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Objective We reviewed our institutional experience of radical prostatectomy with and without preoperative multiparametric magnetic resonance imaging (mpMRI) to assess the impact of preoperative prostate mpMRI on surgical outcomes of radical prostatectomy. Methods We identified patients at our institution who underwent radical prostatectomy for prostate cancer (PCa) between January 2012 and December 2017 (n = 1044). Using propensity scoring analysis, patients who underwent preoperative mpMRI (n = 285) were matched 1:1 to patients who did not receive preoperative mpMRI (n = 285). Multivariable regression analysis was performed to identify factors predictive of operative time, estimated blood loss (EBL), lymph node yield, rates of complications within 30 days, and positive surgical margin (PSM). Results There were no significant differences in operative time, EBL, PSM, lymph node yield, or complication rates between the two cohorts. Multivariable analysis demonstrated that preoperative mpMRI was not predictive of the measured perioperative outcomes. Significant comorbidity (Charlson Comorbidity Index ≥3) was the sole predictor of perioperative complications (P = 0.015). Increasing biopsy Gleason score predicted increased lymph node yield (P < 0.001). The probability of PSM was associated with increasing preoperative prostate-specific antigen (odds ratio 1.036, P = 0.009). Body mass index was a predictor of operative time (P = 0.016) and EBL (P = 0.001). Conclusions Although preoperative mpMRI has an important role in the diagnosis and staging of PCa, it does not impact perioperative radical prostatectomy outcomes. Our findings do not support the routine use of preoperative mpMRI for surgical planning in patients already diagnosed with clinically localized PCa.

Objectives: Our goal was to conduct a hemodynamic analysis of a novel animal model of Fontan physiology. Poor late-term outcomes in Fontan patients are believed to arise from Fontan-induced hemodynamics, but the mechanisms remain poorly understood. Recent advances in surgical experimentation have resulted in the development of a chronic sheep model of Fontan physiology; however, detailed analysis of this model is lacking. Methods: We created a single-stage Fontan model in juvenile sheep with normal biventricular circulation. The superior vena cava was anastomosed to the main pulmonary artery, and the inferior vena cava was connected to the main pulmonary artery using an expanded polytetrafluoroethylene conduit. Longitudinal hemodynamics, including catheterization and magnetic resonance imaging were evaluated. Results: Four out of 12 animals survived, with the longest surviving animal living 3 years after single-stage Fontan. We showed a significant era effect regarding survival (1 out of 8 and subsequently 3 out of 4 animals surviving beyond 2 months) attributed in large part to the procedural learning curve. Key characteristics of Fontan hemodynamics, namely systemic venous hypertension and low normal cardiac output, were observed. However, recapitulation of passive human Fontan hemodynamics is affected by volume loading of the right ventricle given an anatomic difference in sheep azygous venous anatomy draining to the coronary sinus. Conclusions: A significant learning curve exists to ensure long-term survival and future surgical modifications, including banding of the main pulmonary artery and ligation of the azygous to coronary sinus connection are promising strategies to improve the fidelity of model hemodynamics.

Thirty-two family-group names and 161 genus-group names are listed for Scoliidae, including two fossil subfamilies and eight fossil genera, together with identification of type species and critiques of publication history. Campsomerinae was first made available in 1912. Contrary to previous usage, Argaman must be recognised as author of Bellimeris, Catharinimeris (not Cathimeris), Colpacampsomeris, Fasciomeris (not Fascimeris), Garantimeris, Lindenimeris, Phaleromeris (not Phalerimeris), Tetrasciton and Tristomeris. Tristomeris takes precedence as correct spelling over Tristimeris. A summary classification to genus level is provided for Scoliidae. Trielidina stat. nov. is recognised as a subtribe of Campsomerini.

Abstract Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinson’s disease (PD), with 10–30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.

Abstract A novel method for creating “golden” 3D center-out radial MRI sampling trajectories was developed and analyzed. This method, called ELECTRO (ELECTRic potential energy Optimized), uses repulsive forces to minimize electric potential energy. An objective function $$\:G\left(S\right)$$ , the electric potential energies of all subsets of consecutive readouts in a 3D radial trajectory, and its reduced form were minimized using a multi-stage optimization strategy. A metric called normalized mean nearest neighbor angular distance (NMNA) was proposed for describing distributions of points on a sphere. ELECTRO and other relevant golden trajectories were compared in silico using NMNA and point spread function analysis. Consecutive readouts from an ELECTRO trajectory were well spread out, with consistent NMNA values across sphere sizes (σNMNA = 0.005) and between regions on the sphere (NMNA ≈ 1.49). Conversely, the supergolden trajectory had poor consistency in NMNA values (σNMNA = 0.090) and clustering (NMNA = 1.28 at the pole with 40,000 readouts) that lead to artifact in the point spread function. Multi-stage optimization was faster than single-stage and obtained lower values of $$\:G\left(S\right)$$ (e.g., 0.87 vs. 0.91, for a sphere size of 40). In conclusion, ELECTRO trajectories are more golden than other 3D center-out radial trajectories, making them a suitable candidate for dynamic 3D MR imaging.

In the United States in 2021, an outbreak of 4 cases of Burkholderia pseudomallei, the etiologic agent of melioidosis and a Tier One Select Agent (potential for deliberate misuse and subsequent harm), resulted in 2 deaths. The causative strain, B. pseudomallei ATS2021, was unintentionally imported into the United States in an aromatherapy spray manufactured in India. We established that ATS2021 represents a virulent strain of B. pseudomallei capable of robust formation of biofilm at physiologic temperatures that may contribute to virulence. By using mouse melioidosis models, we determined median lethal dose estimates and analyzed the bacteriologic and histopathologic characteristics of the organism, particularly the potential neurologic pathogenesis that is probably associated with the bimABm allele identified in B. pseudomallei strain ATS2021. Our data, combined with previous case reports and the identification of endemic B. pseudomallei strains in Mississippi, support the concept that melioidosis is emerging in the United States.

Introduction: The prevalence of depression and anxiety in cancer patients is approximately 15% and 20%. Unfortunately, depression has been demonstrated to negatively impact patients after spinal fusion surgeries and is associated with worse overall survival in cancer patients. The rates of depression and anxiety have yet to be reported in patients with metastatic spine disease. The objective of this study was to determine the rate of depression and anxiety in patients with metastatic spine disease. MATERIALS AND METHODS: Patients >18 years of age at our institution who presented with metastatic spinal disease between 2017 and 2022 were identified through query search and verified by chart review of operative and biopsy notes. Patients who carried a depression and anxiety diagnosis were identified through a review of documentation in the electronic medical record. Demographic and surgical characteristics were recorded. Results: One hundred and fifty patients were identified. The average age and Charlson Comorbidity Index were 63.5 ± 13.0 and 8.34 ± 2.76, respectively. There were 84 (56.0%) males, 28 (18.7%) patients carrying a diagnosis of diabetes, and 40 (26.7%) current smokers. There were 127 (84.7%) surgeries performed for spinal metastases. The most common operative location was the thoracic spine (42.5%), while the sacrum was the least common (2.36%). Overall, 20.00% of our cohort carried a diagnosis of depression, 17.3% carried a diagnosis of anxiety, and 28.7% carried a diagnosis of either depression or anxiety. The most common primary cancers were lung (20.67%), breast (17.33%), and prostate cancers (15.33%). Conclusion: Our study demonstrates elevated rates of depression and anxiety in patients with spinal metastatic disease relative to the general population. When evaluating patients with spinal metastases, spine surgeons have an opportunity to screen for symptoms and place an early referral to a mental health professional.

