A Brief Alcohol Intervention (BAI) to reduce alcohol use and improve PrEP outcomes among men who have sex with men in Vietnam: study protocol for a randomized controlled trial.

BACKGROUND: In Vietnam and other global settings, men who have sex with men (MSM) have become the population at greatest risk of HIV infection. Although HIV pre-exposure prophylaxis (PrEP) has been implemented as a prevention strategy, PrEP outcomes may be affected by low persistence and adherence among MSM with unhealthy alcohol use. MSM have a high prevalence of unhealthy alcohol use in Vietnam, which may affect PrEP outcomes. METHODS: Design: We will conduct a two-arm hybrid type 1 effectiveness-implementation randomized controlled trial of a brief alcohol intervention (BAI) compared to the standard of care (SOC) at the Sexual Health Promotion (SHP) clinic Hanoi, Vietnam. PARTICIPANTS: Sexually active MSM (n=564) who are newly initiating PrEP or re-initiating PrEP and have unhealthy alcohol use will be recruited and randomized 1:1 to the SOC or BAI arm. A subgroup of participants (n=20) in each arm will be selected for longitudinal qualitative interviews; an additional subset (n=48) in the BAI arm will complete brief quantitative and qualitative interviews after completion of the BAI to assess the acceptability of the intervention. Additional implementation outcomes will be assessed through interviews with clinic staff and stakeholders (n=35). INTERVENTION: Study participants in both arms will receive standard care for PrEP clients. In the BAI arm, each participant will receive two face-to-face intervention sessions and two brief booster phone sessions, based on cognitive behavioral therapy and delivered in motivational interviewing informed style, to address their unhealthy alcohol use. OUTCOMES: Effectiveness (PrEP and alcohol use) and cost-effectiveness outcomes will be compared between the two arms. Intervention implementation outcomes (acceptability, feasibility, adoption) will be assessed among MSM participants, clinic staff, and stakeholders. DISCUSSION: This proposed trial will assess an alcohol intervention for MSM with unhealthy alcohol use who initiate or re-initiate PrEP, while simultaneously preparing for subsequent implementation. The study will measure the effectiveness of the BAI for increasing PrEP persistence through reducing unhealthy alcohol use in a setting where excessive alcohol consumption is a normative behavior. If effective, implementation-focused results will inform future scale-up of the BAI in similar settings. TRIAL REGISTRATION: NCT06094634 on clinicaltrials.gov. Registered 16 October 2023.

Clinical and genomic diversity of Treponema pallidum subspecies pallidum to inform vaccine research: an international, molecular epidemiology study.

BACKGROUND: The increase in syphilis rates worldwide necessitates development of a vaccine with global efficacy. We aimed to explore Treponema pallidum subspecies pallidum (TPA) molecular epidemiology essential for vaccine research by analysing clinical data and specimens from early syphilis patients using whole-genome sequencing (WGS) and publicly available WGS data. METHODS: In this multicentre, cross-sectional, molecular epidemiology study, we enrolled patients with primary, secondary, or early latent syphilis from clinics in China, Colombia, Malawi, and the USA between Nov 28, 2019, and May 27, 2022. Participants aged 18 years or older with laboratory confirmation of syphilis by direct detection methods or serological testing, or both, were included. Patients were excluded from enrolment if they were unwilling or unable to give informed consent, did not understand the study purpose or nature of their participation, or received antibiotics active against syphilis in the past 30 days. TPA detection and WGS were conducted on lesion swabs, skin biopsies, skin scrapings, whole blood, or rabbit-passaged isolates. We compared our WGS data to publicly available genomes and analysed TPA populations to identify mutations associated with lineage and geography. FINDINGS: We screened 2802 patients and enrolled 233 participants, of whom 77 (33%) had primary syphilis, 154 (66%) had secondary syphilis, and two (1%) had early latent syphilis. The median age of participants was 28 years (IQR 22-35); 154 (66%) participants were cisgender men, 77 (33%) were cisgender women, and two (1%) were transgender women. Of the cisgender men, 66 (43%) identified as gay, bisexual, or other sexuality. Among all participants, 56 (24%) had HIV co-infection. WGS data from 113 participants showed a predominance of SS14-lineage strains with geographical clustering. Phylogenomic analyses confirmed that Nichols-lineage strains were more genetically diverse than SS14-lineage strains and clustered into more distinct subclades. Differences in single nucleotide variants (SNVs) were evident by TPA lineage and geography. Mapping of highly differentiated SNVs to three-dimensional protein models showed population-specific substitutions, some in outer membrane proteins (OMPs) of interest. INTERPRETATION: Our study substantiates the global diversity of TPA strains. Additional analyses to explore TPA OMP variability within strains is vital for vaccine development and understanding syphilis pathogenesis on a population level. FUNDING: US National Institutes of Health National Institute for Allergy and Infectious Disease, the Bill & Melinda Gates Foundation, Connecticut Children's, and the Czech Republic National Institute of Virology and Bacteriology.

