Elizna Maasdorp

Background: Data on post-tuberculosis outcomes in adolescents are scarce. Although fluorine-18 fluorodeoxyglucose ( ¹⁸ F-FDG) positron emission tomography/computed tomography (PET/CT) has been used in adult tuberculosis research, little is known about the association between PET/CT findings and functional outcomes in general. Methods: Early FDG PET/CT images of 50 adolescents (31 female, median age 17.2 years) with confirmed pulmonary tuberculosis were read visually and quantitative data of disease burden (total lung volume, cavity volume, total hard volume and total glycolytic activity (TGA)) were extracted and tested for associations with clinical risk factors and spirometry measures after treatment completion. Findings: Involvement of three or more lobes was present in 66% of adolescents, with consolidation in 84%, nodules in 92% and cavities in 84%. Comparatively, smokers had lower TGA values (p=0.034). Larger cavity volume was the strongest predictor of reduced forced expiratory volume in 1 s (FEV ₁ ) and forced vital capacity (FVC) post treatment (β=−1.78– −0.87; p=0.0024–0.047). Corrected total hard volume and corrected TGA were associated with FEV ₁ and FVC z-scores, although no individual predictor coefficients survived correction for multiple comparisons. Interpretation: PET/CT features in this adolescent cohort matched patterns described in adults and were frequently severe. Radiological severity measures were associated with poorer spirometry after treatment. More data, including longitudinal imaging and functional outcomes, are required to better understand pathophysiology in this age group.

IntroductionAlthough there have been significant advances in the genetic etiology of Parkinson’s disease (PD), most of this research has been conducted in European populations. This study aimed to characterize the genetic landscape of PD in South Africa.MethodsWe recruited 689 PD probands across South Africa. These participants were genotyped using the NeuroBooster array in collaboration with the Global Parkinson’s Genetics Program (GP2). An in-house computational workflow was used to identify pathogenic missense variants, which were validated using Sanger sequencing. The CNV-Finder pipeline was used to screen for copy number variations (CNVs), which were validated using Multiplex Ligation-dependent Probe Amplification (MLPA). Previously identified pathogenic variants were used as positive controls in our analysis.ResultsWe identified 16 unique missense variants, confirming 15 with Sanger sequencing, in 47 individuals across seven well-established PD genes. Variants in GBA1 and PRKN were the most frequent. Additionally, 18 variants of unknown significance were found in known genes. Furthermore, seven new CNVs were identified, five in PRKN and two in SNCA, of which six were validated using MLPA. One of the CNVs was in the 5’ untranslated region of SNCA. When combining this data with previous findings, 3.5% of the probands have a genetic basis for their disease.ConclusionsWe conducted the largest pathogenic variant screening to date in this unique and underrepresented population, and our findings highlight the rare contribution of known pathogenic variants. This study underscores the importance of expanding genetic research in African cohorts to improve global understanding of PD etiology.

Introduction: Although there have been significant advances in the genetic etiology of Parkinson’s disease (PD), most of this research has been conducted in European populations. This study aimed to characterize the genetic landscape of PD in South Africa.Methods: We recruited 689 PD probands across South Africa. These participants were genotyped using the NeuroBooster array in collaboration with the Global Parkinson’s Genetics Program (GP2). An in-house computational workflow was used to identify pathogenic missense variants. These were validated using Sanger sequencing. The CNV-Finder pipeline was used to screen for copy number variations (CNVs), which were validated using Multiplex Ligation-dependent Probe Amplification (MLPA). Previously identified pathogenic variants were used as positive controls in our analysis.Results: We identified 16 unique missense variants, confirming 15 with Sanger sequencing, in 47 individuals across seven well-established PD genes. Variants in GBA1 and PRKN were the most frequent. Additionally, 18 variants of unknown significance were found in known genes. Furthermore, seven new CNVs were identified, five in PRKN and two in SNCA, of which six were validated using MLPA. One of the CNVs was in the 5’ untranslated region of SNCA. When combining this data with previous findings, 3.5% of the probands have a genetic basis for their disease.Conclusions: We conducted the largest pathogenic variant screening to date in this unique and underrepresented population, and our findings highlight the rare contribution of known pathogenic variants. This study underscores the importance of expanding genetic research in African cohorts to improve global understanding of PD etiology.

