Prevalence of Mycobacterium tuberculosis in Sputum and Reported Symptoms Among Clinic Attendees Compared With a Community Survey in Rural South Africa.

BACKGROUND: Tuberculosis (TB) case finding efforts typically target symptomatic people attending health facilities. We compared the prevalence of Mycobacterium tuberculosis (Mtb) sputum culture-positivity among adult clinic attendees in rural South Africa with a concurrent, community-based estimate from the surrounding demographic surveillance area (DSA). METHODS: Clinic: Randomly selected adults (≥18 years) attending 2 primary healthcare clinics were interviewed and requested to give sputum for mycobacterial culture. Human immunodeficiency virus (HIV) and antiretroviral therapy (ART) status were based on self-report and record review. Community: All adult (≥15 years) DSA residents were invited to a mobile clinic for health screening, including serological HIV testing; those with ≥1 TB symptom (cough, weight loss, night sweats, fever) or abnormal chest radiograph were asked for sputum. RESULTS: Clinic: 2055 patients were enrolled (76.9% female; median age, 36 years); 1479 (72.0%) were classified HIV-positive (98.9% on ART) and 131 (6.4%) reported ≥1 TB symptom. Of 20/2055 (1.0% [95% CI, .6-1.5]) with Mtb culture-positive sputum, 14 (70%) reported no symptoms. Community: 10 320 residents were enrolled (68.3% female; median age, 38 years); 3105 (30.3%) tested HIV-positive (87.4% on ART) and 1091 (10.6%) reported ≥1 TB symptom. Of 58/10 320 (0.6% [95% CI, .4-.7]) with Mtb culture-positive sputum, 45 (77.6%) reported no symptoms. In both surveys, sputum culture positivity was associated with male sex and reporting >1 TB symptom. CONCLUSIONS: In both clinic and community settings, most participants with Mtb culture-positive sputum were asymptomatic. TB screening based only on symptoms will miss many people with active disease in both settings.

Participant recall and understandings of information on biobanking and future genomic research: experiences from a multi-disease community-based health screening and biobank platform in rural South Africa.

BACKGROUND: Limited research has been conducted on explanations and understandings of biobanking for future genomic research in African contexts with low literacy and limited healthcare access. We report on the findings of a sub-study on participant understanding embedded in a multi-disease community health screening and biobank platform study known as 'Vukuzazi' in rural KwaZulu-Natal, South Africa. METHODS: Semi-structured interviews were conducted with research participants who had been invited to take part in the Vukuzazi study, including both participants and non-participants, and research staff that worked on the study. The interviews were transcribed, and themes were identified from the interview transcripts, manually coded, and thematically analysed. RESULTS: Thirty-nine individuals were interviewed. We found that the research team explained biobanking and future genomic research by describing how hereditary characteristics create similarities among individuals. However, recollection and understanding of this explanation seven months after participation was variable. The large volume of information about the Vukuzazi study objectives and procedures presented a challenge to participant recall. By the time of interviews, some participants recalled rudimentary facts about the genetic aspects of the study, but many expressed little to no interest in genetics and biobanking. CONCLUSION: Participant's understanding of information related to genetics and biobanking provided during the consent process is affected by the volume of information as well as participant's interest (or lack thereof) in the subject matter being discussed. We recommend that future studies undertaking biobanking and genomic research treat explanations of this kind of research to participants as an on-going process of communication between researchers, participants and the community and that explanatory imagery and video graphic storytelling should be incorporated into theses explanations as these have previously been found to facilitate understanding among those with low literacy levels. Studies should also avoid having broader research objectives as this can divert participant's interest and therefore understanding of why their samples are being collected.

Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures.

Psoriasis is a chronic, inflammatory, multisystem disease that affects up to 3.2% of the United States population. This guideline addresses important clinical questions that arise in psoriasis management and care and provides recommendations based on the available evidence. The treatment of psoriasis with topical agents and with alternative medicine will be reviewed, emphasizing treatment recommendations and the role of dermatologists in monitoring and educating patients regarding benefits as well as risks that may be associated. This guideline will also address the severity assessment methods of psoriasis in adults.

The MAIT TCRß chain contributes to discrimination of microbial ligand.

