The Interplay Between Household Risk Perception of Parasitic Infections and Water, Sanitation, and Hygiene (WASH) Practices: Evidence From an Urban Poor Community in the Philippines.

BACKGROUND: Parasitic diseases pose challenges in impoverished urban settlements with limited access to clean water, proper hygiene, and sanitation (WASH). This study assesses WASH practices and risk perceptions of parasitic infections among households in the Bataan Shipyard and Engineering Corporation (BASECO) Compound in Manila, an urban poor community in the Philippines. METHODS: A cross-sectional study design was employed to collect data through a self-administered questionnaire. Descriptive statistical analysis was performed to assess the sociodemographic profile, household WASH practices, and respondents' risk perception of parasitic infections. Linear regression analysis was utilized to examine the relationship between these variables. RESULTS: A survey was conducted with 363 households, of which 237 (65.3%) used distilled and purified water from the water refilling stations in the community for drinking. Meanwhile, 120 households (33.10%) consumed tap water. Boiling water was a commonly used method (n=146; 56.60%) for treating drinking water. Most households had flush toilets with septic tanks (n=244; 67.20%), water sources for handwashing (n=307; 84.57%) and soap for handwashing (n=356; 98.10%). On average, they washed their hands 6-10 times daily (n=159; 43.80%). Most households were aware that drinking untreated water (n=318; 87.6%), improper food washing (n=309; 85.1%), using contaminated water sources (n=301; 82.9%), and consuming raw or undercooked meat (n=298; 82.1%) could lead to parasitic infections. 316 respondents (87.1%) identified diarrhea as the most common symptom of parasitic infection. Relationships were found between access to drinking water and the number of household members (B=0.191; p-value=0.001), personal hygiene and the respondents' knowledge of parasitic infections (B=0.112; p-value=0.047), and the overall WASH score with household income (B=0.105; p-value=0.045). CONCLUSIONS: The WASH conditions in BASECO, Manila need improvement. Factors associated with their WASH practices include risk perception of parasitic diseases, socioeconomic disparity, and household overcrowding. These factors play a crucial role in identifying areas for improvement and promoting health policies for urban poor communities in the Philippines.

The impact of gestational diabetes on functional capacity of the infant gut microbiome is modest and transient.

Gestational diabetes mellitus (GDM) is a metabolic complication that manifests as hyperglycemia during the later stages of pregnancy. In high resource settings, careful management of GDM limits risk to the pregnancy, and hyperglycemia typically resolves after birth. At the same time, previous studies have revealed that the gut microbiome of infants born to mothers who experienced GDM exhibit reduced diversity and reduction in the abundance of several key taxa, including Lactobacillus. What is not known is what the functional consequences of these changes might be. In this case control study, we applied 16S rRNA sequence surveys and metatranscriptomics to profile the gut microbiome of 30 twelve-month-old infants - 16 from mothers with GDM, 14 from mothers without - to examine the impact of GDM during pregnancy. Relative to the mode of delivery and sex of the infant, maternal GDM status had a limited impact on the structure and function of the developing microbiome. While GDM samples were associated with a decrease in alpha diversity, we observed no effect on beta diversity and no differentially abundant taxa. Further, while the mode of delivery and sex of infant affected the expression of multiple bacterial pathways, much of the impact of GDM status on the function of the infant microbiome appears to be lost by twelve months of age. These data may indicate that, while mode of delivery appears to impact function and diversity for longer than anticipated, GDM may not have persistent effects on the function nor composition of the infant gut microbiome.

Staffing Patterns of Non-ACGME Fellowships with 4-Year Residency Programs: A National Survey.

