Correction: Early mortality in tuberculosis patients initially lost to follow up following diagnosis in provincial hospitals and primary health care facilities in Western Cape, South Africa.

[This corrects the article DOI: 10.1371/journal.pone.0252084.].

Association between tuberculosis and pregnancy outcomes: a retrospective cohort study of women in Cape Town, South Africa.

BACKGROUND: Tuberculosis (TB) remains a leading cause of mortality among women of childbearing age and a significant contributor to maternal mortality. Pregnant women with TB are at high risk of adverse pregnancy outcomes. This study aimed to determine risk factors for an adverse pregnancy outcome among pregnant women diagnosed with TB. METHODS: Using TB programmatic data, this retrospective cohort analysis included all women who were routinely diagnosed with TB in the public sector between October 2018 and March 2020 in two health subdistricts of Cape Town, and who were documented to be pregnant during their TB episode. Adverse pregnancy outcome was defined as either a live birth of an infant weighing <2500 g and/or with a gestation period <37 weeks or as stillbirth, miscarriage, termination of pregnancy, maternal or early neonatal death. Demographics, TB and pregnancy characteristics were described by HIV status. Logistic regression was used to determine risk factors for adverse pregnancy outcome. RESULTS: Of 248 pregnant women, half (52%) were living with HIV; all were on antiretroviral therapy at the time of their TB diagnosis. Pregnancy outcomes were documented in 215 (87%) women, of whom 74 (34%) had an adverse pregnancy outcome. Being older (35-44 years vs 25-34 years (adjusted OR (aOR): 3.99; 95% CI: 1.37 to 11.57), living with HIV (aOR: 2.72; 95% CI: 0.99 to 4.63), having an unfavourable TB outcome (aOR: 2.29; 95% CI: 1.03 to 5.08) and having presented to antenatal services ≤1 month prior to delivery (aOR: 10.57; 95% CI: 4.01 to 27.89) were associated with higher odds of an adverse pregnancy outcome. CONCLUSIONS: Pregnancy outcomes among women with TB were poor, irrespective of HIV status. Pregnant women with TB are a complex population who need additional support prior to, during and after TB treatment to improve TB treatment and pregnancy outcomes. Pregnancy status should be considered for inclusion in TB registries.

Reducing Initial Loss to Follow-up Among People With Bacteriologically Confirmed Tuberculosis: LINKEDin, a Quasi-experimental Study in South Africa.

Every person diagnosed with tuberculosis (TB) needs to initiate treatment. The World Health Organization estimated that 61% of people who developed TB in 2021 were included in a TB treatment registration system. Initial loss to follow-up (ILTFU) is the loss of persons to care between diagnosis and treatment initiation/registration. LINKEDin, a quasi-experimental study, evaluated the effect of 2 interventions (hospital recording and an alert-and-response patient management intervention) in 6 subdistricts across 3 high-TB burden provinces of South Africa. Using integrated electronic reports, we identified all persons diagnosed with TB (Xpert MTB/RIF positive) in the hospital and at primary health care facilities. We prospectively determined linkage to care at 30 days after TB diagnosis. We calculated the risk of ILTFU during the baseline and intervention periods and the relative risk reduction in ILTFU between these periods. We found a relative reduction in ILTFU of 42.4% (95% CI, 28.5%-53.7%) in KwaZulu Natal (KZN) and 22.3% (95% CI, 13.3%-30.4%) in the Western Cape (WC), with no significant change in Gauteng. In KZN and the WC, the relative reduction in ILTFU appeared greater in subdistricts where the alert-and-response patient management intervention was implemented (KZN: 49.3%; 95% CI, 32.4%-62%; vs 32.2%; 95% CI, 5.4%-51.4%; and WC: 34.2%; 95% CI, 20.9%-45.3%; vs 13.4%; 95% CI, 0.7%-24.4%). We reported a notable reduction in ILTFU in 2 provinces using existing routine health service data and applying a simple intervention to trace and recall those not linked to care. TB programs need to consider ILTFU a priority and develop interventions specific to their context to ensure improved linkage to care.

Conservative Management of Splenic Injury in Blunt Abdominal Trauma: A Single Center Experience.