Abstract N. gonorrhoeae, which causes the sexually transmissible infection gonorrhoea, remains a significant public health threat globally, with challenges posed by increasing transmission and antimicrobial resistance (AMR). The COVID-19 pandemic introduced exceptional circumstances into communicable disease control, impacting the transmission of gonorrhoea and other infectious diseases. Through phylogenomic and phylodynamic analysis of 5881 N. gonorrhoeae genomes from Australia, we investigated N. gonorrhoeae transmission over five years, including a time period during the COVID-19 pandemic. Using a novel cgMLST-based genetic threshold, we demonstrate persistence of large N. gonorrhoeae genomic clusters over several years, with some persistent clusters associated with heterosexual transmission. We observed a decline in both N. gonorrhoeae transmission and genomic diversity during the COVID-19 pandemic, suggestive of an evolutionary bottleneck. The longitudinal, occult transmission of N. gonorrhoeae over many years further highlights the urgent need for improved diagnostic, treatment, and prevention strategies for gonorrhoea.

Abstract The Clostridia produce and secrete Large Clostridial Glucosylating Toxins (LCGTs) responsible for disease symptoms, but the secretion mechanism is largely unknown. Recently, a holin-like protein was shown to be essential for toxin secretion. Holins, typically bacteriophage-specific proteins, are part of the holin-endo(lysin) system that releases phage progeny. To determine if the clostridia also use a lysin, we investigated two conserved putative lysins, M7404_01910 and M7404_02200, in the release of the LCGTs TcdA and TcdB from a Clostridioides difficile ribotype 027 strain, M7404. Sequence analysis and structural modelling indicates that both proteins are related to N-acetylmuramoyl-l-alanine amidases, similar to CD27L, a lysin from the C. difficile phage ΦCD27. Disruption of these genes reveal that only M7404_02200 contributes to toxin secretion and does so in a non-lytic fashion. Peptidoglycan hydrolysis assays show that recombinant M7404_02200 is an active peptidoglycan amidase, confirming its role in TcdA and TcdB secretion in C. difficile M7404.

Abstract Background Growing evidence suggests that distal regulatory elements are essential for cellular function and states. The sequences within these distal elements, especially motifs for transcription factor binding, provide critical information about the underlying regulatory programs. However, cooperativities between transcription factors that recognize these motifs are nonlinear and multiplexed, rendering traditional modeling methods insufficient to capture the underlying mechanisms. Recent development of attention mechanism, which exhibit superior performance in capturing dependencies across input sequences, makes them well-suited to uncover and decipher intricate dependencies between regulatory elements. Result We present Transcription factors cooperativity Inference Analysis with Neural Attention (TIANA), a deep learning framework that focuses on interpretability. In this study, we demonstrated that TIANA could discover biologically relevant insights into co-occurring pairs of transcription factor motifs. Compared with existing tools, TIANA showed superior interpretability and robust performance in identifying putative transcription factor cooperativities from co-occurring motifs. Conclusion Our results suggest that TIANA can be an effective tool to decipher transcription factor cooperativities from distal sequence data. TIANA can be accessed through: https://github.com/rzzli/TIANA .

Abstract Background Glaucoma patients with irreversible visual field loss often experience decreased quality of life, impaired mobility, and mental health challenges. Perceptual learning (PL) and transcranial electrical stimulation (tES) have emerged as promising interventions for vision rehabilitation, showing potential in restoring residual visual functions. The Glaucoma Rehabilitation using ElectricAI Transcranial stimulation (GREAT) project aims to investigate whether combining PL and tES is more effective than using either method alone in maximizing the visual function of glaucoma patients. Additionally, the study will assess the impact of these interventions on brain neural activity, blood biomarkers, mobility, mental health, quality of life, and fear of falling. Methods The study employs a three-arm, double-blind, randomized, superiority-controlled design. Participants are randomly allocated in a 1:1:1 ratio to one of three groups receiving: (1) real PL and real tES, (2) real PL and sham tES, and (3) placebo PL and sham tES. Each participant undergoes 10 sessions per block (~ 1 h each), with a total of three blocks. Assessments are conducted at six time points: baseline, interim 1, interim 2, post-intervention, 1-month post-intervention, and 2-month post-intervention. The primary outcome is the mean deviation of the 24-2 visual field measured by the Humphrey visual field analyzer. Secondary outcomes include detection rate in the suprathreshold visual field, balance and gait functions, and electrophysiological and biological responses. This study also investigates changes in neurotransmitter metabolism, biomarkers, self-perceived quality of life, and psychological status before and after the intervention. Discussion The GREAT project is the first study to assess the effectiveness of PL and tES in the rehabilitation of glaucoma. Our findings will offer comprehensive assessments of the impact of these treatments on a wide range of brain and vision-related metrics including visual field, neural activity, biomarkers, mobility, mental health, fear of falling, and quality of life. Trial registration ClinicalTrials.gov NCT05874258 . Registered on May 15, 2023.

Abstract Background Accurately assessing corneal structural status is challenging when thickness deviates from the average. Polarization-sensitive optical coherence tomography (PS-OCT) measures tissue-specific polarization changes, providing additional contrast for accurate segmentations and aids in phase retardation (PR) measurements. Previous studies have shown PR's effectiveness in identifying sub-clinical keratoconus (KC) in asymmetric cases. Thus, this study aims to assess PR distribution in thick corneas with and without KC. Methods In this retrospective and cross-sectional study, 45 thick corneas from 30 Asian-Indian subjects, categorized into healthy (n = 26) and KC (n = 19) groups were analyzed. All eyes underwent standard clinical evaluations, tomographic assessments, and corneal biomechanics measurements. PR and individual layer thicknesses were measured using custom-designed ultrahigh-resolution PS-OCT. PR en-face maps were generated. Individual layer thicknesses and PR analysis was conducted across multiple zones, extending up to 8–10 mm in diameter. All eyes in the study had not undergone interventions, received topical medications, or had previous corneal disease history. Results Significant differences were found in spherical and cylindrical powers, keratometry, pachymetry, and biomechanical indices (all P

Abstract Background Sexually transmitted infections (STIs) pose a significant global public health challenge. Early diagnosis and treatment reduce STI transmission, but rely on recognising symptoms and care-seeking behaviour of the individual. Digital health software that distinguishes STI skin conditions could improve health-seeking behaviour. We developed and evaluated a deep learning model to differentiate STIs from non-STIs based on clinical images and symptoms. Methods We used 4913 clinical images of genital lesions and metadata from the Melbourne Sexual Health Centre collected during 2010–2023. We developed two binary classification models to distinguish STIs from non-STIs: (1) a convolutional neural network (CNN) using images only and (2) an integrated model combining both CNN and fully connected neural network (FCN) using images and metadata. We evaluated the model performance by the area under the ROC curve (AUC) and assessed metadata contributions to the Image-only model. Results Our study included 1583 STI and 3330 non-STI images. Common STI diagnoses were syphilis (34.6%), genital warts (24.5%) and herpes (19.4%), while most non-STIs (80.3%) were conditions such as dermatitis, lichen sclerosis and balanitis. In both STI and non-STI groups, the most frequently observed groups were 25–34 years (48.6% and 38.2%, respectively) and heterosexual males (60.3% and 45.9%, respectively). The Image-only model showed a reasonable performance with an AUC of 0.859 (SD 0.013). The Image + Metadata model achieved a significantly higher AUC of 0.893 (SD 0.018) compared to the Image-only model (p