Parkinson’s disease (PD) is a complex neurodegenerative disorder with a substantial genetic influence. To better characterize the genetic landscape of PD in South Africa, we conducted the largest genetic screening to date for pathogenic single nucleotide and copy number variations (CNVs) using genotyping array data from 689 PD probands. We identified 16 unique missense variants, confirming 15 with Sanger sequencing, in 47 individuals across seven well-established PD genes, with GBA1 and PRKN being most frequent. Also in known PD genes, 18 variants of unknown significance were found. Additionally, CNV analysis using CNV-Finder revealed seven novel CNVs, five in PRKN and two in SNCA , of which, six were validated with Multiplex Ligation-dependent Probe Amplification. The findings highlight the contribution of both rare variants and structural rearrangements to PD in this underrepresented population. This study underscores the importance of expanding genetic research in African cohorts to improve global understanding of PD etiology.

Background: As individuals progress through adolescence, their risk of tuberculosis (TB) increases, and the type of disease that develops changes, with increasing cavitary formation and parenchymal tissue destruction. While it is widely assumed that the changes in risk and disease phenotype are due to puberty exerting an impact on host immune responses to Mycobacterium tuberculosis, this relationship has been poorly studied. Methods: Teen TB was an observational study that recruited 50 adolescents with pulmonary TB and 50 controls exposed to TB in Cape Town, South Africa. Blood was collected at baseline and again at month 2 from those with TB. Concentrations of 43 cytokines and 19 hormones were measured and compared between individuals with TB and controls, and changes were monitored over time in those with TB. The relationship between Tanner stage and cytokine/endocrine concentrations was also assessed. Results: IL-1ra, IP-10, SAP, cortisol, lipocalin 2, and resistin were higher, while ghrelin, T3, and DHEAS were lower, in adolescents with TB vs healthy controls. DHEAS, progesterone, luteinizing hormone, testosterone, C peptide, estradiol, and cortisol were positively correlated and T3 negatively correlated with Tanner stage in healthy controls. In adolescents with TB, there was no association between Tanner stage and cytokine/endocrine markers. Conclusions: While in healthy individuals there was a strong association between Tanner stage and endocrine markers, this relationship was absent in adolescents with TB. TB disease appears to disrupt the normal physiologic process of puberty. This could have a substantial impact on growth and development for adolescents developing TB during this critical time.

Priestia megaterium strain AB-S79 isolated from active gold mine soil previously expressed in vitro heavy metal resistance and has a 5.7 Mb genome useful for biotechnological exploitation. This study used web-based bioinformatic resources to analyze P. megaterium AB-S79 genomic relatedness, decipher its secondary metabolite biosynthetic gene clusters (BGCs), and better comprehend its taxa. Genes were highly conserved across the 14 P . megaterium genomes examined here. The pangenome reflected a total of 61,397 protein-coding genes, 59,745 homolog protein family hits, and 1,652 singleton protein family hits. There were also 7,735 protein families, including 1,653 singleton families and 6,082 homolog families. OrthoVenn3 comparison of AB-S79 protein sequences with 13 other P. megaterium strains, 7 other Priestia spp., and 6 other Bacillus spp. highlighted AB-S79’s unique genomic and evolutionary trait. antiSMASH identified two key transcription factor binding site regulators in AB-S79’s genome: zinc-responsive repressor (Zur) and antibiotic production activator (AbrC3), plus putative enzymes for the biosynthesis of terpenes and ranthipeptides. AB-S79 also harbors BGCs for two unique siderophores (synechobactins and schizokinens), phosphonate, dienelactone hydrolase family protein, and phenazine biosynthesis protein (phzF), which is significant for this study. Phosphonate particularly showed specificity for the P. megaterium sp. validating the effect of gene family expansion and contraction. P. megaterium AB-S79 looks to be a viable source for value-added compounds. Thus, this study contributes to the theoretical framework for the systematic metabolic and genetic exploitation of the P. megaterium sp., particularly the value-yielding strains. IMPORTANCE: This study explores microbial natural product discovery using genome mining, focusing on Priestia megaterium . Key findings highlight the potential of P. megaterium , particularly strain AB-S79, for biotechnological applications. The research shows a limited output of P. megaterium genome sequences from Africa, emphasizing the importance of the native strain AB-S79. Additionally, the study underlines the strain’s diverse metabolic capabilities, reinforcing its suitability as a model for microbial cell factories and its foundational role in future biotechnological exploitation.