Introduction: Emergency medicine (EM) is one of few specialties with variable training lengths. Hiring a three-year graduate to continue fellowship training in a department that supports a four-year residency program can lead to conflicts around resident supervision. We sought to understand hiring and clinical supervision, or staffing, patterns of non-Accreditation Council for Graduate Medical Education (ACGME) fellowships hosted at institutions supporting four-year residency programs. Methods: We performed a web-based, cross-sectional survey of non-ACGME fellowship directors (FD) hosted at institutions supporting four-year EM residency programs. We calculated descriptive statistics. Our primary outcome was the proportion of programs with four-year EM residencies that hire non-ACGME fellows graduating from three-year EM residencies. Results: Of 119 eligible FDs, 88 (74%) completed the survey. Seventy FDs (80%) indicated that they hire graduates of three-year residencies. Fifty-six (80%) indicated that three-year graduates supervise residents. Most FDs (74%) indicated no additional requirements exist to supervise residents outside of being hired as faculty. The FDs cited department policy, concerns about quality and length of training, and resident complaints as reasons for not hiring three-year graduates. A majority (10/18, 56%) noted that not hiring fellows from three-year programs negatively impacts recruitment and gives them access to a smaller applicant pool. Conclusion: Most non-ACGME fellowships at institutions with four-year EM programs recruit three-year graduates and allow them to supervise residents. This survey provides programs information on how comparable fellowships recruit and staff their departments, which may inform policies that fit the needs of their learners, the fellowship, and the department.

Consensus-based ethical best practices for performing educational point-of-care ultrasonography in the emergency department.

Objectives: There is no standardized protocol for performing educational point-of-care ultrasonography (POCUS) that addresses patient-centered ethical issues such as obtaining informed consent. This study sought to define principles for ethical application of educational POCUS and develop consensus-based best practice guidance. Methods: A questionnaire was developed by a trained ethicist after literature review with the help of a medical librarian. A diverse panel including experts in medical education, law, and bioethics; medical trainees; and individuals with no medical background was convened. The panel voted on their level of agreement with ethical principles and degree of appropriateness of behaviors in three rounds of a modified Delphi process. A high level of agreement was defined as 80% or greater consensus. Results: Panelists voted on 38 total items: 15 related to the patient consent and selection process, eight related to practices while performing educational POCUS, and 15 scenarios involving POCUS application. A high level of agreement was achieved for 13 items related to patient consent and selection, eight items related to performance practices, and 10 scenarios of POCUS application. Conclusions: Based on expert consensus, ethical best practices include obtaining informed consent before performing educational POCUS, allowing patients to decline educational POCUS, informing patients the examination is not intended to be a part of their medical evaluation and is not billed, using appropriate draping techniques, maintaining a professional environment, and disclosing incidental findings in coordination with the primary team caring for the patient. These practices could be implemented at institutions to encourage ethical use of educational POCUS when training physicians, fellows, residents, and medical students.

Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge.

Fc-mediated antibody effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), can contribute to the containment HIV-1 replication but whether such activities are sufficient for protection is unclear. We previously identified an antibody to the variable 2 (V2) apex of the HIV-1 Env trimer (PGT145) that potently directs the lysis of SIV-infected cells by NK cells but poorly neutralizes SIV infectivity. To determine if ADCC is sufficient for protection, separate groups of six rhesus macaques were treated with PGT145 or a control antibody (DEN3) by intravenous infusion followed five days later by intrarectal challenge with SIVmac239. Despite high concentrations of PGT145 and potent ADCC activity in plasma on the day of challenge, all animals became infected and viral loads did not differ between the PGT145- and DEN3-treated animals. To determine if PGT145 can protect against a neutralization-sensitive virus, two additional groups of six macaques were treated with PGT145 and DEN3 and challenged with an SIVmac239 variant with a single amino acid change in Env (K180S) that increases PGT145 binding and renders the virus susceptible to neutralization by this antibody. Although there was no difference in virus acquisition, peak and chronic phase viral loads were significantly lower and time to peak viremia was significantly delayed in the PGT145-treated animals compared to the DEN3-treated control animals. Env changes were also selected in the PGT145-treated animals that confer resistance to both neutralization and ADCC. These results show that ADCC is not sufficient for protection by this V2-specific antibody. However, protection may be achieved by increasing the affinity of antibody binding to Env above the threshold required for neutralization.

