Genotypic determinants of fluoroquinolone and macrolide resistance in Neisseria gonorrhoeae.

Background:High rates of antimicrobial resistance (AMR) in Neisseria gonorrhoeae hinder effective treatment, but molecular AMR diagnostics may help address the challenge. This study aimed to appraise the literature for resistance-associated genotypic markers linked to fluoroquinolones and macrolides, to identify and review their use in diagnostics. Methods: Medline and EMBASE databases were searched and data pooled to evaluate associations between genotype and phenotypic resistance. The minimum inhibitory concentration (MIC) cut-offs were ≤ 0.06 mg L-1 for non-resistance to ciprofloxacin and ≤ 0.5 mg L-1 for non-resistance to azithromycin. Results: Diagnostic accuracy estimates were limited by data availability and reporting. It was found that: 1) S91 and D95 mutations in the GyrA protein independently predicted ciprofloxacin resistance and, used together, gave 98.6% (95% confidence interval (CI) 98.0-99.0%) sensitivity and 91.4% (95%CI 88.6-93.7%) specificity; 2) the number of 23S rRNA gene alleles with C2611T or A2059G mutations was highly correlated with azithromycin resistance, with mutation in any allele giving a sensitivity and specificity of 66.1% (95%CI 62.1-70.0%) and 98.9% (95%CI 97.5-99.5%) respectively. Estimated negative (NPV) and positive predictive values (PPV) for a 23S rRNA diagnostic were 98.6% (95%CI 96.8-99.4%) and 71.5% (95%CI 68.0-74.8%) respectively; 3) mutation at amino acid position G45 in the MtrR protein independently predicted azithromycin resistance; however, when combined with 23S rRNA, did not improve the PPV or NPV. Conclusions: Viable candidates for markers of resistance detection for incorporation into diagnostics were demonstrated. Such tests may enhance antibiotic stewardship and treatment options

The Role of Emergency and Primary Care in Combating the Rise of Gonorrhea: Another Purview Paradox?

INTRODUCTION: Drug-resistant Neisseria gonorrhoeae is an urgent threat to public health. Novel prevention and treatment strategies are emerging, including immunizations, pharmacologic post-exposure prophylaxis, rapid molecular resistance assays, and novel antibiotics. However, where and how such strategies are optimally implemented remains unclear. METHODS: We conducted a retrospective interrupted time series analysis of gonorrhea cases reported to the Massachusetts Department of Public Health. We collected names of treating providers from 2011 (n = 100) and 2022 (n = 108), and cross-referenced provider names with publicly available records from the Massachusetts Boards of Registration in Medicine and Nursing to identify provider type, specialty, year of terminal degree or licensure, and clinic type. RESULTS: Of 208 providers, 111 (53.4%) were advanced care practitioners. Providers treated cases predominantly in community health centers (n = 65, 31.3%) and emergency departments or urgent care centers (n = 60, 28.8%). Only 11 (12.4%) of 89 physicians were trained in either adult or pediatric infectious diseases. CONCLUSION: Our results indicate that the majority of gonorrhea cases in the Massachusetts are treated in non-specialty settings. The time is now to plan for implementation of the emerging strategies to avoid underutilization and assure uptake of interventions in settings positioned to reach persons diagnosed with gonorrhea who will benefit most

The Development and Performance of a Machine Learning Based Mobile Platform for Visually Determining the Etiology of Penile Pathology

Machine-learning algorithms can facilitate low-cost, user-guided visual diagnostic platforms for addressing disparities in access to sexual health services. We developed a clinical image dataset using original and augmented images for five penile diseases: herpes eruption, syphilitic chancres, penile candidiasis, penile cancer, and genital warts. We used a U-net architecture model for semantic pixel segmentation into background or subject image, the Inception-ResNet version 2 neural architecture to classify each pixel as diseased or non-diseased, and a salience map using GradCAM++. We trained the model on a random 91% sample of the image database using 150 epochs per image, and evaluated the model on the remaining 9% of images, assessing recall (or sensitivity), precision, specificity, and F1-score (accuracy). Of the 239 images in the validation dataset, 45 (18.8%) were of genital warts, 43 (18.0%) were of HSV infection, 29 (12.1%) were of penile cancer, 40 (16.7%) were of penile candidiasis, 37 (15.5%) were of syphilitic chancres, and 45 (18.8%) were of non-diseased penises. The overall accuracy of the model for correctly classifying the diseased image was 0.944. Between July 1st and October 1st 2023, there were 2,640 unique users of the mobile platform. Among a random sample of submissions (n=437), 271 (62.0%) were from the United States, 64 (14.6%) from Singapore, 41 (9.4%) from Candia, 40 (9.2%) from the United Kingdom, and 21 (4.8%) from Vietnam. The majority (n=277 [63.4%]) were between 18 and 30 years old. We report on the development of a machine-learning model for classifying five penile diseases, which demonstrated excellent performance on a validation dataset. That model is currently in use globally and has the potential to improve access to diagnostic services for penile diseases.Comment: 12 pages, 2 figure, 2 table