Abstract Increasing placental perfusion (PP) could improve outcomes of growth‐restricted fetuses. One way of increasing PP may be by using phosphodiesterase (PDE)‐5 inhibitors, which induce vasodilatation of vascular beds. We used a combination of clinically relevant magnetic resonance imaging (MRI) techniques to characterize the impact that tadalafil infusion has on maternal, placental and fetal circulations. At 116–117 days’ gestational age (dGA; term, 150 days), pregnant ewes (n = 6) underwent fetal catheterization surgery. At 120–123 dGA ewes were anaesthetized and MRI scans were performed during three acquisition windows: a basal state and then ∼15–75 min (TAD 1) and ∼75–135 min (TAD 2) post maternal administration (24 mg; intravenous bolus) of tadalafil. Phase contrast MRI and T2 oximetry were used to measure blood flow and oxygen delivery. Placental diffusion and PP were assessed using the Diffusion‐Relaxation Combined Imaging for Detailed Placental Evaluation—‘DECIDE’ technique. Uterine artery (UtA) blood flow when normalized to maternal left ventricular cardiac output (LVCO) was reduced in both TAD periods. DECIDE imaging found no impact of tadalafil on placental diffusivity or fetoplacental blood volume fraction. Maternal‐placental blood volume fraction was increased in the TAD 2 period. Fetal DO2 and V̇O2 were not affected by maternal tadalafil administration. Maternal tadalafil administration did not increase UtA blood flow and thus may not be an effective vasodilator at the level of the UtAs. The increased maternal–placental blood volume fraction may indicate local vasodilatation of the maternal intervillous space, which may have compensated for the reduced proportion of UtA DO2.

Gait asymmetries are a common problem in clinical populations, such as those with a history of stroke or Parkinson’s disease. The use of a split-belt treadmill is one way to enhance gait symmetry but relies on specialty (and typically expensive) equipment. Alternatively, visual cues have been shown as a method to alter gait mechanics, but their utility in altering gait symmetry has been relatively understudied. Before deploying this method to clinical populations, a proof-of-concept study is needed to explore using visual cues to alter gait symmetry in healthy adults. Therefore, the purpose of this study was to examine the extent to which healthy adults could synchronize to an asymmetric visual cue with a small or large gait asymmetry using wearable sensors to measure gait asymmetries. Seventy-two healthy adults (ages: 23.89 ± 6.08 years) walked on the treadmill for two conditions: with and without the visual cue. Each walking condition lasted 10 min at the participant’s preferred walking speed. Inertial sensors were used to measure gait asymmetries. Some participants did not respond to the visual cue, and groups were separated into responders and non-responders. Participants in the small and large asymmetry-responder groups exhibited statistically significant increased asymmetries in single limb support % (p < 0.01) and step duration (s) (p < 0.05, p < 0.01, respectively). Only the large asymmetry-responder group showed statistically significant (p < 0.01) increased asymmetries in stride length. Overall, asymmetrical walking visual cues can alter gait asymmetries, and inertial sensors were sensitive enough to detect small changes in gait asymmetries.

Abstract Our study aims to delineate the phenotypes of chronic neuropsychiatric symptoms among adult subjects recovering from their first COVID that occurred more than one year ago. We also aim to explore the clinical and socioeconomic risk factors of having a high loading of chronic neuropsychiatric symptoms. We recruited a post-COVID group who suffered from their first pre-Omicron COVID more than a year ago, and a control group who had never had COVID. The subjects completed app-based questionnaires on demographic, socioeconomic and health status, a COVID symptoms checklist, mental and sleep health measures, and neurocognitive tests. The post-COVID group has a statistically significantly higher level of fatigue compared to the control group (p

Abstract The recommended first-line treatment for Mycoplasma genitalium infections is azithromycin. However, the prevalence of macrolide resistance for M. genitalium has increased to more than 50% worldwide. In 2013, Australia introduced a resistance-guided therapy (RGT) strategy to manage M. genitalium infections. This study assesses the cost-effectiveness of the RGT approach compared to no RGT (i.e., without macrolide resistance profile test) in women, men who have sex with men (MSM), and men who have sex with women (MSW) in Australia. We constructed dynamic transmission models of M. genitalium infections in women, MSM, and MSW in Australia, each with a population of 100,000. These models compared the costs and quality-adjusted life-years (QALYs) gained between RGT and no RGT scenarios from a healthcare perspective over ten years. All costs are reported in 2022 Australian dollars (Australian $). In our model, RGT is cost saving in women and MSM, with the incremental net monetary benefit of $1.3 million and $17.9 million, respectively. In MSW, the RGT approach is not cost-effective, with an incremental cost-effectiveness ratio of -$106.96 per QALY gained. RGT is cost saving compared to no RGT for M. genitalium infections in women and MSM, supporting its adoption as the national management strategy for these two population groups.

ABSTRACT The ruminant-microorganism symbiosis is unique by providing high-quality food from fibrous materials but also contributes to the production of one of the most potent greenhouse gases—methane. Mitigating methanogenesis in ruminants has been a focus of interest in the past decades. One of the promising strategies to combat methane production is the use of feed supplements, such as seaweeds, that might mitigate methanogenesis via microbiome modulation and direct chemical inhibition. We conducted in vitro investigations of the effect of three seaweeds (Ascophyllum nodosum, Asparagopsis taxiformis, and Fucus vesiculosus) harvested at different locations (Iceland, Scotland, and Portugal) on methane production. We applied metataxonomics (16S rRNA gene amplicons) and metagenomics (shotgun) methods to uncover the interplay between the microbiome’s taxonomical and functional states, methanogenesis rates, and seaweed supplementations. Methane concentration was reduced by A. nodosum and F. vesiculosus, both harvested in Scotland and A. taxiformis, with the greatest effect of the latter. A. taxiformis acted through the reduction of archaea-to-bacteria ratios but not eukaryotes-to-bacteria. Moreover, A. taxiformis application was accompanied by shifts in both taxonomic and functional profiles of the microbial communities, decreasing not only archaeal ratios but also abundances of methanogenesis-associated functions. Methanobrevibacter “SGMT” (M. smithii, M. gottschalkii, M. millerae or M. thaueri; high methane yield) to “RO” (M. ruminantium and M. olleyae; low methane yield) clades ratios were also decreased, indicating that A. taxiformis application favored Methanobrevibacter species that produce less methane. Most of the functions directly involved in methanogenesis were less abundant, while the abundances of the small subset of functions that participate in methane assimilation were increased.IMPORTANCEThe application of A. taxiformis significantly reduced methane production in vitro. We showed that this reduction was linked to changes in microbial function profiles, the decline in the overall archaeal community counts, and shifts in ratios of Methanobrevibacter “SGMT” and “RO” clades. A. nodosum and F. vesiculosus, obtained from Scotland, also decreased methane concentration in the total gas, while the same seaweed species from Iceland did not.