CasPEDIA Database: a functional classification system for class 2 CRISPR-Cas enzymes.

CRISPR-Cas enzymes enable RNA-guided bacterial immunity and are widely used for biotechnological applications including genome editing. In particular, the Class 2 CRISPR-associated enzymes (Cas9, Cas12 and Cas13 families), have been deployed for numerous research, clinical and agricultural applications. However, the immense genetic and biochemical diversity of these proteins in the public domain poses a barrier for researchers seeking to leverage their activities. We present CasPEDIA (http://caspedia.org), the Cas Protein Effector Database of Information and Assessment, a curated encyclopedia that integrates enzymatic classification for hundreds of different Cas enzymes across 27 phylogenetic groups spanning the Cas9, Cas12 and Cas13 families, as well as evolutionarily related IscB and TnpB proteins. All enzymes in CasPEDIA were annotated with a standard workflow based on their primary nuclease activity, target requirements and guide-RNA design constraints. Our functional classification scheme, CasID, is described alongside current phylogenetic classification, allowing users to search related orthologs by enzymatic function and sequence similarity. CasPEDIA is a comprehensive data portal that summarizes and contextualizes enzymatic properties of widely used Cas enzymes, equipping users with valuable resources to foster biotechnological development. CasPEDIA complements phylogenetic Cas nomenclature and enables researchers to leverage the multi-faceted nucleic-acid targeting rules of diverse Class 2 Cas enzymes.

Glucocorticoid Receptor (GR) Activation Is Associated with Increased cAMP/PKA Signaling in Castration-Resistant Prostate Cancer.

In castration-resistant prostate cancer (CRPC), increased glucocorticoid receptor (GR) expression and ensuing transcriptional activity have been proposed as an oncogenic "bypass" mechanism in response to androgen receptor (AR) signaling inhibition (ARSi). Here, we report that GR transcriptional activity acquired following ARSi is associated with the upregulation of cyclic adenosine monophosphate (cAMP)-associated gene expression pathways in both model systems and metastatic prostate cancer patient samples. In the context of ARSi, the expression of GR-mediated genes encoding cAMP signaling pathway-associated proteins can be inhibited by treatment with selective GR modulators (SGRMs). For example, in the context of ARSi, we found that GR activation resulted in upregulation of protein kinase inhibitor beta (PKIB) mRNA and protein levels, leading to nuclear accumulation of the cAMP-dependent protein kinase A catalytic subunit (PKA-c). Increased PKA-c, in turn, is associated with increased cAMP response element-binding protein phosphorylation and activity. Furthermore, enzalutamide and SGRM combination therapy in mice bearing CRPC xenografts delayed CRPC progression compared with enzalutamide therapy alone, and reduced tumor PKIB mRNA expression. Supporting the clinical importance of GR/PKA signaling activation in CRPC, we found a significant enrichment of both cAMP pathway signaling-associated gene expression and high NR3C1 (GR) activity in patient-derived xenograft models and metastatic human CRPC samples. These findings suggest a novel mechanism linking CRPC-induced GR transcriptional activity with increased cAMP signaling in AR-antagonized CRPC. Furthermore, our findings suggest that GR-specific modulation in addition to AR antagonism may delay GR+ CRPC time to recurrence, at least in part, by inhibiting tumor cAMP/PKA pathways.

Focused Cardiac Ultrasound Findings of Fluid Tolerance and Fluid Resuscitation in Septic Shock.