Presynaptic sensor and silencer of peptidergic transmission reveal neuropeptides as primary transmitters in pontine fear circuit.

Neurons produce and release neuropeptides to communicate with one another. Despite their importance in brain function, circuit-based mechanisms of peptidergic transmission are poorly understood, primarily due to the lack of tools for monitoring and manipulating neuropeptide release in vivo. Here, we report the development of two genetically encoded tools for investigating peptidergic transmission in behaving mice: a genetically encoded large dense core vesicle (LDCV) sensor that detects presynaptic neuropeptide release and a genetically encoded silencer that specifically degrades neuropeptides inside LDCVs. Using these tools, we show that neuropeptides, not glutamate, encode the unconditioned stimulus in the parabrachial-to-amygdalar threat pathway during Pavlovian threat learning. We also show that neuropeptides play important roles in encoding positive valence and suppressing conditioned threat response in the amygdala-to-parabrachial endogenous opioidergic circuit. These results show that our sensor and silencer for presynaptic peptidergic transmission are reliable tools to investigate neuropeptidergic systems in awake, behaving animals.

E-Scooter facial fractures: A comparative cohort study.

It was the aim of the study to analyze the distribution and pattern of facial fractures following e-scooter trauma. Prospective audit data of facial fractures were retrospectively collected to investigate the impact of e-scooter hire, specifically in the form of facial fractures associated with their use. Data collected included patient demographics, mode of injury, date of injury, facial bones involved, presence of soft tissue injury, and factors associated with injury, including intoxication and helmet use. A total of 849 patients were treated for facial fractures during the study period, of which 34 were attributed to e-scooter use. One-half of those injured riding e-scooters were intoxicated, and one-quarter were wearing helmets. There have been an increasing number of facial fractures associated with e-scooter use following the start of the shared e-scooter trial. Zygomaticomaxillary complex fractures were the most common pattern of facial fracture seen. Most patients required surgical management of their injuries. Policymakers should consider how to improve the enforcement of current regulations, given the healthcare cost associated with the management of these preventable injuries.

Clinical presentation of early syphilis and genomic sequences of Treponema pallidum strains in patient specimens and isolates obtained by rabbit inoculation.

BACKGROUND: The global resurgence of syphilis necessitates vaccine development. METHODS: We collected ulcer exudates and blood from 17 primary syphilis (PS) participants and skin biopsies and blood from 51 secondary syphilis (SS) participants in Guangzhou, China for Treponema pallidum subsp. pallidum (TPA) qPCR, whole genome sequencing (WGS), and isolation of TPA in rabbits. RESULTS: TPA DNA was detected in 15 of 17 ulcer exudates and 3 of 17 blood PS specimens. TPA DNA was detected in 50 of 51 SS skin biopsies and 27 of 51 blood specimens. TPA was isolated from 47 rabbits with success rates of 71% (12/17) and 69% (35/51), respectively, from ulcer exudates and SS bloods. We obtained paired genomic sequences from 24 clinical samples and corresponding rabbit isolates. Six SS14- and two Nichols-clade genome pairs contained rare discordances. Forty-one of the 51 unique TPA genomes clustered within SS14 subgroups largely from East Asia, while 10 fell into Nichols C and E subgroups. CONCLUSIONS: Our TPA detection rate was high from PS ulcer exudates and SS skin biopsies and over 50% from SS blood, with TPA isolation in over two-thirds of samples. Our results support the use of WGS from rabbit isolates to inform vaccine development.