Objectives: The saliva of individuals with oropharyngeal gonorrhoea can contain viable Neisseria gonorrhoeae. This study examined if using saliva as a lubricant for masturbation is a risk factor for urethral gonorrhoea among men who have sex with men (MSM). Methods: In this cross-sectional study, MSM aged ≥18 years attending the Melbourne Sexual Health Centre between February 2021 and December 2023 were surveyed. Data were collected on sexual activities in the past 7 days, including receiving fellatio, condomless insertive anal sex, docking, and using saliva for masturbation. Multivariable logistic regression examined associations between these exposures and urethral gonorrhoea. Results: The median age of the 3114 men was 32 (IQR: 27-40), with 4.7% (n = 145) testing positive for urethral gonorrhoea. Urethral gonorrhoea was independently associated with an increasing number of partners for condomless insertive anal sex (P < 0.001). It was not significantly associated with receiving fellatio (P = 0.613), docking (P = 0.207), or using saliva for masturbation (P = 0.117). However, of the 110 men who only used saliva for masturbation, two (1.8%) had urethral gonorrhoea, and one (0.9%) had both urethral and oropharyngeal gonorrhoea. Conclusion: Condomless insertive anal sex is the leading risk factor for urethral gonorrhoea and not using saliva as a lubricant for masturbation.

Objective Awareness of one's individual risk of sexually transmitted infections (STIs) and human immunodeficiency virus (HIV) is a necessary precursor to engagement with prevention strategies and sexual health care. Web-based sexual health applications may improve engagement in sexual health prevention and care by providing individualised and evidence-based sexual health information. The STARTOnline ( Supporting Timely and Appropriate Review and Treatment Online ) study sought the views of sexual health service users on three web-based sexual health applications to better understand their usefulness, acceptability and accessibility. This paper reports the views and experiences of users of one of the applications called MySTIRisk. MySTIRisk estimates the risk of three common STIs and HIV using data from attendees of a metropolitan sexual health service. Methods This study used a bespoke qualitative design, informed by a developmental evaluation approach. Melbourne Sexual Health Centre clinic attendees’ views were sought using semi-structured interviews conducted between October 2023 and January 2024 via videoconferencing, telephone and on site at the clinic. Data was analysed using qualitative data analysis methods. Results A diverse group of 14 participants described an ideal pathway to better sexual health outcomes that might be facilitated by use of the MySTIRisk application, particularly for individuals with limited sexual health knowledge, or affected by stigma and geographical barriers. This pathway was described as: 1) being concerned about my sexual health ; 2) checking my STI risk easily and privately; 3) understanding and trusting the result ; and 4) deciding how to look after my health . Factors that might influence this pathway were also described, including areas for improvement in accessibility and acceptability. Conclusion These findings support the role of web-based sexual health applications in facilitating access to sexual health education and behavioural change and underscore the importance of codesign approaches in improving their uptake and impact.

Summary: Background: Gay and bisexual men (GBM) remain overrepresented among syphilis diagnoses in Australia and globally. The extent to which changes in sexual networks associated with HIV pre-exposure prophylaxis (PrEP) and treatment as prevention (TasP) may have influenced syphilis transmission among GBM at the population-level is poorly understood. We describe trends in syphilis testing and incidence among GBM in Australia over eleven years spanning widespread uptake of HIV PrEP and TasP. Methods: We analysed linked clinical data from GBM aged 16 years or older across a sentinel surveillance network in Australia from January 1, 2012, to December 31, 2022. Individuals with at least two clinic visits and with at least two syphilis tests during the observations period were included in testing and incidence analyses, respectively. Annual rates of testing and infectious syphilis incidence from 2012 to 2022 were disaggregated by HIV status and PrEP use (record of PrEP prescription; retrospectively categorised as ever or never-PrEP user). Cox regression explored associations between demographics, PrEP use and history of bacterial sexually transmissible infections (STIs) and infectious syphilis diagnosis. Findings: Among 129,278 GBM (mean age, 34.6 years [SD, 12.2]) included in testing rate analyses, 7.4% were living with HIV at entry and 31.1% were prescribed PrEP at least once during the study period. Overall syphilis testing rate was 114.0/100 person-years (py) and highest among GBM with HIV (168.4/100 py). Syphilis testing increased from 72.8/100 py to 151.8/100 py; driven largely by increases among ever-PrEP users. Among 94,710 GBM included in incidence analyses, there were 14,710 syphilis infections diagnosed over 451,560 person-years (incidence rate = 3.3/100 py). Syphilis incidence was highest among GBM with HIV (6.5/100 py), followed by ever-PrEP users (3.5/100 py) and never-PrEP users (1.4/100 py). From 2012 to 2022, syphilis incidence increased among ever-PrEP users from 1.3/100 py to 5.1/100 py, and fluctuated between 5.4/100 py and 6.6/100 py among GBM with HIV. In multivariable Cox regression, previous syphilis diagnosis (adjusted hazard ratio [aHR] = 1.98, 95% CI = 1.83–2.14), living with HIV (aHR = 1.83, 95% CI = 1.12–1.25) and recent (past 12 m) prescription of PrEP (aHR = 1.78, 95% CI = 1.61–1.97) were associated with syphilis diagnosis. Interpretation: Syphilis trends between GBM with HIV and GBM with evidence of PrEP use have converged over the past decade in Australia. Our findings recommend targeting emergent syphilis control strategies (e.g. doxycycline post-exposure prophylaxis) to GBM with prior syphilis diagnoses, using HIV PrEP or who are living with HIV. Funding: Australian Department of Health and Aged Care, National Health and Medical Research Council.

Abstract Introduction Social network‐based testing approaches (SNAs) encourage individuals (“test promoters”) to motivate sexual partners and/or those in their social networks to test for HIV. We conducted a systematic review to examine the effectiveness, acceptability and cost‐effectiveness of SNA. Methods We searched five databases from January 2010 to May 2023, and included studies that compared SNA with non‐SNA. We used random‐effects meta‐analysis to combine effect estimates. Certainty was assessed using the GRADE approach. Results We identified 47 studies. SNA may increase uptake of HIV testing compared to non‐SNA (RR 2.04, 95% CI: 1.06–3.95, Low certainty). The proportion of first‐time testers was probably higher among partners or social contacts of test promoters using SNA compared to non‐SNA (RR 1.49, 95% CI: 1.22–1.81, Moderate certainty). The proportion of people who tested positive for HIV may be higher among partners or social contacts of test promoters using SNA compared to non‐SNA (RR 1.84, 95% CI: 1.01–3.35, Low certainty). There were no reports of any adverse events or harms associated with SNA. Based on six cost‐effectiveness studies, SNA was generally cheaper per person tested and per person diagnosed compared to non‐SNA. Based on 23 qualitative studies, SNA is likely to be acceptable to a variety of populations. Discussion Our review collated evidence for SNA to HIV testing covering the key populations and the general population who may benefit from HIV testing. We summarized evidence for the effectiveness, acceptability and cost‐effectiveness of different models of SNA. While we did not identify an ideal model of SNA that could be immediately scaled up, for each setting and population targeted, we recommend various implementation considerations as our meta‐analysis showed the effectiveness might differ due to factors which include the testing modality (i.e. use of HIV self‐testing), type of test promoters, long or short duration of recruitment and use of financial incentives. Conclusions Social network‐based approaches may enhance HIV testing uptake, increase the proportion of first‐time testers and those testing positive for HIV. Heterogeneity among studies highlights the need for context‐specific adaptations, but the overall positive impact of SNA on HIV testing outcomes could support its integration into existing HIV testing services.