Mucosal-associated invariant T (MAIT) cells are key players in the immune response against microbial infection. The MAIT T-cell receptor (TCR) recognizes a diverse array of microbial ligands, and recent reports have highlighted the variability in the MAIT TCR that could further contribute to discrimination of ligand. The MAIT TCR complementarity determining region (CDR)3ß sequence displays a high level of diversity across individuals, and clonotype usage appears to be dependent on antigenic exposure. To address the relationship between the MAIT TCR and microbial ligand, we utilized a previously defined panel of MAIT cell clones that demonstrated variability in responses against different microbial infections. Sequencing of these clones revealed four pairs, each with shared (identical) CDR3α and different CDR3ß sequences. These pairs demonstrated varied responses against microbially infected dendritic cells as well as against 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil, a ligand abundant in Salmonella enterica serovar Typhimurium, suggesting that the CDR3ß contributes to differences in ligand discrimination. Taken together, these results highlight a key role for the MAIT CDR3ß region in distinguishing between MR1-bound antigens and ligands.

Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis in pediatric patients.

Psoriasis is a chronic, multisystem, inflammatory disease that affects approximately 1% of children, with onset most common during adolescence. This guideline addresses important clinical questions that arise in psoriasis management and provides evidence-based recommendations. Attention will be given to pediatric patients with psoriasis, recognizing the unique physiology, pharmacokinetics, and patient-parent-provider interactions of patients younger than 18 years old. The topics reviewed here mirror those discussed in the adult guideline sections, excluding those topics that are irrelevant to, or lack sufficient information for, pediatric patients.

Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies.

Psoriasis is a chronic inflammatory disease involving multiple organ systems and affecting approximately 2% of the world's population. In this guideline, we focus the discussion on systemic, nonbiologic medications for the treatment of this disease. We provide detailed discussion of efficacy and safety for the most commonly used medications, including methotrexate, cyclosporine, and acitretin, and provide recommendations to assist prescribers in initiating and managing patients on these treatments. Additionally, we discuss newer therapies, including tofacitinib and apremilast, and briefly touch on a number of other medications, including fumaric acid esters (used outside the United States) and therapies that are no longer widely used for the treatment of psoriasis (ie, hydroxyurea, leflunomide, mycophenolate mofetil, thioguanine, and tacrolimus).

Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis with phototherapy.

Psoriasis is a chronic inflammatory disease involving multiple organ systems and affecting approximately 3.2% of the world's population. In this section of the guidelines of care for psoriasis, we will focus the discussion on ultraviolet (UV) light-based therapies, which include narrowband and broadband UVB, UVA in conjunction with photosensitizing agents, targeted UVB treatments such as with an excimer laser, and several other modalities and variations of these core phototherapies, including newer applications of pulsed dye lasers, intense pulse light, and light-emitting electrodes. We will provide an in-depth, evidence-based discussion of efficacy and safety for each treatment modality and provide recommendations and guidance for the use of these therapies alone or in conjunction with other topical and/or systemic psoriasis treatments.

Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities.

Psoriasis is a chronic, inflammatory, multisystem disease that affects up to 3.2% of the US population. This guideline addresses important clinical questions that arise in psoriasis management and care, providing recommendations on the basis of available evidence.

Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics.

Psoriasis is a chronic, inflammatory multisystem disease that affects up to 3.2% of the US population. This guideline addresses important clinical questions that arise in psoriasis management and care, providing recommendations based on the available evidence. The treatment of psoriasis with biologic agents will be reviewed, emphasizing treatment recommendations and the role of the dermatologist in monitoring and educating patients regarding benefits as well as associated risks.

The role of mucosal-associated invariant T cells in infectious diseases.

Mucosal-associated invariant T (MAIT) cells are donor-unrestricted lymphocytes that are surprisingly abundant in humans, representing 1-10% of circulating T cells and further enriched in mucosal tissues. MAIT cells recognize and are activated by small molecule ligands produced by microbes and presented by MR1, a highly conserved MHC-related antigen-presenting protein that is ubiquitously expressed in human cells. Increasing evidence suggests that MAIT cells play a protective role in anti-bacterial immunity at mucosal interfaces. Some fungi are known to produce MAIT-activating ligands, but the role of MAIT cells in fungal infections has not yet been investigated. In viral infections, specifically HIV, which has received the most study, MAIT cell biology is clearly altered, but the mechanisms explaining these alterations and their clinical significance are not yet understood. Many questions remain unanswered about the potential of MAIT cells for protection or pathogenesis in infectious diseases. Because they interact with the universal, donor-unrestricted ligand-presenting MR1 molecule, MAIT cells may be attractive immunotherapy or vaccine targets. New tools, including the development of MR1-ligand tetramers and next-generation T-cell receptor sequencing, have the potential to accelerate MAIT cell research and lead to new insights into the role of this unique set of lymphocytes in infectious diseases.

