins, which are used to treat serious infections in both human and veterinary medicine. Bacteria carrying extended-spectrum cephalosporin resistance genes, including blaCTX-M and blaCMY, are frequently found in dairy manure. Manure treatment influences the loads and diversity of bacteria, including those carrying antimicrobial resistance genes, such as Enterobacterales and Escherichia coli. Any bacteria that survive the treatment process are subsequently applied to the environment. Enterobacterales carrying blaCTX-M or blaCMY can contaminate soil and crops consumed by humans and animals, thereby increasing the potential for antimicrobial resistance genes to integrate into the human gut microflora through horizontal gene transfer. This furthers the dissemination of resistance. Therefore, it is imperative to understand the effects manure treatments have on ESC-resistance in environmentally applied manure.

Longitudinal association between cardiovascular risk factors and depression in young people: a systematic review and meta-analysis of cohort studies.

BACKGROUND: Depression is a common and serious mental illness that begins early in life. An association between cardiovascular disease (CVD) and subsequent depression is clear in adults. We examined associations between individual CVD risk factors and depression in young people. METHODS: We searched MEDLINE, EMBASE, and PsycINFO databases from inception to 1 January 2020. We extracted data from cohort studies assessing the longitudinal association between CVD risk factors [body mass index (BMI), smoking, systolic blood pressure (SBP), total cholesterol, high-density lipoprotein] and depression, measured using a validated tool in individuals with mean age of 24 years or younger. Random effect meta-analysis was used to combine effect estimates from individual studies, including odds ratio (OR) for depression and standardised mean difference for depressive symptoms. RESULTS: Based on meta-analysis of seven studies, comprising 15 753 participants, high BMI was associated with subsequent depression [pooled OR 1.61; 95% confidence interval (CI) 1.21-2.14; I2 = 31%]. Based on meta-analysis of eight studies, comprising 30 539 participants, smoking was associated with subsequent depression (pooled OR 1.73; 95% CI 1.36-2.20; I2 = 74%). Low, but not high, SBP was associated with an increased risk of depression (pooled OR 3.32; 95% CI 1.68-6.55; I2 = 0%), although this was based on a small pooled high-risk sample of 893 participants. Generalisability may be limited as most studies were based in North America or Europe. CONCLUSIONS: Targeting childhood/adolescent smoking and obesity may be important for the prevention of both CVD and depression across the lifespan. Further research on other CVD risk factors including blood pressure and cholesterol in young people is required.

Neuronal expression of ndst3 in early zebrafish development is responsive to Wnt signaling manipulation.

Heparan sulfate proteoglycans (HSPGs) are constituents of the cell surface and extracellular matrix and are vital for various activities within the cell. The N-deacetylase/N-sulfotransferase (heparin glucosaminyl) family of enzymes, or NDST, modifies heparan sulfate (HS) by catalyzing both the N-deacetylation and the N-sulfation of N-acetylglucosamine residues. In zebrafish, a single ndst3 gene is an orthologue of both mammalian NDST3 and NDST4 genes. The role of ndst3 in zebrafish development has not been investigated and such study may provide insight into the role(s) of both mammalian orthologues. Here, we characterized expression of ndst3 during early development in zebrafish and found it to be predominately neuronal. We found that expression of ndst3 is sensitive to Wnt signaling manipulation, with stimulation of the Wnt pathway resulting in robust expansion of ndst3 expression domains. Finally, using CRISPR/Cas9 genome editing, we mutagenized the ndst3 gene and isolated an allele, ndst3nu20, resulting in a frameshift and premature protein truncation. We discovered Ndst3 is not essential for zebrafish survival as ndst3nu20 homozygous mutants are viable and fertile.