The study of the geometric organization of biological tissues has a rich history in the literature. However, the geometry and architecture of individual cells within tissues has traditionally relied upon manual or indirect measures of shape. Such rudimentary measures are largely a result of challenges associated with acquiring high resolution images of cells and cellular components, as well as a lack of computational approaches to analyze large volumes of high-resolution data. This is especially true with brain tissue, which is composed of a complex array of cells. Here we review computational tools that have been applied to unravel the cellular nanoarchitecture of astrocytes, a type of brain cell that is increasingly being shown to be essential for brain function. Astrocytes are among the most structurally complex and functionally diverse cells in the mammalian body and are essential partner cells of neurons. Light microscopy does not allow adequate resolution of astrocyte morphology, however, large-scale serial electron microscopy data, which provides nanometer resolution 3D models, is enabling the visualization of the fine, convoluted structure of astrocytes. Application of computer vision methods to the resulting nanoscale 3D models is helping reveal the geometry and organizing principles of astrocytes, but a complete understanding of astrocyte structure and its functional implications will require further adaptation of existing computational tools, as well as development of new approaches.

BackgroundThe 2022 global outbreak of mpox has significantly impacted health facilities, and necessitated additional infection prevention and control measures and alterations to clinic processes. Early identification of suspected mpox cases will assist in mitigating these impacts. ObjectiveWe aimed to develop and evaluate an artificial intelligence (AI)–based tool to differentiate mpox lesion images from other skin lesions seen in a sexual health clinic. MethodsWe used a data set with 2200 images, that included mpox and non-mpox lesions images, collected from Melbourne Sexual Health Centre and web resources. We adopted deep learning approaches which involved 6 different deep learning architectures to train our AI models. We subsequently evaluated the performance of each model using a hold-out data set and an external validation data set to determine the optimal model for differentiating between mpox and non-mpox lesions. ResultsThe DenseNet-121 model outperformed other models with an overall area under the receiver operating characteristic curve (AUC) of 0.928, an accuracy of 0.848, a precision of 0.942, a recall of 0.742, and an F1-score of 0.834. Implementation of a region of interest approach significantly improved the performance of all models, with the AUC for the DenseNet-121 model increasing to 0.982. This approach resulted in an increase in the correct classification of mpox images from 79% (55/70) to 94% (66/70). The effectiveness of this approach was further validated by a visual analysis with gradient-weighted class activation mapping, demonstrating a reduction in false detection within the background of lesion images. On the external validation data set, ResNet-18 and DenseNet-121 achieved the highest performance. ResNet-18 achieved an AUC of 0.990 and an accuracy of 0.947, and DenseNet-121 achieved an AUC of 0.982 and an accuracy of 0.926. ConclusionsOur study demonstrated it was possible to use an AI-based image recognition algorithm to accurately differentiate between mpox and common skin lesions. Our findings provide a foundation for future investigations aimed at refining the algorithm and establishing the place of such technology in a sexual health clinic.

Background: Medicare Part D plans are required to provide Medication therapy management (MTM) services to eligible beneficiaries to optimize medication utilization. Comprehensive medication review (CMR) is a core element of the MTM program. Despite the availability of advanced medical treatment for patients with chronic obstructive pulmonary disease (COPD), medication adherence to maintenance medications poses a continued challenge for patients with COPD. Objective: To examine the effects of CMR on medication adherence among patients with COPD. Methods: Medicare data for 2016–2017 linked to Area Health Resource Files were analyzed. The study population was Medicare beneficiaries with COPD. The intervention group consisted of beneficiaries who received CMR in 2017 but not in 2016. Patients who were eligible for MTM services but did not receive these services in 2016 or 2017 made up the control group. Propensity score matching was used to select an intervention and control group with balanced characteristics. The study outcome was adherence to COPD medications with the proportion of days covered at or above 80%. A difference-in-differences approach was adopted in the logistic regression analyses with an interaction term between the status of CMR receipt and the year 2017. Results: The study sample included 25,564 patients with COPD. The proportions of adherent patients were similar in the control group in both years but increased significantly from 60.08% in 2016 to 69.38% in 2017 in the intervention group (P

Objectives: The purpose of this study is to identify if construct length affects the rate of surgical complications and instrumentation revision following surgical fixation of subaxial and thoracolumbar Type B and C fractures. This study evaluates the effect of ankylosing spondylitis/diffuse idiopathic skeletal hyperostosis (AS/DISH) within this population on outcomes. Methods: Retrospective review of 91 cervical and 89 thoracolumbar Type B and C fractures. Groups were divided by construct length for analysis: short-segment (constructs spanning two or less segments adjacent to the fracture) and long-segment (constructs spanning more than two segments adjacent to the vertebral fracture). Results: For cervical fractures, construct length did not impact surgical complications (P = 0.641), surgical hardware revision (P = 0.167), or kyphotic change (P = 0.994). For thoracolumbar fractures, construct length did not impact surgical complications (P = 0.508), surgical hardware revision (P = 0.224), and kyphotic change (P = 0.278). Cervical Type B fractures were nonsignificantly more likely to have worsened kyphosis (P = 0.058) than Type C fractures. Assessing all regions of the spine, a diagnosis of AS/DISH was associated with an increase in kyphosis (P = 0.030) and a diagnosis of osteoporosis was associated with surgical hardware failure (P = 0.006). Conclusion: Patients with short-segment instrumentation have similar surgical outcomes and changes in kyphosis compared to those with long-segment instrumentation. A diagnosis of AS/DISH or osteoporosis was associated with worse surgical outcomes.

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

The research career of Justin O. Schmidt (1947–2023) is reviewed and assessed. The pioneering nature of his research lay in treating the defensive means and tactics of aculeate hymenoptera and some arachnids as features of their overall anti-predator strategies. He devised methods for comparing the effects of hymenopteran venoms and stings that challenged the assumed correlation between venom potency and the pain that it induces.