The incidence of new cases of syphilis has skyrocketed globally in the twenty-first century. This global resurgence requires new strategies, including vaccine development. As part of an NIH funded Cooperative Research Center to develop a syphilis vaccine, we established a clinical research site in Guangzhou, China to better define the local syphilis epidemic and obtain samples from patients with primary and secondary syphilis for whole genome sequencing (WGS) of circulating Treponema pallidum strains. Inoculation of rabbits enabled us to obtain T. pallidum genomic sequences from spirochetes disseminating in blood, a compartment of immense importance for syphilis pathogenesis. Collectively, our results further clarify the molecular epidemiology of syphilis in southern China, enrich our understanding of the manifestations of early syphilis, and demonstrate that the genomic sequences of spirochetes obtained by rabbit inoculation accurately represent those of the spirochetes infecting the corresponding patients.

Scaling up a brief alcohol intervention to prevent HIV infection in Vietnam: a cluster randomized, implementation trial.

BACKGROUND: Evidence-based interventions (EBIs) often address normative behaviors. If a behavior is also common among clinicians, they may be skeptical about the necessity or effectiveness of an EBI. Alternatively, clinicians' attitudes and behaviors may be misaligned, or they may lack the knowledge and self-efficacy to deliver the EBI. Several EBIs address unhealthy alcohol use, a common and often culturally acceptable behavior. But unhealthy alcohol use may be particularly harmful to people with HIV (PWH). Here, we present an implementation trial using an experiential implementation strategy to address clinicians' knowledge, attitudes, and behaviors. Clinicians receive the experiential intervention before they begin delivering an evidence-based brief alcohol intervention (BAI) to PWH with unhealthy alcohol use. METHODS: Design: In this hybrid type 3 implementation-effectiveness cluster randomized controlled trial, ART clinics (n = 30) will be randomized 1:1 to facilitation, a flexible strategy to address implementation barriers, or facilitation plus the experiential brief alcohol intervention (EBAI). In the EBAI arm, clinicians, irrespective of their alcohol use, will be offered the BAI as experiential learning. EBAI will address clinicians' alcohol-related attitudes and behaviors and increase their knowledge and confidence to deliver the BAI. PARTICIPANTS: ART clinic staff will be enrolled and assessed at pre-BAI training, post-BAI training, 3, 12, and 24 months. All PWH at the ART clinics who screen positive for unhealthy alcohol use will be offered the BAI. A subset of PWH (n = 810) will be enrolled and assessed at baseline, 3, and 12 months. OUTCOMES: We will compare implementation outcomes (acceptability, fidelity, penetration, costs, and sustainability) and effectiveness outcomes (viral suppression and alcohol use) between the two arms. We will assess the impact of site-level characteristics on scaling-up the BAI. We will also evaluate how experiencing the BAI affected clinical staff's alcohol use and clinic-level alcohol expectations in the EBAI arm. DISCUSSION: This trial contributes to implementation science by testing a novel strategy to implement a behavior change intervention in a setting in which clinicians themselves may engage in the behavior. Experiential learning may be useful to address normative and difficult to change lifestyle behaviors that contribute to chronic diseases. TRIAL REGISTRATION: NCT06358885 (04/10/2024), https://clinicaltrials.gov/study/NCT06358885 .

Orodental malformations associated with human MSX1 sequence variants.