OBJECTIVES: Compliance with the fluid bonus component of the SEP-1 (severe sepsis and septic shock management) bundle remains poor due to concerns for iatrogenic harm from fluid overload. We sought to assess whether patients who received focused cardiac ultrasound (FCU) and were found to be fluid tolerant (FT) were more likely to receive the recommended 30 mL/kg fluid bolus within 3 hours of sepsis identification. DESIGN: Retrospective, observational cohort study. SETTING: University-affiliated, tertiary-care hospital in the United States. PATIENTS: Emergency department patients presenting with septic shock from 2018 to 2021. The primary exposure was receipt of FCU with identification of fluid tolerance 3 hours from onset of septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred ninety-two of 1,024 patients with septic shock received FCU within 3 hours of sepsis onset. One hundred seventy-seven were determined to be FT. One hundred fifteen patients were determined to have poor fluid tolerance (pFT). FT patients were more likely to reach the recommended 30 mL/kg fluid bolus amount compared with pFT (FT 52.0% vs. pFT 31.3%, risk difference: 20.7%, [95% CI, 9.4-31.9]). Patients who did not receive FCU met the bolus requirement 34.3% of the time. FT patients received more fluid within 3 hours (FT 2,271 mL vs. pFT 1,646 mL, mean difference 625 mL [95% CI, 330-919]). Multivariable logistic regression was used to estimate the association between fluid tolerance FCU findings and compliance with 30 mL/kg bolus after adjustment for patient characteristics and markers of hemodynamic instability. FT with associated with a higher likelihood of meeting bolus requirement (odds ratio 2.17 [1.52-3.12]). CONCLUSIONS: Patients found to be FT by FCU were more likely to receive the recommended 30 mL/kg bolus in the SEP-1 bundle when compared with patients found with pFT or those that did not receive FCU. There was no difference between groups in 28-day mortality, vasopressor requirement, or need for mechanical ventilation.

Short-term effect of a carbon fiber custom dynamic orthosis and integrated rehabilitation on self-reported physical function, pain, speed, and agility in civilians.

BACKGROUND: Ankle-foot orthoses (AFOs) are widely used to restore mobility and reduce pain in individuals with lower extremity pain and disability. The use of a carbon fiber custom dynamic orthosis (CDO) with integrated physical training and psychosocial intervention has been shown to improve outcomes in a military setting, but civilian data are limited. OBJECTIVES: To use existing clinical data to evaluate the initial effectiveness of an integrated CDO and rehabilitative program and identify baseline characteristics that impact patient response to the intervention. STUDY DESIGN: Retrospective cohort. METHODS: Records of 131 adult patients who received a CDO and device specific training were reviewed. Patient-reported measures of pain and lower extremity function and physical measurements of walking and agility were extracted at baseline and on training completion. RESULTS: A majority of patients reported improved or greatly improved physical function (92%), maximum pain (69%), and typical pain (55%) and experienced improved or greatly improved walking speed (92%) and agility (52%) irrespective of age and sex. Regression models for examining short-term improvement in pain and physical function accounted for 52% (p < 0.001) and 26% (p < 0.001) of the outcome variance, respectively. Improvement in typical pain was influenced by baseline typical and maximum pain, and functional improvement was influenced by sex and baseline physical function. CONCLUSIONS: Most patients (92.4%) reported a positive initial outcome after intervention as measured using patient-reported and objective measures.

Predictors of long-term pain and function in individuals who received a custom dynamic orthosis and device-centric care pathway.

INTRODUCTION: Carbon fiber custom dynamic orthoses (CDOs) have been shown to effectively reduce pain and improve function in military service members with lower-limb impairment, but data are limited for civilians. OBJECTIVES: To evaluate the long-term outcomes of individuals who completed a CDO-centric care pathway in a civilian clinic by comparing baseline pain, mobility, and function with outcomes at long-term follow-up. To identify baseline characteristics and postintervention outcomes predictive of outcomes at long-term follow-up. METHODS: Records of 131 adult patients who received a CDO and CDO-centric training were reviewed. Patient-reported measures of pain and physical function and timed assessment of walking and agility collected during routine clinical care were extracted. These patients were contacted on average 4 (±1) years postintervention to complete a survey including measures of pain and physical function. RESULTS: The 63 participants who responded reported improved or greatly improved function, maximum pain, and typical pain on average, irrespective of age or sex (P < 0.001). Change in function from baseline to long-term follow-up was predicted by short-term change in function (35.1% of the variance; P < 0.001). Change in pain from baseline to long-term follow-up was predicted by baseline typical pain and change in four square step test time (63% of variance; P < 0.001). CONCLUSIONS: Most survey respondents reported positive outcomes. Long-term pain reduction and improved function were predicted by baseline status and by short-term changes associated with receiving a CDO and completing an intensive training program.