Magnesium nebulization utilization in management of pediatric asthma (MagNUM PA) trial: study protocol for a randomized controlled trial

BACKGROUND: Up to 30 % of children with acute asthma are refractory to initial therapy, and 84 % of this subpopulation needs hospitalization. Finding safe, noninvasive, and effective strategies to treat this high-risk group would substantially decrease hospitalizations, healthcare costs, and the psycho-social burden of the disease. Whereas intravenous magnesium (Mg) is effective in severe refractory asthma, its use is sporadic due to safety concerns, with the main treatment goal being to prevent intensive care unit admission. In contrast, nebulized Mg is noninvasive, allows higher pulmonary drug concentrations, and has a much higher safety potential due to the lower rate of systemic delivery. Previous studies of inhaled Mg show disparate results due to the use of unknown/inefficient delivery methods and other methodological flaws. METHODS/DESIGN: The study is a randomized double-blind controlled trial in seven Canadian pediatric Emergency Departments (two-center pilot 2011 to 2014, Canada-wide November 2014 to December 2017). The trial will include 816 otherwise healthy children who are 2 to 17 years old, having had at least one previous wheezing episode, have received systemic corticosteroids, and have a Pediatric Respiratory Assessment Measure (PRAM) ≥ 5 points after three salbutamol and ipratropium treatments for a current acute asthma exacerbation. Eligible consenting children will receive three experimental treatments of nebulized salbutamol with either 600 mg of Mg sulfate or placebo 20 min apart, using an Aeroneb Go nebulizer, which has been shown to maximize pulmonary delivery while maintaining safety. The primary outcome is hospitalization within 24 h of the start of the experimental therapy for persistent respiratory distress or supplemental oxygen. Secondary outcomes include all-cause hospitalization within 24 h, PRAM, vital signs, number of bronchodilator treatments by 240 min, and the association between the difference in the primary outcome between the groups, age, gender, baseline PRAM, atopy, and “viral induced wheeze” phenotype (Fig. 1). DISCUSSION: If effective, inhaled Mg may represent an effective strategy to minimize morbidity in pediatric refractory acute asthma. Unlike previous works, this trial targets nonresponders to optimized initial therapy who are the most likely to benefit from inhaled Mg. Future dissemination of results will include knowledge translation, incorporation into a Cochrane Review, presentation at scientific meetings, and a peer-reviewed publication. TRIAL REGISTRATION: NCTO1429415, registered 2 September 2011. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-015-1151-x) contains supplementary material, which is available to authorized users

Mapping Peptidergic Cells in Drosophila: Where DIMM Fits In

The bHLH transcription factor DIMMED has been associated with the differentiation of peptidergic cells in Drosophila. However, whether all Drosophila peptidergic cells express DIMM, and the extent to which all DIMM cells are peptidergic, have not been determined. To address these issues, we have mapped DIMM expression in the central nervous system (CNS) and periphery in the late larval stage Drosophila. At 100 hr after egg-laying, DIMM immunosignals are largely congruent with a dimm-promoter reporter (c929-GAL4) and they present a stereotyped pattern of 306 CNS cells and 52 peripheral cells. We assigned positional values for all DIMM CNS cells with respect to reference gene expression patterns, or to patterns of secondary neuroblast lineages. We could assign provisional peptide identities to 68% of DIMM-expressing CNS cells (207/306) and to 73% of DIMM-expressing peripheral cells (38/52) using a panel of 24 markers for Drosophila neuropeptide genes. Furthermore, we found that DIMM co-expression was a prevalent feature within single neuropeptide marker expression patterns. Of the 24 CNS neuropeptide gene patterns we studied, six patterns are >90% DIMM-positive, while 16 of 22 patterns are >40% DIMM-positive. Thus most or all DIMM cells in Drosophila appear to be peptidergic, and many but not all peptidergic cells express DIMM. The co-incidence of DIMM-expression among peptidergic cells is best explained by a hypothesis that DIMM promotes a specific neurosecretory phenotype we term LEAP. LEAP denotes Large cells that display Episodic release of Amidated Peptides