BACKGROUND: MSX1 sequence variants have been known to cause human tooth agenesis (TA) with or without orofacial clefts. However, their roles during the whole processes of tooth development are not fully understood. This study aimed to characterize a 4-membered family with TA carrying a novel MSX1 pathogenic variant and investigate the disease mechanism. METHODS: The authors conducted whole exome analysis to define the disease-causing sequence variant. They performed microcomputed tomography, morphometric analyses, transcriptome profiling, and molecular characterization to study the affected teeth and the gene variant. RESULTS: The authors identified an MSX1 pathogenic variant, p.Glu232∗, in affected family members with TA and concomitant orodental anomalies, namely, prominent maxillary labial frenum, central incisor diastema, median maxillary anterior alveolar cleft, tooth fusion, mandibular molar dysmorphology, thin dentin layer, and slender dental roots. MSX1-defective teeth were not apparently microdontic but had thin dentin layers. The mandibular molars showed a homeotic transformation to maxillary counterparts. Genes involved in extracellular matrix organization and dentinogenesis, such as DMP1 and MMP20, were downregulated in dental pulp tissues of MSX1-defective teeth. The p.Glu232∗-truncated MSX1 properly localized to the nucleus but partially lost its transactivation ability. Analyzing reported cases indicated that truncation sequence variants within the homeobox domain of MSX1 caused a more severe TA phenotype than those outside of the homeobox domain, probably due to dominant negativity compared with haploinsufficiency. CONCLUSIONS: This study provides in vivo evidence that MSX1 contributes to developmental processes of various orodental tissues in humans. PRACTICAL IMPLICATIONS: Clinically, hypertrophic labial frenum, incisor diastema, and median maxillary anterior alveolar cleft might be considered diagnostic for MSX1-associated TA.

Comprehensive assessment of pediatric acute and inpatient care at a tertiary referral hospital in Malawi: opportunities for quality improvement.

BACKGROUND: Despite the reduction in global under-5 mortality over the last decade, childhood deaths remain high. To combat this, there has been a shift in focus from disease-specific interventions to use of healthcare data for resource allocation, evaluation of performance and impact, and accountability. This is a descriptive analysis of data derived from a prospective cohort study describing paediatric admissions to a tertiary referral hospital in Malawi for the purpose of process evaluation and quality improvement. METHODS: Using a REDCap database, we collected data for patients admitted acutely to Kamuzu Central Hospital, a tertiary referral centre in the central region. Data were collected from 17 123 paediatric inpatients from 2017 to 2020. RESULTS: Approximately 6% of patients presented with either two or more danger signs or severely abnormal vital signs. Infants less than 6 months, who had the highest mortality rate, were also the most critically ill on arrival to the hospital. Sepsis was diagnosed in about 20% of children across all age groups. Protocols for the management of high-volume, lower-acuity conditions such as uncomplicated malaria and pneumonia were generally well adhered to, but there was a low rate of completion for labs, radiology studies and subspecialty consultations required to provide care for high acuity or complex conditions. The overall mortality rate was 4%, and 60% of deaths occurred within the first 48 hours of admission. CONCLUSION: Our data highlight the need to improve the quality of care provided at this tertiary-level centre by focusing on the initial stabilisation of high-acuity patients and augmenting resources to provide comprehensive care. This may include capacity building through the training of specialists, implementation of clinical processes, provision of specialised equipment and increasing access to and reliability of ancillary services. Data collection, analysis and routine use in policy and decision-making must be a pillar on which improvement is built.

Update on T-Cell Lymphoma Epidemiology.