Intravenous Bacille Calmette-Guérin vaccination protects simian immunodeficiency virus-infected macaques from tuberculosis.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the most common cause of death in people living with human immunodeficiency virus (HIV). Intra-dermal Bacille Calmette-Guérin (BCG) delivery is the only licensed vaccine against tuberculosis; however, it offers little protection from pulmonary tuberculosis in adults and is contraindicated in people living with HIV. Intravenous BCG confers protection against Mtb infection in rhesus macaques; we hypothesized that it might prevent tuberculosis in simian immunodeficiency virus (SIV)-infected macaques, a model for HIV infection. Here intravenous BCG-elicited robust airway T cell influx and elevated plasma and airway antibody titres in both SIV-infected and naive animals. Following Mtb challenge, all 7 vaccinated SIV-naive and 9 out of 12 vaccinated SIV-infected animals were protected, without any culturable bacteria detected from tissues. Peripheral blood mononuclear cell responses post-challenge indicated early clearance of Mtb in vaccinated animals, regardless of SIV infection. These data support that intravenous BCG is immunogenic and efficacious in SIV-infected animals.

CD8+ cells and small viral reservoirs facilitate post-ART control of SIV replication in M3+ Mauritian cynomolgus macaques initiated on ART two weeks post-infection.

Sustainable HIV remission after antiretroviral therapy (ART) withdrawal, or post-treatment control (PTC), remains a top priority for HIV treatment. We observed surprising PTC in an MHC-haplomatched cohort of MHC-M3+ SIVmac239+ Mauritian cynomolgus macaques (MCMs) initiated on ART at two weeks post-infection (wpi). None of the MCMs possessed MHC haplotypes previously associated with SIV control. For six months after ART withdrawal, we observed undetectable or transient viremia in seven of the eight MCMs, despite detecting replication competent SIV using quantitative viral outgrowth assays. In vivo depletion of CD8α+ cells induced rebound in all animals, indicating the observed PTC was mediated, at least in part, by CD8α+ cells. With intact proviral DNA assays, we found that MCMs had significantly smaller viral reservoirs two wpi than a cohort of identically infected rhesus macaques, a population that rarely develops PTC. We found a similarly small viral reservoir among six additional SIV+ MCMs in which ART was initiated at eight wpi, some of whom exhibited viral rebound. These results suggest that an unusually small viral reservoir is a hallmark among SIV+ MCMs. By evaluating immunological differences between MCMs that did and did not rebound, we identified that PTC was associated with a reduced frequency of CD4+ and CD8+ lymphocyte subsets expressing exhaustion markers. Together, these results suggest a combination of small reservoirs and immune-mediated virus suppression contribute to PTC in MCMs. Further, defining the immunologic mechanisms that engender PTC in this model may identify therapeutic targets for inducing durable HIV remission in humans.

BONCAT-FACS-Seq reveals the active fraction of a biocrust community undergoing a wet-up event.