High expression of CD26 accurately identifies human bacteria-reactive MR1-restricted MAIT cells.

Mucosa-associated invariant T (MAIT) cells express the semi-invariant T-cell receptor TRAV1-2 and detect a range of bacteria and fungi through the MHC-like molecule MR1. However, knowledge of the function and phenotype of bacteria-reactive MR1-restricted TRAV1-2(+) MAIT cells from human blood is limited. We broadly characterized the function of MR1-restricted MAIT cells in response to bacteria-infected targets and defined a phenotypic panel to identify these cells in the circulation. We demonstrated that bacteria-reactive MR1-restricted T cells shared effector functions of cytolytic effector CD8(+) T cells. By analysing an extensive panel of phenotypic markers, we determined that CD26 and CD161 were most strongly associated with these T cells. Using FACS to sort phenotypically defined CD8(+) subsets we demonstrated that high expression of CD26 on CD8(+)  TRAV1-2(+) cells identified with high specificity and sensitivity, bacteria-reactive MR1-restricted T cells from human blood. CD161(hi) was also specific for but lacked sensitivity in identifying all bacteria-reactive MR1-restricted T cells, some of which were CD161(dim) . Using cell surface expression of CD8, TRAV1-2, and CD26(hi) in the absence of stimulation we confirm that bacteria-reactive T cells are lacking in the blood of individuals with active tuberculosis and are restored in the blood of individuals undergoing treatment for tuberculosis.

Simultaneous alleviation of verification and reference standard biases in a community-based tuberculosis screening study using Bayesian latent class analysis.

BACKGROUND: Estimation of prevalence and diagnostic test accuracy in tuberculosis (TB) prevalence surveys suffer from reference standard and verification biases. The former is attributed to the imperfect reference test used to bacteriologically confirm TB disease. The latter occurs when only the participants screening positive for any TB-compatible symptom or chest X-ray abnormality are selected for bacteriological testing (verification). Bayesian latent class analysis (LCA) alleviates the reference standard bias but suffers verification bias in TB prevalence surveys. This work aims to identify best-practice approaches to simultaneously alleviate the reference standard and verification biases in the estimates of pulmonary TB prevalence and diagnostic test performance in TB prevalence surveys. METHODS: We performed a secondary analysis of 9869 participants aged ≥15 years from a community-based multimorbidity screening study in a rural district of KwaZulu-Natal, South Africa (Vukuzazi study). Participants were eligible for bacteriological testing using Xpert Ultra and culture if they reported any cardinal TB symptom or had an abnormal chest X-ray finding. We conducted Bayesian LCA in five ways to handle the unverified individuals: (i) complete-case analysis, (ii) analysis assuming the unverified individuals would be negative if bacteriologically tested, (iii) analysis of multiply-imputed datasets with imputation of the missing bacteriological test results for the unverified individuals using multivariate imputation via chained equations (MICE), and simultaneous imputation of the missing bacteriological test results in the analysis model assuming the missing bacteriological test results were (iv) missing at random (MAR), and (v) missing not at random (MNAR). We compared the results of (i)-(iii) to the analysis based on a composite reference standard (CRS) of Xpert Ultra and culture. Through simulation with an overall true prevalence of 2.0%, we evaluated the ability of the models to alleviate both biases simultaneously. RESULTS: Based on simulation, Bayesian LCA with simultaneous imputation of the missing bacteriological test results under the assumption that the missing data are MAR and MNAR alleviate the reference standard and verification biases. CRS-based analysis and Bayesian LCA assuming the unverified are negative for TB alleviate the biases only when the true overall prevalence is <3.0%. Complete-case analysis produced biased estimates. In the Vukuzazi study, Bayesian LCA with simultaneous imputation of the missing bacteriological test results under the MAR and MNAR assumptions produced overall PTB prevalence of 0.9% (95% Credible Interval (CrI): 0.6-1.9) and 0.7% (95% CrI: 0.5-1.1) respectively alongside realistic estimates of overall diagnostic test sensitivity and specificity with substantially overlapping 95% CrI. The CRS-based analysis and Bayesian LCA assuming the unverified were negative for TB produced 0.7% (95% CrI: 0.5-0.9) and 0.7% (95% CrI: 0.5-1.2) overall PTB prevalence respectively with realistic estimates of overall diagnostic test sensitivity and specificity. Unlike CRS-based analysis, Bayesian LCA of multiply-imputed data using MICE mitigates both biases. CONCLUSION: The findings demonstrate the efficacy of these advanced techniques in alleviating the reference standard and verification biases, enhancing the robustness of community-based screening programs. Imputing missing values as negative for bacteriological tests is plausible under realistic assumptions.