Abstract Background Gastric emptying (GE), with wide inter-individual but lesser intra-individual variations, is a major determinant of postprandial glycaemia in health and type 2 diabetes (T2D). However, it is uncertain whether GE of a carbohydrate-containing liquid meal is predictive of the glycaemic response to physiological meals, and whether antecedent hyperglycaemia influences GE in T2D. We evaluated the relationships of (i) the glycaemic response to both a glucose drink and mixed meals with GE of a 75 g glucose drink, and (ii) GE of a glucose drink with antecedent glycaemic control, in T2D. Methods Fifty-five treatment-naive Chinese adults with newly diagnosed T2D consumed standardised meals at breakfast, lunch and dinner with continuous interstitial glucose monitoring. On the subsequent day, a 75 g glucose drink containing 150 mg 13C-acetate was ingested to assess GE (breath test) and plasma glucose response. Serum fructosamine and HbA1c were also measured. Results Plasma glucose incremental area under the curve (iAUC) within 2 hours after oral glucose was related inversely to the gastric half-emptying time (T50) (r = −0.34, P = 0.012). The iAUCs for interstitial glucose within 2 hours after breakfast (r = −0.34, P = 0.012) and dinner (r = −0.28, P = 0.040) were also related inversely to the T50 of oral glucose. The latter, however, was unrelated to antecedent fasting plasma glucose, 24-hour mean interstitial glucose, serum fructosamine, or HbA1c. Conclusions In newly diagnosed, treatment-naive, Chinese with T2D, GE of a 75 g glucose drink predicts the glycaemic response to both a glucose drink and mixed meals, but is not influenced by spontaneous short-, medium- or longer-term elevation in glycaemia.

Abstract Drosophila melanogaster is unique among animal models because it has a fully defined synthetic diet available to study nutrient-gene interactions. However, use of this diet is limited to adult studies due to impaired larval development and survival. Here, we provide an adjusted formula that reduces the developmental period, restores fat levels, enhances body mass, and fully rescues survivorship without compromise to adult lifespan. To demonstrate an application of this formula, we explored pre-adult diet compositions of therapeutic potential in a model of an inherited metabolic disorder affecting the metabolism of branched-chain amino acids. We reveal rapid, specific, and predictable nutrient effects on the disease state consistent with observations from mouse and patient studies. Together, our diet provides a powerful means with which to examine the interplay between diet and metabolism across all life stages in an animal model.

Abstract Advancements in congenital heart surgery have heightened the importance of durable biomaterials for adult survivors. Dystrophic calcification poses a significant risk to the long-term viability of prosthetic biomaterials in these procedures. Herein, we describe the natural history of calcification in the most frequently used vascular conduits, expanded polytetrafluoroethylene grafts. Through a retrospective clinical study and an ovine model, we compare the degree of calcification between tissue-engineered vascular grafts and polytetrafluoroethylene grafts. Results indicate superior durability in tissue-engineered vascular grafts, displaying reduced late-term calcification in both clinical studies (p

Abstract The value and uncertainty associated with choice alternatives constitute critical features relevant for decisions. However, the manner in which reward and risk representations are temporally organized in the brain remains elusive. Here we leverage the spatiotemporal precision of intracranial electroencephalography, along with a simple card game designed to elicit the unfolding computation of a set of reward and risk variables, to uncover this temporal organization. Reward outcome representations across wide-spread regions follow a sequential order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We further highlight the role of the anterior insula in generalizing between reward prediction error and risk prediction error codes. Together our results emphasize the importance of neural dynamics for understanding value-based decisions under uncertainty.

The Victorian Government introduced a time-limited human papillomavirus (HPV) catch-up program for gay, bisexual, and other men who have sex with men (GBMSM) aged ≤ 26 years in 2017–2019. We conducted a retrospective observational study to examine the accuracy of the self-report of HPV vaccination status using computer-assisted self-interviewing versus their immunization history via electronic health records. We included GBMSM aged 23–30 years visiting the Melbourne Sexual Health Centre (MSHC) in 2020–2021 because they were age-eligible for the HPV catch-up program in Victoria, Australia. Individuals who were unsure about their vaccination status were categorized as ‘unvaccinated’. Of the 1,786 eligible men, 1,665 men self-reported their HPV vaccination status: 48.8% (n = 812) vaccinated, 17.4% (n = 289) unvaccinated, and 33.9% (n = 564) unsure. Self-reported HPV vaccination had a sensitivity of 61.3% (95%CI: 58.3 to 64.2%; 661/1079), a specificity of 74.2% (95%CI: 70.5 to 77.7%; 435/586), a positive predictive value of 81.4% (95%CI: 78.6 to 84.0%; 661/812), a negative predictive value of 51.0% (95%CI: 47.6 to 54.4%; 435/853), and an accuracy of 52.6% (95%CI: 50.1 to 55.0%). Our results showed that only half of GBMSM know and report their HPV vaccination status correctly. Novel approaches such as digital vaccine passports may be useful for individuals to accurately report their vaccination status to guide accurate clinical decisions and management.

Objective: HIV pre-exposure prophylaxis (PrEP) became available in Victoria, Australia, in 2016. We examined non-occupational post-exposure prophylaxis (nPEP) usage among gay, bisexual and other men who have sex with men (MSM) before and after PrEP became available. Methods: We included MSM attending Melbourne Sexual Health Centre for nPEP between 2011 and 2021. We analysed three periods: the ‘pre-PrEP’ (01 Jan 2011 to 25 Jul 2016), ‘PrEP before COVID-19’ (26 Jul 2016 to 31 Dec 2019), and ‘PrEP during COVID-19’ (01 Jan 2020 to 31 Dec 2021). Results: There were 222,978 consultations for MSM; 8292 (3.7%) were nPEP consultations. The proportion of nPEP consultations increased from 3.3% (3093/94263) in the pre-PrEP period to 4.3% (3843/89251) in the PrEP before COVID-19 period then dropped to 3.4% (1356/39464) during the COVID-19 period. Compared to Australian-born MSM, MSM born in Central/South America (adjusted odds ratio [aOR]: 1.75; 95% confidence interval [CI]: 1.27–2.40) had the highest odds of accessing nPEP, followed by Asian-born MSM (aOR: 1.47; 95% CI: 1.27–1.71) after adjusting for PrEP availability and COVID-19. Those newly arrived in Australia in ≤4 years had higher odds (aOR: 1.14; 95% CI: 1.05–1.22) of accessing nPEP than those living in Australia for >4 years. Conclusion: nPEP prescriptions declined with PrEP availability. Newly arrived overseas-born MSM who are unlikely to have access to subsidised PrEP have a higher demand of nPEP. Implications for Public Health: Increasing PrEP education and ensuring equal access is vital in the drive to reduce new HIV diagnoses.