Determining which microorganisms are active within soil communities remains a major technical endeavor in microbial ecology research. One promising method to accomplish this is coupling bioorthogonal non-canonical amino acid tagging (BONCAT) with fluorescence activated cell sorting (FACS) which sorts cells based on whether or not they are producing new proteins. Combined with shotgun metagenomic sequencing (Seq), we apply this method to profile the diversity and potential functional capabilities of both active and inactive microorganisms in a biocrust community after being resuscitated by a simulated rain event. We find that BONCAT-FACS-Seq is capable of discerning the pools of active and inactive microorganisms, especially within hours of applying the BONCAT probe. The active and inactive components of the biocrust community differed in species richness and composition at both 4 and 21 h after the wetting event. The active fraction of the biocrust community is marked by taxa commonly observed in other biocrust communities, many of which play important roles in species interactions and nutrient transformations. Among these, 11 families within the Firmicutes are enriched in the active fraction, supporting previous reports indicating that the Firmicutes are key early responders to biocrust wetting. We highlight the apparent inactivity of many Actinobacteria and Proteobacteria through 21 h after wetting, and note that members of the Chitinophagaceae, enriched in the active fraction, may play important ecological roles following wetting. Based on the enrichment of COGs in the active fraction, predation by phage and other bacterial members, as well as scavenging and recycling of labile nutrients, appear to be important ecological processes soon after wetting. To our knowledge, this is the first time BONCAT-FACS-Seq has been applied to biocrust samples, and therefore we discuss the potential advantages and shortcomings of coupling metagenomics to BONCAT to intact soil communities such as biocrust. In all, by pairing BONCAT-FACS and metagenomics, we are capable of highlighting the taxa and potential functions that typifies the microbes actively responding to a rain event.

Quantum-enhanced Markov chain Monte Carlo.

Quantum computers promise to solve certain computational problems much faster than classical computers. However, current quantum processors are limited by their modest size and appreciable error rates. Recent efforts to demonstrate quantum speedups have therefore focused on problems that are both classically hard and naturally suited to current quantum hardware, such as sampling from complicated-although not explicitly useful-probability distributions1-3. Here we introduce and experimentally demonstrate a quantum algorithm that is similarly well suited to current hardware, but which samples from complicated distributions arising in several applications. The algorithm performs Markov chain Monte Carlo (MCMC), a prominent iterative technique4, to sample from the Boltzmann distribution of classical Ising models. Unlike most near-term quantum algorithms, ours provably converges to the correct distribution, despite being hard to simulate classically. But like most MCMC algorithms, its convergence rate is difficult to establish theoretically, so we instead analysed it through both experiments and simulations. In experiments, our quantum algorithm converged in fewer iterations than common classical MCMC alternatives, suggesting unusual robustness to noise. In simulations, we observed a polynomial speedup between cubic and quartic over such alternatives. This empirical speedup, should it persist to larger scales, could ease computational bottlenecks posed by this sampling problem in machine learning5, statistical physics6 and optimization7. This algorithm therefore opens a new path for quantum computers to solve useful-not merely difficult-sampling problems.

Hierarchical Clifford Transformations to Reduce Entanglement in Quantum Chemistry Wave Functions.

The performance of computational methods for many-body physics and chemistry is strongly dependent on the choice of the basis used to formulate the problem. Hence, the search for similarity transformations that yield better bases is important for progress in the field. So far, tools from theoretical quantum information have not been thoroughly explored for this task. Here we take a step in this direction by presenting efficiently computable Clifford similarity transformations for the molecular electronic structure Hamiltonian, which expose bases with reduced entanglement in the corresponding molecular ground states. These transformations are constructed via block-diagonalization of a hierarchy of truncated molecular Hamiltonians, preserving the full spectrum of the original problem. We show that the bases introduced here allow for more efficient classical and quantum computations of ground-state properties. First, we find a systematic reduction of bipartite entanglement in molecular ground states as compared to standard problem representations. This entanglement reduction has implications in classical numerical methods, such as those based on the density matrix renormalization group. Then, we develop variational quantum algorithms that exploit the structure in the new bases, showing again improved results when the hierarchical Clifford transformations are used.

Short partial doffs of release/relock sockets may effectively stabilize limb fluid volume in prosthesis users with transtibial amputation.