Subclinical tuberculosis linkage to care and completion of treatment following community-based screening in rural South Africa.

Background: Tuberculosis (TB), a leading cause of infectious death, is curable when patients complete a course of multi-drug treatment. Because entry into the TB treatment cascade usually relies on symptomatic individuals seeking care, little is known about linkage to care and completion of treatment in people with subclinical TB identified through community-based screening. Methods: Participants of the Vukuzazi study, a community-based survey that provided TB screening in the rural uMkhanyakude district of KwaZulu-Natal from May 2018 - March 2020, who had a positive sputum (GeneXpert or Mtb culture, microbiologically-confirmed TB) or a chest x-ray consistent with active TB (radiologically-suggested TB) were referred to the public health system. Telephonic follow-up surveys were conducted from May 2021 - January 2023 to assess linkage to care and treatment status. Linked electronic TB register data was accessed. We analyzed the effect of baseline HIV and symptom status (by WHO 4-symptom screen) on the TB treatment cascade. Results: Seventy percent (122/174) of people with microbiologically-confirmed TB completed the telephonic survey. In this group, 84% (103/122) were asymptomatic and 46% (56/122) were people living with HIV (PLWH). By self-report, 98% (119/122) attended a healthcare facility after screening, 94% (115/122) started TB treatment and 93% (113/122) completed treatment. Analysis of electronic TB register data confirmed that 67% (116/174) of eligible individuals started TB treatment. Neither symptom status nor HIV status affected linkage to care. Among people with radiologically-suggested TB, 48% (153/318) completed the telephonic survey, of which 80% (122/153) were asymptomatic and 52% (79/153) were PLWH. By self-report, 75% (114/153) attended a healthcare facility after screening, 16% (24/153) started TB treatment and 14% (22/153) completed treatment. Nine percent (28/318) of eligible individuals had TB register data confirming that they started treatment. Conclusions: Despite high rates of subclinical TB, most people diagnosed with microbiologically-confirmed TB after community-based screening were willing to link to care and complete TB treatment. Lower rates of linkage to care in people with radiologically-suggested TB highlight the importance of streamlined care pathways for this group. Clearer guidelines for the management of people who screen positive during community-based TB screening are needed. Supplementary Information: The online version contains supplementary material available at 10.1186/s44263-024-00059-0.

Convergence of HIV and non-communicable disease epidemics: geospatial mapping of the unmet health needs in an HIV hyperendemic community in South Africa.