ABSTRACT Treatment outcomes for Mycobacteroides abscessus (Mab, also known as Mycobacterium abscessus) disease are still unsatisfactory, mainly due to issues with drug toxicity, tolerability, and efficacy. Treating Mab disease is challenging due to its high baseline antibiotic resistance, initial requirement for intravenous therapy, and poor medication tolerance. Omadacycline, a new tetracycline, is active against Mab. Since any new antibiotic effective against Mab is expected to be used in combination with other antibiotics, we evaluated the efficacy of two triple-drug combinations comprising omadacycline, omadacycline + amikacin + imipenem, and omadacycline + clofazimine + linezolid against two contemporary Mab clinical isolates in a mouse model of Mab lung disease. Antibiotic administration was initiated 1-week post-infection and was given daily, with Mab burden in the lungs at treatment completion serving as the endpoint. Omadacycline alone moderately reduced Mab levels and maintained better health in mice compared to untreated ones, which typically suffered from the infection. The omadacycline + clofazimine + linezolid combination showed immediate bactericidal activity and enhanced efficacy over 6 weeks, particularly against the more resistant strain (M9507). However, the clofazimine + linezolid combination lacked early bactericidal activity. When combined with amikacin and imipenem, omadacycline did not improve the regimen’s effectiveness over 4 weeks of treatment. Our study showed that omadacycline + clofazimine + linezolid exhibited significant bactericidal activity over an extended treatment duration. However, adding omadacycline to amikacin and imipenem did not improve regimen effectiveness against the evaluated clinical isolates within 4 weeks. Further research in Mab disease patients is needed to determine the most effective omadacycline-containing regimen.IMPORTANCEMycobacteroides abscessus is a common environmental bacterium that causes infections in people with compromised lung function, including those with bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, and weakened immune systems, especially among older individuals. Treating M. abscessus disease is challenging due to the limited effectiveness and toxicity of current antibiotics, which often require prolonged use. Omadacycline, a new antibiotic, shows promise against M. abscessus. Using a mouse model that mimics M. abscessus disease in humans, we studied the effectiveness of including omadacycline with recommended antibiotics. Adding omadacycline to clofazimine and linezolid significantly improved treatment outcomes, rapidly clearing the bacteria from the lungs and maintaining effectiveness throughout. This oral combination is convenient for patients. However, adding omadacycline to amikacin and imipenem did not improve treatment effectiveness within 4 weeks. Further study with M. abscessus patients is necessary to optimize omadacycline-based treatment strategies for this disease.

Buprenorphine has been successfully used for decades in the treatment of opioid use disorder, yet there are complexities to its use that warrant attention to maximize its utility. While the package insert of the combination product buprenorphine\naloxone continues to recommend a maximum dose of 16 mg daily for maintenance, the emergence of fentanyl and synthetic analogs in the current drug supply may be limiting the effectiveness of this standard dose. Many practitioners have embraced and appropriately implemented novel practices to mitigate the sequelae of our current crisis. It has become common clinical practice to stabilize patients with 24 - 32 mg of buprenorphine daily at treatment initiation. Many of these patients, however, are maintained on these high doses (>16 mg/d) indefinitely, even after prolonged stability. Although this may be a necessary strategy in the short term, there is little evidence to support its safety and efficacy, and these high doses may be exposing patients to more complications and side effects than standard doses. Commonly known side effects of buprenorphine that are likely dose-related include hyperhidrosis, sedation, decreased libido, constipation, and hypogonadism. There are also complications related to the active metabolite of buprenorphine (norbuprenorphine) which is a full agonist at the mu opioid receptor and does not have a ceiling on respiratory suppression. Such side effects can lead to medical morbidity as well as decreased medication adherence, and we, therefore, recommend that after a period of stabilization, practitioners consider a trial of decreasing the dose of buprenorphine toward standard dose recommendations. Some patients’ path of recovery may never reach this stabilization phase (i.e., several months of adherence to medications, opioid abstinence, and other clinical indicators of stability). Side effects of buprenorphine may not have much salience when patients are struggling for survival and safety, but for those who are fortunate enough to advance in their recovery, the side effects become more problematic and can limit quality of life and adherence.

Placental function plays a crucial role in fetal development, as it serves as the primary interface for delivery of nutrients and oxygen from the mother to fetus. Magnetic resonance imaging (MRI) has significantly improved our ability to visualize and understand the placenta's complex structure and function. This review provides an up-to-date examination of the most common and novel placental MRI techniques. It will also discuss the clinical applications of MRI in diagnosing and monitoring placental insufficiency, as well as its implications for fetal growth restriction (FGR) and congenital heart disease (CHD). Ongoing research using multi-parametric MRI techniques aims to develop novel biomarkers and uncover the relationships between placental parameters and pre-onset diseased states, ultimately contributing to better maternal and fetal health outcomes, which is essential to better guide clinical judgement.

The Bacillus Calmette Guerin (BCG) vaccine has been shown to induce non-specific protection against diseases other than tuberculosis in vaccinated individuals, attributed to the induction of trained immunity. We have previously demonstrated that BCG administration induces innate immune training in mixed peripheral blood mononuclear cells and monocytes in calves. Gamma Delta (γδ) T cells are non-conventional T cells that exhibit innate and adaptive immune system features. They are in higher proportion in the peripheral blood of cattle than humans or rodents and play an essential role in bovine immune response to pathogens. In the current study, we determined if BCG administration induced innate immune training in bovine γδ T cells. A group of 16 pre-weaned Holstein calves (2-4 d age) were enrolled in the study and randomly assigned to vaccine and control groups (n=8/group). The vaccine group received two doses of 106 colony forming units (CFU) BCG Danish strain subcutaneously, separated by 2 weeks. The control group remained unvaccinated. Gamma delta T cells were purified from peripheral blood using magnetic cell sorting three weeks after receiving the 1st BCG dose. We observed functional changes in the γδ T cells from BCG-treated calves shown by increased IL-6 and TNF-α cytokine production in response to in vitro stimulation with Escherichia coli LPS and PAM3CSK4. ATAC-Seq analysis of 78,278 regions of open chromatin (peaks) revealed that γδ T cells from BCG-treated calves had an altered epigenetic status compared to cells from the control calves. Differentially accessible peaks (DAP) found near the promoters of innate immunity-related genes like Siglec14, Irf4, Ifna2, Lrrfip1, and Tnfrsf10d were 1 to 4-fold more accessible in cells from BCG-treated calves. MOTIF enrichment analysis of the sequences within DAPs, which explores transcription factor binding motifs (TFBM) upstream of regulatory elements, revealed TFBM for Eomes and IRF-5 were among the most enriched transcription factors. GO enrichment analysis of genes proximal to the DAPs showed enrichment of pathways such as regulation of IL-2 production, T-cell receptor signaling pathway, and other immune regulatory pathways. In conclusion, our study shows that subcutaneous BCG administration in pre-weaned calves can induce innate immune memory in the form of trained immunity in γδ T cells. This memory is associated with increased chromatin accessibility of innate immune response-related genes, thereby inducing a functional trained immune response evidenced by increased IL-6 and TNF-α cytokine production.

Summary: Polymyxins are often the only effective antibiotics against the “Critical” pathogen Acinetobacter baumannii. Worryingly, highly polymyxin-resistant A. baumannii displaying dependence on polymyxins has emerged in the clinic, leading to diagnosis and treatment failures. Here, we report that arginine metabolism is essential for polymyxin-dependent A. baumannii. Specifically, the arginine degradation pathway was significantly altered in polymyxin-dependent strains compared to wild-type strains, with critical metabolites (e.g., L-arginine and L-glutamate) severely depleted and expression of the astABCDE operon significantly increased. Supplementation of arginine increased bacterial metabolic activity and suppressed polymyxin dependence. Deletion of astA, the first gene in the arginine degradation pathway, decreased phosphatidylglycerol and increased phosphatidylethanolamine levels in the outer membrane, thereby reducing the interaction with polymyxins. This study elucidates the molecular mechanism by which arginine metabolism impacts polymyxin dependence in A. baumannii, underscoring its critical role in improving diagnosis and treatment of life-threatening infections caused by “undetectable” polymyxin-dependent A. baumannii.