PURPOSE OF REVIEW: T-cell lymphomas (TCLs) are a group of rare subtypes of non-Hodgkin lymphoma derived from mature T-lymphocytes. Recent updates in lymphoma classification based on the cell-of-origin pathogenesis have shed new light on TCL epidemiology and outcomes. Contemporary regional consortia and international studies, including those conducted recently in Asia and South America, have provided an updated delineation of the major subtypes across various global regions. RECENT FINDINGS: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), remains the most common subtype globally except in Asia, where extra-nodal NK-T cell lymphoma (ENKTL) has emerged as the most prevalent. Angioimmunoblastic T-cell lymphoma (AITL) is the second most common subtype globally except in South America where its incidence falls behind adult T-cell leukemia/lymphoma (ATLL) and ENKTL. ALK-negative anaplastic large cell lymphoma (ALCL) has been recognized as the second most common subtype in some parts of South America. Studies on the newly classified breast implant-associated ALCL (BIA-ALCL) are beginning to reveal its distribution and risk factors. Deciphering the epidemiology of TCLs is a challenging endeavor due to the rarity of these entities and ongoing refinement in classification. Collaborative efforts on prospective registries based on the most current WHO classifications will help capture the true epidemiology of TCL subtypes to better focus resources for diagnostic, prognostic, and therapeutic efforts.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence.

PURPOSE: Chronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN. EXPERIMENTAL DESIGN: We randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. RESULTS: The Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. CONCLUSIONS: With dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions. SIGNIFICANCE: Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes.

Craniofacial and olfactory sensory changes after long-term unilateral nasal obstruction-an animal study using MMP-3-LUC transgenic rats.

Nasal obstruction exerts considerable physiological effects on the respiratory system and craniofacial morphology during the developmental stage. This study used MMP-3-LUC transgenic rats for in vivo tracking of long-term expression in the rat nasal region after unilateral nasal obstruction. Skeletal changes of the craniofacial, nasal, and sinus regions were measured through micro-computed tomography examination and analysis with 3D image processing and calculation. Matrix metalloproteinase-3 and olfactory marker protein expression were also investigated through immunohistochemistry (IHC). Unilateral nasal obstruction significantly reduced the MMP-3 signal in the nasal region of MMP-3-LUC transgenic rats, which was mainly expressed in the respiratory epithelium. Long-term obstruction also caused morphological changes of the craniofacial hard tissue, such as nasal septal deviation, longer inter-jaw distance, and increased maxillary molar dental height. It also caused compensatory growth in olfactory nerve bundles and the olfactory epithelium, as confirmed by IHC. In our study, long-term unilateral nasal obstruction caused nasal septal deviation toward the unobstructed side, hyper divergent facial development including longer molar dental height, and reduced MMP-3 production. However, further investigation is necessary to explore the mechanism in depth.

Molecular signaling and mechanisms of low-level laser-induced gene expression in cells involved in orthodontic tooth movement.

BACKGROUND: The study aimed to observe molecular signaling, including reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm), to evaluate the alteration of gene expression by low-level laser therapy (LLLT) and the correlation between its mechanisms and the NF-kB pathway in cells involved in orthodontic tooth movement. METHODS: Osteoblast-like cells (MG63), immortalized periodontal ligament cells (iPDL), and M1 macrophage-like cells were irradiated by 980-nm LLLT with energy densities of 1 and 10 J/cm2 ΔΨm and intracellular ROS were monitored using fluorescent probes. The changes of mRNA expression were assessed using reverse transcription polymerase chain reaction (RT-PCR). NF-kB inhibitor, ROS scavenger, and ΔΨm suppressor were used to analyze signals associated with the regulation of gene expression. Finally, Western blot analysis was performed to confirm NF-kB signaling after LLLT. RESULTS: We found the increases of ΔΨm and ROS in all three cell types after LLLT, but no significant difference was observed between 1 and 10 J/cm2 LLLT. Regarding gene expression, some target genes were upregulated in MG63 6 h, 12 h, and 1 day after LLLT and in iPDL cells 12 h and 1 day after LLLT. However, no changes occurred in M1 cells. The inhibitor that significantly reduced most changes in gene expression was NF-kB inhibitor. Western blot analysis showed the increase in p-IkBα level after LLLT in iPDL and MG63, but not in M1. CONCLUSION: The 980-nm LLLT increased ΔΨm and ROS production in all three cell types. However, changes in gene regulation were found only in MG63 and iPDL cells, which related to the NF-kB pathway.

Novel treatment for mantle cell lymphoma - impact of BTK inhibitors and beyond.