BACKGROUND: Road traffic accidents are the greatest cause of death worldwide. Most intra-abdominal injuries caused by blunt abdominal trauma have been treated surgically for a very long period. Over the past few decades, conservative care has gained in popularity and effectiveness as a treatment choice for blunt abdominal trauma. OBJECTIVE: To determine the efficacy of conservative management in patients suffering from splenic injury in blunt abdominal trauma. METHODS: The study included 62 cases of blunt abdominal trauma treated non-operatively in the general surgery department of the Hayatabad Medical Complex Peshawar between June 2021 and December 2022. RESULTS: Minimal hemoperitoneum was observed in 47 (75.8%) cases, moderate hemoperitoneum was noted in 11 (17.7%) cases, and 4 (6.4%) patients didn't have free fluid in the abdomen. There was no massive hemoperitoneum among the study patients. No major complications were observed during the study period. Only 7 (11.3%) cases develop minimal pleural effusion while 2 (3.2%) patients developed splenic abscess. Mortality was observed in only 1 (1.6%) case. CONCLUSIONS: Conservative management is a safe and efficient strategy and should be considered as a first line of treatment for all hemodynamically stable patients who suffered blunt splenic injury.

From acute abdomen to hormonal crisis: Case report on a long-delayed Sheehan's syndrome diagnosis.

INTRODUCTION: Sheehan's syndrome (SS) is a rare cause of hypopituitarism resulting from postpartum haemorrhage and pituitary necrosis. It remains an underdiagnosed condition, especially in developing countries due to poor obstetric care and home deliveries. This case report highlights the significance of recognizing atypical presentations of SS, such as pancytopenia, to aid in early diagnosis and management. CASE PRESENTATION: A 40-year-old female presented with acute abdomen symptoms and was initially diagnosed with acalculous cholecystitis. However, a detailed history revealed a history of postpartum haemorrhage 18 years prior, leading to a provisional diagnosis of SS. Further investigations confirmed panhypopituitarism, including hypothyroidism, hypocortisolism, and hypogonadism. Notably, the patient also exhibited pancytopenia, a rarely reported haematological manifestation of SS. DISCUSSION: SS often presents with nonspecific symptoms, leading to delayed or missed diagnoses. In this case, the patient's initial presentation of acute abdomen symptoms was attributed to secondary adrenal insufficiency due to panhypopituitarism. The presence of pancytopenia, along with hyponatremia, further complicated the clinical picture. Hormone replacement therapy led to a remarkable improvement in the patient's condition, emphasizing the importance of early diagnosis and intervention. CONCLUSION: SS is a common cause of panhypopituitarism in developing countries, but its atypical presentations, such as pancytopenia, are rare and often overlooked. This case highlights the need for increased awareness among clinicians to consider SS in patients with unexplained haematological abnormalities, particularly in regions with high rates of postpartum haemorrhage. Early recognition and appropriate hormone replacement therapy can significantly improve patients' outcomes and prevent long-term complications associated with this underdiagnosed syndrome.

An unusual presentation of cryptorchidism: A case report of Spigelian-cryptorchidism syndrome.

INTRODUCTION: Spigelian hernia is an uncommon hernia presenting as a protrusion of abdominal contents through the spigelian fascia, lateral to the rectus abdominis. In some rare cases, Spigelian hernia can occur alongside cryptorchidism, which forms a recognized syndrome found in male infants with Spigelian hernia. This is a relatively unreported syndrome with very limited literature available regarding it, none of which is reported in Pakistan in adults. PRESENTATION OF CASE: We report a case of a 65-year-old male with right sided obstructed spigelian hernia along with the rare finding of testis in the hernial sac. The patient was successfully managed by transperitoneal primary repair (herniotomy) with orchiectomy. The patient recovered uneventfully and was discharged 5 days after the surgery. DISCUSSION: The exact pathophysiology of this syndrome remains unclear. Three theories have been proposed to explain this syndrome, including the primary defect being Spigelian hernia leading to undescended testes (Al-Salem), testicular maldescent preceding the formation of the hernia (Raveenthiran), or the absence of the inguinal canal leading to the development of a rescue canal due to the undescended testes (Rushfeldt et al.). In this case, the absence of gubernaculum was confirmed suggesting the findings to be consistent with Rushfeldt's theory. The surgical team proceeded with hernial repair and orchiectomy. CONCLUSION: In conclusion, Spigelian-Cryptorchidism syndrome is a rare syndrome in adult male, with an unclear pathophysiology. Management of this condition involves repair of the hernia along with either orchiopexy or orchiectomy, depending upon the risk factors involved.

Drivers of sex differences in the South African adult tuberculosis incidence and mortality trends, 1990-2019.