Background: Current clinical care for common bacterial STIs (Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Mycoplasma genitalium (MG)) involves empiric antimicrobial therapy when clients are symptomatic, or if asymptomatic, waiting for laboratory testing and recall if indicated. Near-to-patient testing (NPT) can improve pathogen-specific prescribing and reduce unnecessary or inappropriate antibiotic use in treating sexually transmitted infections (STI) by providing same-day delivery of results and treatment. Methods: We compared the economic cost of NPT to current clinic practice for managing clients with suspected proctitis, non-gonococcal urethritis (NGU), or as an STI contact, from a health provider’s perspective. With a microsimulation of 1000 clients, we calculated the cost per client tested and per STI- and pathogen- detected for each testing strategy. Sensitivity analyses were conducted to assess the robustness of the main outcomes. Costs are reported as Australian dollars (2023). Results: In the standard care arm, cost per client tested for proctitis, NGU in men who have sex with men (MSM) and heterosexual men were the highest at $247.96 (95% Prediction Interval (PI): 246.77–249.15), $204.23 (95% PI: 202.70–205.75) and $195.01 (95% PI: 193.81–196.21) respectively. Comparatively, in the NPT arm, it costs $162.36 (95% PI: 161.43–163.28), $158.39 (95% PI: 157.62–159.15) and $149.17 (95% PI: 148.62–149.73), respectively. Using NPT resulted in cost savings of 34.52%, 22.45% and 23.51%, respectively. Among all the testing strategies, substantial difference in cost per client tested between the standard care arm and the NPT arm was observed for contacts of CT or NG, varying from 27.37% to 35.28%. Conclusion: We found that NPT is cost-saving compared with standard clinical care for individuals with STI symptoms and sexual contacts of CT, NG, and MG.

IntroductionThe fetal haemodynamic response to acute episodes of hypoxaemia are well characterised. However, how these responses change when the hypoxaemia becomes more chronic in nature such as that associated with fetal growth restriction (FGR), is less well understood. Herein, we utilised a combination of clinically relevant MRI techniques to comprehensively characterize and differentiate the haemodynamic responses occurring during acute and chronic periods of fetal hypoxaemia.MethodsPrior to conception, carunclectomy surgery was performed on non-pregnant ewes to induce FGR. At 108–110 days (d) gestational age (GA), pregnant ewes bearing control (n = 12) and FGR (n = 9) fetuses underwent fetal catheterisation surgery. At 117–119 days GA, ewes underwent MRI sessions where phase-contrast (PC) and T2 oximetry were used to measure blood flow and oxygenation, respectively, throughout the fetal circulation during a normoxia and then an acute hypoxia state.ResultsFetal oxygen delivery (DO2) was lower in FGR fetuses than controls during the normoxia state but cerebral DO2 remained similar between fetal groups. Acute hypoxia reduced both overall fetal and cerebral DO2. FGR increased ductus venosus (DV) and foramen ovale (FO) blood flow during both the normoxia and acute hypoxia states. Pulmonary blood flow (PBF) was lower in FGR fetuses during the normoxia state but similar to controls during the acute hypoxia state when PBF in controls was decreased.ConclusionDespite a prevailing level of chronic hypoxaemia, the FGR fetus upregulates the preferential streaming of oxygen-rich blood via the DV-FO pathway to maintain cerebral DO2. However, this upregulation is unable to maintain cerebral DO2 during further exposure to an acute episode of hypoxaemia. The haemodynamic alterations required at the level of the liver and lung to allow the DV-FO pathway to maintain cerebral DO2, may have lasting consequences on hepatic function and pulmonary vascular regulation after birth.

Summary: Background: In Australia the incidence of HIV has declined steadily, yet sustained reduction of HIV transmission in this setting requires improved public health responses. As enhanced public health responses and prioritisation of resources may be guided by molecular epidemiological data, here we aimed to assess the applicability of these approaches in Victoria, Australia. Methods: A comprehensive collection of HIV-1 pol sequences from individuals diagnosed with HIV in Victoria, Australia, between January 1st 2000 and December 31st 2020 were deidentified and used as the basis of our assessment. These sequences were subtyped and surveillance drug resistance mutations (SDRMs) identified, before definition of transmission groups was performed using HIV-TRACE (0.4.4). Phylodynamic methods were applied using BEAST (2.6.6), assessing effective reproductive numbers for large groups, and additional demographic data were integrated to provide a high resolution view of HIV transmission in Victoria on a decadal time scale. Findings: Based on standard settings for HIV-TRACE, 70% (2438/3507) of analysed HIV-1 pol sequences were readily assigned to a transmission group. Individuals in transmission groups were more commonly males (aOR 1.50), those born in Australia (aOR 2.13), those with probable place of acquisition as Victoria (aOR 6.73), and/or those reporting injectable drug use (aOR 2.13). SDRMs were identified in 375 patients (10.7%), with sustained transmission of these limited to a subset of smaller groups. Informative patterns of epidemic growth, stabilisation, and decline were observed; many transmission groups showed effective reproductive numbers (Re) values reaching greater than 4.0, representing considerable epidemic growth, while others maintained low Re values. Interpretation: This study provides a high resolution view of HIV transmission in Victoria, Australia, and highlights the potential of molecular epidemiology to guide and enhance public health responses in this setting. This informs ongoing discussions with community groups on the acceptability and place of molecular epidemiological approaches in Australia. Funding: National Health and Medical Research Council, Australian Research Council.

Summary: Background: High coverage of pre-exposure prophylaxis (PrEP) will reduce HIV transmission and help end the HIV/AIDS pandemic. However, PrEP users face challenges, including long-term adherence. The study aimed to document the proportions of individuals who restart HIV PrEP after they stop and the reasons for restarting PrEP. Methods: This study is a systematic review and meta-analysis. We systematically searched CINAHL, Embase, Emcare, Global Health, Medline, Scopus, and PsychINFO for peer-reviewed with no date restrictions. A grey literature search was conducted through Google search, a search of abstract books of AIDS conferences and the websites of WHO and UNAIDS. The data search was conducted in April 2023 and updated in February 2024. Two authors extracted data on the proportion of people who stopped and then restarted PrEP, reasons for restarting, and strategies to support people restarting PrEP. Two authors appraised the data using the Joanna Briggs Institute Appraisal Tools. We used a random-effects meta-analysis to pool estimates of restarting. We conducted meta-regression to determine potential sources of heterogeneity. This study is registered with PROSPERO, CRD42023416777. However, we deviated from our original plan as we did not identify enough studies for strategies to support restarting PrEP (primary objective). Subsequently, we revised our plan to strengthen our secondary objective to quantify the proportion of people who stopped and restarted PrEP, and explore possible reasons for its heterogeneity. Findings: Of 988 studies, 30 unique studieswere included: 27 reported the proportion restarting PrEP, and of these, 7 also reported reasons for restarting PrEP, and 3 studies reported only on the reasons for restarting PrEP. No study evaluated interventions for restarting PrEP. For the meta-analysis, we included 27 studies. Most studies were from high-income countries (17/27, 63%) or the USA (15/27, 56%). Overall, 23.8% (95% CI: 15.9–32.7, I2 = 99.8%, N = 85,683) of people who stopped PrEP restarted PrEP. There was a lower proportion of restarting in studies from middle-income countries compared to high-income countries (adjusted odds ratio (aOR) 0.6, 95% CI: 0.50–0.73, p 1 month compared to those who stopped