Mantle cell lymphoma (MCL) primarily affects older adults, accounting for 3-10% of all non-Hodgkin lymphoma (NHL) in western countries. The disease course of MCL is heterogenous; driven by clinical, cytogenetics, and molecular features that shape differences in outcomes, including proliferation index, MIPI scores, and mutational profile such as TP53 aberration. The advent of novel agents has fundamentally evolved the treatment landscape for MCL with treatment strategies that can now be more effectively tailored based on both patient- and disease-specific factors. In this review, we discuss the major classes of novel agents used for the treatment of MCL, focusing on efficacy and notable toxicities of BTK inhibitors. We further examine effective novel combination regimens and, lastly, discuss future directions for the evolution of targeted approaches for the treatment of MCL.

Orthodontic correction of acquired open bite with TMJ degeneration: A retrospective study of outcomes and stability.

BACKGROUND/PURPOSE: Newly developed temporary anchorage devices (TADs) serve a strong orthodontic anchorage to intrude molars for correction of anterior open bite (AOB). We measured cephalometric changes in skeletal open bite patients which developed subsequently to temporomandibular joint disorders with bilateral point contacts at terminal molars. METHODS: We retrospectively recruited 32 patients who had been treated their TMD before orthodontic correction (overbite: -3.14 ± 1.86 mm). Partial orthodontic appliances were used to intrude posterior teeth using TADs until positive OB obtained (T1). Full fixed appliances were then used to achieve proper overjet and overbite (T2). We collected lateral cephalograms before (T0), during (T1) and after (T2) treatment, and at follow-ups (T3). Using ANOVA, we analyzed the differences among these time points to determine treatment changes and stability of orthodontic results. RESULTS: In this group predominantly comprising young adult women, orthodontic treatment with TADs significantly reduced upper posterior dental heights (T2-T0:-1.84 ± 0.66 mm) and facilitated the retraction and uprighting upper incisors (T2-T0: -9.92 ± 1.72°), to achieve appropriate OJ (T2-T0: -3.21 ± 0.49 mm) and OB (T2-T0: 4.10 ± 0.28 mm) with p < 0.05. Except upper posterior dental height, most of cephalometric changes including OJ, OB, and upper incisal axis remained significant at follow-ups with retention time of 3.7 ± 2.6 years. Only three out of 30 patients experienced small amount of open bite at T3. CONCLUSION: Orthodontic correction of OJ remained relatively stable among 90 % of patients with TMJ degeneration by intrusion via TADs. This modern but conservative orthodontic approach can improve occlusal functions in skeletal open bites.

Promising developments in gonococcal vaccines.

PURPOSE OF REVIEW: While effective vaccines to prevent invasive infections by Neisseria meningitidis have been deployed around the world, development of a vaccine to prevent Neisseria gonorrhoeae has lagged. After multiple failed vaccine candidates, vaccine development for N. gonorrhoeae is showing promise for the first time in several decades. This review highlights recent progress in the field. RECENT FINDINGS: Vaccines containing outer-membrane vesicles (OMV) have been used to manage outbreaks of the serogroup B N. meningitidis in a number of countries. Epidemiologic studies indicate these vaccination campaigns were associated with reductions in reported N. gonorrhoeae infections. Recently, a serogroup B N. meningitidis vaccine containing both recombinant antigens and OMV has been licensed through much of the world. Epidemiologic studies also demonstrate associations between 4CMenB immunization and reduced N. gonorrhoeae infections. Additionally, mathematical modeling studies have begun to identify potential strategies for vaccine deployment to maximize reduction of infections. SUMMARY: After several decades with little progress towards an effective gonococcal vaccine, large observational studies have provided evidence that a new generation of group B N. meningitidis vaccines containing OMV have serendipitously restarted the field. Ongoing clinical trials will soon provide definitive evidence regarding the efficacy of these vaccines in preventing N. gonorrhoeae infection.

Efficacy of Two Evidence-Based Alcohol Consumption Interventions on Positive, Negative, and Neutral Days Among Hazardous Alcohol Users Living with HIV in Vietnam.