BACKGROUND: A challenge often faced by people with lower extremity amputation is management of prosthetic socket fit due to changes in fluid volume within their residual limb. Prior research suggests that intermittently doffing the prosthetic socket may help stabilize daily residual limb fluid volume. METHODS: To assess the effects of partial doff duration on residual limb fluid volume retention, participants with transtibial amputation were tested by walking on a treadmill in a controlled, laboratory setting under three conditions. An automated system to release the locking pin and enlarge the socket was used to produce the partial doffing. Percent limb fluid volume changes after partial doffing for 4 min (Short Rest) and for 10 min (Long Rest) were compared with no partial doffing (No Release). Limb fluid volume was monitored using bioimpedance analysis. FINDINGS: Mean percent fluid volume changes in the posterior region were  -1.2% for No Release, 2.7% for Short Rest, and 1.0% for Long Rest. Short and Long Rests had larger increases than No Release (P = 0.005 and 0.03, respectively); Short and Long Rests were not statistically different (P = 0.10). Eight of the thirteen participants experienced a higher percent fluid volume gain for both release protocols while four experienced a higher percent fluid volume gain for only one release protocol. INTERPRETATION: A partial doff duration as short as 4 min may be an effective strategy to stabilize limb fluid volume in prosthesis users with transtibial amputation. Trials in at-home settings should be pursued.

Vaccination with intravenous BCG protects macaques with pre-existing SIV infection from tuberculosis.

Tuberculosis (TB) is the most common cause of death in people living with HIV. BCG delivered intradermally (ID) is the only licensed vaccine to prevent TB. However, it offers little protection from pulmonary TB in adults. Intravenous (IV) BCG, but not ID BCG, confers striking protection against Mycobacterium tuberculosis (Mtb) infection and disease in rhesus macaques. We investigated whether IV BCG could protect against TB in macaques with a pre-existing SIV infection. There was a robust influx of airway T cells following IV BCG in both SIV-infected and SIV-naïve animals, with elevated antibody titers in plasma and airways. Following Mtb challenge, all 7 SIV-naïve and 9 out of 12 SIV-infected vaccinated animals were completely protected, without any culturable bacilli in their tissues. PBMC responses post-challenge indicated early clearance of Mtb in vaccinated animals regardless of SIV infection. These data support that IV BCG is immunogenic and efficacious in SIV-infected animals.

Host Immunity to Mycobacterium tuberculosis Infection Is Similar in Simian Immunodeficiency Virus (SIV)-Infected, Antiretroviral Therapy-Treated and SIV-Naïve Juvenile Macaques.

Pre-existing HIV infection increases tuberculosis (TB) risk in children. Antiretroviral therapy (ART) reduces, but does not abolish, this risk in children with HIV. The immunologic mechanisms involved in TB progression in both HIV-naive and HIV-infected children have not been explored. Much of our current understanding is based on human studies in adults and adult animal models. In this study, we sought to model childhood HIV/Mycobacterium tuberculosis (Mtb) coinfection in the setting of ART and characterize T cells during TB progression. Macaques equivalent to 4 to 8 year-old children were intravenously infected with SIVmac239M, treated with ART 3 months later, and coinfected with Mtb 3 months after initiating ART. SIV-naive macaques were similarly infected with Mtb alone. TB pathology and total Mtb burden did not differ between SIV-infected, ART-treated and SIV-naive macaques, although lung Mtb burden was lower in SIV-infected, ART-treated macaques. No major differences in frequencies of CD4+ and CD8+ T cells and unconventional T cell subsets (Vγ9+ γδ T cells, MAIT cells, and NKT cells) in airways were observed between SIV-infected, ART-treated and SIV-naive macaques over the course of Mtb infection, with the exception of CCR5+ CD4+ and CD8+ T cells which were slightly lower. CD4+ and CD8+ T cell frequencies did not differ in the lung granulomas. Immune checkpoint marker levels were similar, although ki-67 levels in CD8+ T cells were elevated. Thus, ART treatment of juvenile macaques, 3 months after SIV infection, resulted in similar progression of Mtb and T cell responses compared to Mtb in SIV-naive macaques.