Males have higher tuberculosis incidence and mortality rates than females. This study aimed to assess how sex differences in tuberculosis incidence and mortality could be explained by sex differences in HIV, antiretroviral treatment (ART) uptake, smoking, alcohol abuse, undernutrition, diabetes, social contact rates, health-seeking patterns, and treatment discontinuation. We developed an age-sex-stratified dynamic tuberculosis transmission model and calibrated it to South African data. We estimated male-to-female (M:F) tuberculosis incidence and mortality ratios, the effect of the abovementioned factors on the M:F ratios and PAFs for the tuberculosis risk factors. Over the period 1990-2019, the M:F ratios for tuberculosis incidence and mortality rates persisted above 1.0, and the figures reached 1.70 and 1.65, respectively, by the end of 2019. In 2019, HIV contributed greater increases in tuberculosis incidence among females than males (54.5% vs. 45.6%); however, females experienced more reductions due to ART than males (38.3% vs. 17.5%). PAFs for tuberculosis incidence due to alcohol abuse, smoking, and undernutrition, in men were 51.4%, 29.5%, and 16.1%, respectively, higher than females (30.1%, 15.4%, and 10.7%, respectively); the PAF due to diabetes was higher in females than males (22.9% vs. 17.5%). Lower health-seeking rates in males accounted for a 7% higher mortality rate in men. The higher burden of tuberculosis in men highlights the need to improve men's access to routine screening and ensure earlier diagnosis. Sustained efforts in providing ART remain critical in reducing HIV-associated tuberculosis. Additional interventions to reduce alcohol abuse and tobacco smoking are also needed.

A scoping review of patient-centred tuberculosis care interventions: Gaps and opportunities.

Tuberculosis (TB) is a leading cause of death globally. In 2015, the World Health Organization hailed patient-centred care as the first of three pillars in the End TB strategy. Few examples of how to deliver patient-centred care in TB programmes exist in practice; TB control efforts have historically prioritised health systems structures and processes, with little consideration for the experiences of people affected by TB. We aimed to describe how patient-centred care interventions have been implemented for TB, highlighting gaps and opportunities. We conducted a scoping review of the published peer-reviewed research literature and grey literature on patient-centred TB care interventions between January 2005 and March 2020. We found limited information on implementing patient-centred care for TB programmes (13 research articles, 7 project reports, and 19 conference abstracts). Patient-centred TB care was implemented primarily as a means to improve adherence, reduce loss to follow-up, and improve treatment outcomes. Interventions focused on education and information for people affected by TB, and psychosocial, and socioeconomic support. Few patient-centred TB care interventions focused on screening, diagnosis, or treatment initiation. Patient-centred TB care has to go beyond programmatic improvements and requires recognition of the diverse needs of people affected by TB to provide holistic care in all aspects of TB prevention, care, and treatment.

A systematic review of risk factors for mortality among tuberculosis patients in South Africa.

BACKGROUND: Tuberculosis (TB)-associated mortality in South Africa remains high. This review aimed to systematically assess risk factors associated with death during TB treatment in South African patients. METHODS: We conducted a systematic review of TB research articles published between 2010 and 2018. We searched BioMed Central (BMC), PubMed®, EBSCOhost, Cochrane, and SCOPUS for publications between January 2010 and December 2018. Searches were conducted between August 2019 and October 2019. We included randomised control trials (RCTs), case control, cross sectional, retrospective, and prospective cohort studies where TB mortality was a primary endpoint and effect measure estimates were provided for risk factors for TB mortality during TB treatment. Due to heterogeneity in effect measures and risk factors evaluated, a formal meta-analysis of risk factors for TB mortality was not appropriate. A random effects meta-analysis was used to estimate case fatality ratios (CFRs) for all studies and for specific subgroups so that these could be compared. Quality assessments were performed using the Newcastle-Ottawa scale or the Cochrane Risk of Bias Tool. RESULTS: We identified 1995 titles for screening, 24 publications met our inclusion criteria (one cross-sectional study, 2 RCTs, and 21 cohort studies). Twenty-two studies reported on adults (n = 12561) and two were restricted to children < 15 years of age (n = 696). The CFR estimated for all studies was 26.4% (CI 18.1-34.7, n = 13257 ); 37.5% (CI 24.8-50.3, n = 5149) for drug-resistant (DR) TB; 12.5% (CI 1.1-23.9, n = 1935) for drug-susceptible (DS) TB; 15.6% (CI 8.1-23.2, n = 6173) for studies in which drug susceptibility was mixed or not specified; 21.3% (CI 15.3-27.3, n = 7375) for people living with HIV/AIDS (PLHIV); 19.2% (CI 7.7-30.7, n = 1691) in HIV-negative TB patients; and 6.8% (CI 4.9-8.7, n = 696) in paediatric studies. The main risk factors associated with TB mortality were HIV infection, prior TB treatment, DR-TB, and lower body weight at TB diagnosis. CONCLUSIONS: In South Africa, overall mortality during TB treatment remains high, people with DR-TB have an elevated risk of mortality during TB treatment and interventions to mitigate high mortality are needed. In addition, better prospective data on TB mortality are needed, especially amongst vulnerable sub-populations including young children, adolescents, pregnant women, and people with co-morbidities other than HIV. Limitations included a lack of prospective studies and RCTs and a high degree of heterogeneity in risk factors and comparator variables. SYSTEMATIC REVIEW REGISTRATION: The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42018108622. This study was funded by the Bill and Melinda Gates Foundation (Investment ID OPP1173131) via the South African TB Think Tank.