Social events and stressful settings can be catalysts for alcohol consumption. Motivational enhancement therapy (MET) and cognitive behavioral therapy (CBT) are widely used in alcohol interventions. We assessed how alcohol consumption varied across three types of days (positive/social, negative/stressful, and neutral) among hazardous alcohol users living with HIV in Vietnam. We further evaluated how those consumption patterns changed after two MET/CBT alcohol reduction interventions versus the standard of care (SOC). The 'combined' intervention offered 6 individual sessions and 3 group sessions; the 'brief' intervention offered 2 individual sessions and 2 phone calls. A 30-day timeline follow-back was administered at study visits, detailing daily drinks and events. Days were categorized as neutral, positive/social, or negative/stressful; negative binomial models and generalized estimating equations were used to estimate drinks consumed by type of day at baseline and 12 months. Prior to intervention, more drinks were consumed on positive/social days (5.2 drinks; 95% Confidence Interval [CI]:4.8, 5.7) than negative/stressful (1.5; 95% CI:1.3, 1.9) and neutral days (2.2; 95% CI: 1.9, 2.5). After the brief intervention, drinks consumed decreased on neutral days (ratio: 0.5: 95% CI: 0.4, 0.7). After the combined intervention, drinks consumed decreased on neutral days (ratio: 0.4; 95% CI: 0.3, 0.6), positive/social days (ratio: 0.6; 95% CI: 0.5, 0.7) and negative/stressful days (ratio: 0.3; 95% CI: 0.2, 0.6). No reductions in consumption were observed in the SOC group. Social/positive days had the highest alcohol consumption prior to intervention, and the combined intervention showed the greatest decrease in consumption on those days. CLINICAL TRIAL REGISTRATION: The study is registered at clinicaltrials.gov (NCT02720237).

Dramatic Shift in the Etiology of Genital Ulcer Disease Among Patients Visiting a Sexually Transmitted Infections Clinic in Lilongwe, Malawi.

BACKGROUND: Genital ulcer diseases (GUDs) are a common syndrome associated with sexually transmitted infections. Genital ulcer diseases increase the risk of HIV transmission, necessitating appropriate diagnosis and treatment. We provide an updated GUD etiology assessment in Malawi to guide diagnostic development and treatment algorithms. METHODS: We enrolled patients 18 years or older presenting with GUD at a sexually transmitted infection clinic in Lilongwe, Malawi, between May and October 2021. We purposively sampled by HIV status. Swabs of ulcers were tested for Treponema pallidum, herpes simplex virus (HSV)-1 and HSV-2, Haemophilus ducreyi, and Chlamydia trachomatis using polymerase chain reaction. Blood was collected for syphilis and HSV-2 serologies and acute HIV testing. Participants were treated per Malawi guidelines. Ulcer resolution (size reduced by >50%) was evaluated 14 days later. RESULTS: Fifty participants enrolled (30 without HIV, 2 with acute HIV infection, 18 with HIV seropositivity; 32 men, 18 women). Forty-six (92%) had an etiology identified. Syphilis was more common among those without HIV (22 of 30 [73%]) than participants with HIV (PWH; 8 of 20 [40%]; P = 0.04). Herpes simplex virus was more common among PWH (11 of 20 [55%]) than participants without (2 of 30 [7%]; P = 0.0002). One-fifth (9 of 50 [18%]) had H. ducreyi. Among those who returned for follow-up (n = 45), 9 (20%) had unresolved ulcers; persistent GUD was slightly more common in PWH (6 of 19 [32%]) than participants without (3 of 26 [12%]; P = 0.14). CONCLUSIONS: We observed a dramatic increase in syphilis ulcer proportion in a population whose GUDs were previously HSV predominant. Observed differences in etiology and resolution by HIV status could play an important role in the ongoing transmission and treatment evaluation of GUD.

Early syphilis in Guangzhou, China: presentation, molecular detection of Treponema pallidum , and genomic sequences in clinical specimens and isolates obtained by rabbit infectivity testing.