INTRODUCTION: As people living with HIV (PLHIV) are experiencing longer survival, the co-occurrence of HIV and non-communicable diseases has become a public health priority. In response to this emerging challenge, we aimed to characterise the spatial structure of convergence of chronic health conditions in an HIV hyperendemic community in KwaZulu-Natal, South Africa. METHODS: In this cross-sectional study, we used data from a comprehensive population-based disease survey conducted in KwaZulu-Natal, South Africa, which collected data on HIV, diabetes and hypertension. We implemented a novel health needs scale to categorise participants as: diagnosed and well-controlled (Needs Score 1), diagnosed and suboptimally controlled (Score 2), diagnosed but not engaged in care (Score 3) or undiagnosed and uncontrolled (Score 4). Scores 2-4 were indicative of unmet health needs. We explored the geospatial structure of unmet health needs using different spatial clustering methods. RESULTS: The analytical sample comprised 18 041 individuals. We observed a similar spatial structure for HIV among those with combined needs Score 2-3 (diagnosed but uncontrolled) and Score 4 (undiagnosed and uncontrolled), with most PLHIV with unmet needs clustered in the southern urban and peri-urban areas. Conversely, a high prevalence of need Scores 2 and 3 for diabetes and hypertension was mostly distributed in the more rural central and northern part of the surveillance area. A high prevalence of need Score 4 for diabetes and hypertension was mostly distributed in the rural southern part of the surveillance area. Multivariate clustering analysis revealed a significant overlap of all three diseases in individuals with undiagnosed and uncontrolled diseases (unmet needs Score 4) in the southern part of the catchment area. CONCLUSIONS: In an HIV hyperendemic community in South Africa, areas with the highest needs for PLHIV with undiagnosed and uncontrolled disease are also areas with the highest burden of unmet needs for other chronic health conditions, such as diabetes and hypertension. Our study has revealed remarkable differences in the distribution of health needs across the rural to urban continuum even within this relatively small study site. The identification and prioritisation of geographically clustered vulnerable communities with unmet health needs for both HIV and non-communicable diseases provide a basis for policy and implementation strategies to target communities with the highest health needs.

Identification and molecular characterization of Mycobacterium bovis DNA in GeneXpert® MTB/RIF ultra-positive, culture-negative sputum from a rural community in South Africa.

This study investigated the presence of Mycobacterium bovis (M. bovis) DNA in archived human sputum samples previously collected from residents who reside adjacent to the M. bovis-endemic Hluhluwe-iMfolozi wildlife park, South Africa (SA). Sixty-eight sputum samples were GeneXpert MTB/RIF Ultra-positive for M. tuberculosis complex (MTBC) DNA but culture negative for M. tuberculosis. Amplification and Sanger sequencing of hsp65 and rpoB genes from DNA extracted from stored heat-inactivated sputum samples confirmed the presence of detectable amounts of MTBC from 20 out of the 68 sputum samples. Region of difference PCR, spoligotyping and gyrB long-read amplicon deep sequencing identified M. bovis (n = 10) and M. tuberculosis (n = 7). Notably, M. bovis spoligotypes SB0130 and SB1474 were identified in 4 samples, with SB0130 previously identified in local cattle and wildlife and SB1474 exclusively in African buffaloes in the adjacent park. M. bovis DNA in sputum, from people living near the park, underscores zoonotic transmission potential in SA. Identification of spoligotypes specifically associated with wildlife only and spoligotypes found in livestock as well as wildlife, highlights the complexity of TB epidemiology at wildlife-livestock-human interfaces. These findings support the need for integrated surveillance and control strategies to curb potential spillover and for the consideration of human M. bovis infection in SA patients with positive Ultra results.

HIV transmission dynamics and population-wide drug resistance in rural South Africa.

Despite expanded antiretroviral therapy (ART) in South Africa, HIV-1 transmission persists. Integrase strand transfer inhibitors (INSTI) and long-acting injectables offer potential for superior viral suppression, but pre-existing drug resistance could threaten their effectiveness. In a community-based study in rural KwaZulu-Natal, prior to widespread INSTI usage, we enroled 18,025 individuals to characterise HIV-1 drug resistance and transmission networks to inform public health strategies. HIV testing and reflex viral load quantification were performed, with deep sequencing (20% variant threshold) used to detect resistance mutations. Phylogenetic and geospatial analyses characterised transmission clusters. One-third of participants were HIV-positive, with 21.7% having detectable viral loads; 62.1% of those with detectable viral loads were ART-naïve. Resistance to older reverse transcriptase (RT)-targeting drugs was found, but INSTI resistance remained low (<1%). Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, particularly to rilpivirine (RPV) even in ART-naïve individuals, was concerning. Twenty percent of sequenced individuals belonged to transmission clusters, with geographic analysis highlighting higher clustering in peripheral and rural areas. Our findings suggest promise for INSTI-based strategies in this setting but underscore the need for RPV resistance screening before implementing long-acting cabotegravir (CAB) + RPV. The significant clustering emphasises the importance of geographically targeted interventions to effectively curb HIV-1 transmission.