Enhancement Technique Based on the Breast Density Level for Mammogram for Computer-Aided Diagnosis.

Mass detection in mammograms has a limited approach to the presence of a mass in overlapping denser fibroglandular breast regions. In addition, various breast density levels could decrease the learning system's ability to extract sufficient feature descriptors and may result in lower accuracy performance. Therefore, this study is proposing a textural-based image enhancement technique named Spatial-based Breast Density Enhancement for Mass Detection (SbBDEM) to boost textural features of the overlapped mass region based on the breast density level. This approach determines the optimal exposure threshold of the images' lower contrast limit and optimizes the parameters by selecting the best intensity factor guided by the best Blind/Reference-less Image Spatial Quality Evaluator (BRISQUE) scores separately for both dense and non-dense breast classes prior to training. Meanwhile, a modified You Only Look Once v3 (YOLOv3) architecture is employed for mass detection by specifically assigning an extra number of higher-valued anchor boxes to the shallower detection head using the enhanced image. The experimental results show that the use of SbBDEM prior to training mass detection promotes superior performance with an increase in mean Average Precision (mAP) of 17.24% improvement over the non-enhanced trained image for mass detection, mass segmentation of 94.41% accuracy, and 96% accuracy for benign and malignant mass classification. Enhancing the mammogram images based on breast density is proven to increase the overall system's performance and can aid in an improved clinical diagnosis process.

The prevalence of pulmonary hypertension after successful tuberculosis treatment in a community sample of adult patients.

There are an estimated 155 million survivors of tuberculosis (TB). Clinical experience suggests that post tuberculosis lung disease (PTLD) is an important cause of Group 3 pulmonary hypertension (PH). However, TB is not listed as a cause of PH in most guidelines. A cross-sectional, community-based study was conducted in nonhealthcare seeking adults who had successfully completed TB treatment. Subjects underwent questionnaires, spirometry, a 6-min walk distance test (6MWD) and transthoracic echocardiography (TTE). Screen probable PH was defined on TTE as an estimated pulmonary artery peak systolic pressure (PASP) of ≥40 mmHg. One hundred adults (71 males) were enrolled, with a mean age of 42 years (SD 13.8 years) and a median of one TB episode (interquartile range: 1-2). Co-morbidities included hypertension (21%), diabetes (16%), human immunodeficiency virus (10%) and asthma/COPD (5%). Only 25% had no residual symptoms after TB. Probable PH was found in 9%, while 7% had borderline raised PASP values (PASP 35-40 mmHg). An association was found between PH and the number of previous TB episodes, with each additional episode of TB increasing the odds of PH-postTB 2.13-fold (confidence interval [CI]: 1.17-3.88; p = 0.013). All of those found to have PH were smokers or ex-smokers yielding an unadjusted odds ratio for PH-postTB of 3.67 (95% CI: 0.77-17.46). There was no statistical difference in spirometry or 6MWD, between those with and without PH. Neither symptoms nor co-morbidities demonstrated significant association with PH. PH after TB was a common finding in this community-based population. Further research is needed to confirm and determine the significance of these findings.

The impact of HIV and tuberculosis interventions on South African adult tuberculosis trends, 1990-2019: a mathematical modeling analysis.