Background: The global resurgence of syphilis requires novel prevention strategies. Whole genome sequencing (WGS) of Treponema pallidum ( TPA ) using different specimen types is essential for vaccine development. Methods: Patients with primary (PS) and secondary (SS) syphilis were recruited in Guangzhou, China. We collected ulcer exudates and blood from PS participants, and skin biopsies and blood from SS participants for TPA polA polymerase chain reaction (PCR); ulcer exudates and blood were also used to isolate TPA strains by rabbit infectivity testing (RIT). TPA WGS was performed on 52 ulcer exudates and biopsy specimens and 25 matched rabbit isolates. Results: We enrolled 18 PS and 51 SS participants from December 2019 to March 2022. Among PS participants, TPA DNA was detected in 16 (89%) ulcer exudates and three (17%) blood specimens. Among SS participants, TPA DNA was detected in 50 (98%) skin biopsies and 27 (53%) blood specimens. TP A was isolated from 48 rabbits, with a 71% (12/17) success rate from ulcer exudates and 69% (36/52) from SS bloods. Twenty-three matched SS14 clade genomes were virtually identical, while two Nichols clade pairs had discordant tprK sequences. Forty-two of 52 unique TPA genomes clustered in an SS14 East Asia subgroup, while ten fell into two East Asian Nichols subgroups. Conclusions: Our TPA detection rate was high from PS ulcer exudates and SS skin biopsies and over 50% from SS whole blood, with RIT isolation in over two-thirds of samples. Our results support the use of WGS from rabbit isolates to inform vaccine development. Summary: We performed Treponema pallidum molecular detection and genome sequencing from multiple specimens collected from early syphilis patients and isolates obtained by rabbit inoculation. Our results support the use of whole genome sequencing from rabbit isolates to inform syphilis vaccine development.

Cigarette smoke stimulates clonal expansion of Jak2V617F and Tet2-/- cells.

Introduction: Somatic mutations in myeloid growth factor pathway genes, such as JAK2, and genes involved in epigenetic regulation, such as TET2, in hematopoietic stem cells (HSCs) leads to clonal hematopoiesis of indeterminate potential (CHIP) which presents a risk factor for hematologic malignancy and cardiovascular disease. Smoking behavior has been repeatedly associated with the occurrence of CHIP but whether smoking is an environmental inflammatory stressor in promoting clonal expansion has not been investigated. Methods: We performed in vivo smoke exposures in both wildtype (WT) mice and transplanted mice carrying Jak2V617F mutant and Tet2 knockout (Tet-/-) cells to determine the impact of cigarette smoke (CS) in the HSC compartment as well as favoring mutant cell expansion. Results: WT mice exposed to smoke displayed increased oxidative stress in long-term HSCs and suppression of the hematopoietic stem and progenitor compartment but smoke exposure did not translate to impaired hematopoietic reconstitution in primary bone marrow transplants. Gene expression analysis of hematopoietic cells in the bone marrow identified an imbalance between Th17 and Treg immune cells suggesting a local inflammatory environment. We also observed enhanced survival of Jak2V617F cells exposed to CS in vivo and cigarette smoke extract (CSE) in vitro. WT bone marrow hematopoietic cells from WT/Jak2V617F chimeric mice exposed to CS demonstrated an increase in neutrophil abundance and distinct overexpression of bone marrow stromal antigen 2 (Bst2) and retinoic acid early transcript 1 (Raet1) targets. Bst2 and Raet1 are indicative of increased interferon signaling and cellular stress including oxidative stress and DNA damage, respectively. In chimeric mice containing both WT and Tet2-/- cells, we observed an increased percentage of circulating mutant cells in peripheral blood post-cigarette smoke exposure when compared to pre-exposure levels while this difference was absent in air-exposed controls. Conclusion: Altogether, these findings demonstrate that CS results in an inflamed bone marrow environment that provides a selection pressure for existing CHIP mutations such as Jak2V617F and Tet2 loss-of-function.