Background: Pulmonary tuberculosis (PTB) is associated with many forms of chronic lung disease including the development of chronic airflow obstruction (AFO). However, the nature, evolution and mechanisms responsible for the AFO after PTB are poorly understood. The aim of this study was to examine the progression of changes in lung physiology in patients treated for PTB. Methods: Immunocompetent, previously healthy, adult patients receiving ambulatory treatment for a first episode of tuberculosis were prospectively followed up with serial lung physiology and quantitative computed tomography (CT) lung scans performed at diagnosis of tuberculosis, 2, 6, 12 and 18 months during and after the completion of treatment. Results: Forty-nine patients (median age 26 years; 37.2% males) were included, and 43 were studied. During treatment, lung volumes improved and CT fibrosis scores decreased, but features of AFO and gas trapping emerged, while reduced diffusing capacity (DLco) seen in a majority of patients persisted. Significant increases in total lung capacity (TLC) by plethysmography were seen in the year following treatment completion (median change 5.9% pred., P< 0.01) and were driven by large increases in residual volume (RV) (median change +19%pred., P< 0.01) but not inspiratory capacity (IC; P=0.41). The change in RV/TLC correlated with significant progression of radiological gas trapping after treatment (P=0.04) but not with emphysema scores. One year after completing treatment, 18.6% of patients had residual restriction (total lung capacity, TLC < 80%pred), 16.3% had AFO, 32.6% had gas trapping (RV/TLC> 45%), and 78.6% had reduced DLco. Conclusion: Simple spirometry alone does not fully reveal the residual respiratory impairments resulting after a first episode of PTB. Changes in physiology evolve after treatment completion, and these findings when taken together, suggest emergence of gas trapping after treatment likely caused by progression of small airway pathology during the healing process.

Background: There is a growing interest in the use of F-18 FDG PET-CT to monitor tuberculosis (TB) treatment response. Tuberculosis lung lesions are often complex and diffuse, with dynamic changes during treatment and persisting metabolic activity after apparent clinical cure. This poses a challenge in quantifying scan-based markers of burden of disease and disease activity. We used semi-automated, whole lung quantification of lung lesions to analyse serial FDG PET-CT scans from the Catalysis TB Treatment Response Cohort to identify characteristics that best correlated with clinical and microbiological outcomes. Results: Quantified scan metrics were already associated with clinical outcomes at diagnosis and 1 month after treatment, with further improved accuracy to differentiate clinical outcomes after standard treatment duration (month 6). A high cavity volume showed the strongest association with a risk of treatment failure (AUC 0.81 to predict failure at diagnosis), while a suboptimal reduction of the total glycolytic activity in lung lesions during treatment had the strongest association with recurrent disease (AUC 0.8 to predict pooled unfavourable outcomes). During the first year after TB treatment lesion burden reduced; but for many patients, there were continued dynamic changes of individual lesions. Conclusions: Quantification of FDG PET-CT images better characterised TB treatment outcomes than qualitative scan patterns and robustly measured the burden of disease. In future, validated metrics may be used to stratify patients and help evaluate the effectiveness of TB treatment modalities.