OBJECTIVES: To quantify the South African adult tuberculosis (TB) incidence and mortality attributable to HIV between 1990 and 2019 and to estimate the reduction in TB incidence due to directly observed therapy, antiretroviral therapy (ART), isoniazid preventive therapy, increased TB screening, and Xpert MTB/RIF. METHODS: We developed a dynamic TB transmission model for South Africa. A Bayesian approach was used to calibrate the model to South African-specific data sources. Counterfactual scenarios were simulated to estimate TB incidence and mortality attributable to HIV and the impact of interventions on TB incidence. RESULTS: Between 1990 and 2019, 8.8 million (95% confidence interval [CI] 8.3-9.3 million) individuals developed TB, and 2.1 million (95% CI 2.0-2.2 million) died from TB. A total of 55% and 69% of TB cases and mortality were due to HIV, respectively. Overall, TB screening and ART substantially reduced TB incidence by 28.2% (95% CI 26.4-29.8%) and 20.0% (95% CI 19.2-20.7%), respectively, in 2019; other interventions had minor impacts. CONCLUSION: HIV has dramatically increased TB incidence and mortality in South Africa. The provision of ART and intensification of TB screening explained most recent declines in TB incidence.

Toward a conceptual framework of the acceptability of tuberculosis treatment in children using a theory generative approach.

To describe an early-stage holistic framework towards evaluating factors that impact the overall acceptability of TB treatment along the TB care cascade in children. We developed a conceptual framework utilising a theory generative approach. Domains were developed through review of existing definitions and analysis of existing qualitative data undertaken in acceptability studies of TB treatment in children. Clarity of domain definitions was achieved through iterative refinement among the research team. Three domains, each comprising several dimensions, were identified to holistically evaluate treatment acceptability: (1) usability, which involves the alignment between the requirements of treatment use and caregivers' and children's ability to integrate TB treatment into their everyday routines, (2) receptivity, which describes the end-user's perception and expectations of treatment and its actual use, and (3) integration, which describes the relationship between available health services and caregivers/children's capacity to make use of those services. Our framework addresses the gaps in current research which do not account for the influence of caregivers' and children's contexts on TB treatment uptake and overall acceptability. This approach may support the development of more standard, holistic measures to improve TB treatment delivery and experiences and future research in children.

Linkage to TB care: A qualitative study to understand linkage from the patients' perspective in the Western Cape Province, South Africa.

BACKGROUND: Delayed linkage to tuberculosis (TB) treatment leads to poor patient outcomes and increased onward transmission. Between 12% and 25% of people diagnosed with TB are never linked to a primary health care facility for continued care. The TB health program is for creating processes that promote and facilitates easy access to care. We explored how TB patients experience TB services and how this influenced their choices around linkage to TB care and treatment. METHODS: We enrolled 20 participants routinely diagnosed with TB in hospital or at primary health care facilities (PHC) in a high TB/HIV burdened peri-urban community in South Africa. Using the Western Cape Provincial Health Data centre (PHDC) which consolidates person-level clinical data, we used dates of diagnosis and treatment initiation to select participants who had been linked (immediately, after a delay, or never). Between June 2019 and January 2020, we facilitated in-depth discussions to explore both the participants' experience of their TB diagnosis and their journey around linking to TB care at a primary health care facility. We analysed the data using case descriptions. RESULTS: Twelve of twenty (12/20) participants interviewed who experienced a delay linking were diagnosed at the hospital. Participants who experienced delays in linking or never linked explained this as a result of lack of information and support from health care providers. Unpleasant previous TB treatment episodes made it difficult to 'face' TB again and being uncertain of their TB diagnosis. In contrast, participants said the main motivator for linking was a personal will to get better. CONCLUSION: The health care system, especially in hospitals, should focus on strengthening patient-centred care. Communication and clear messaging on TB processes is key, to prepare patients in transitioning from a hospital setting to PHC facilities for continuation of care. This should not just include a thorough explanation of their TB diagnosis but ensure that patients understand treatment processes. Former TB patients may require additional counselling and support to re-engage in care.

Mortality during tuberculosis treatment in South Africa using an 8-year analysis of the national tuberculosis treatment register.

In 2011, the South African HIV treatment eligibility criteria were expanded to allow all tuberculosis (TB) patients lifelong ART. The impact of this change on TB mortality in South Africa is not known. We evaluated mortality in all adults (≥ 15 years old) treated for drug-susceptible TB in South Africa between 2009 and 2016. Using a Cox regression model, we quantified risk factors for mortality during TB treatment and present standardised mortality ratios (SMR) stratified by year, age, sex, and HIV status. During the study period, 8.6% (219,618/2,551,058) of adults on TB treatment died. Older age, male sex, previous TB treatment and HIV infection (with or without the use of ART) were associated with increased hazard of mortality. There was a 19% reduction in hazard of mortality amongst all TB patients between 2009 and 2016 (adjusted hazard ratio: 0.81 95%CI 0.80-0.83). The highest SMR was in 15-24-year-old women, more than double that of men (42.3 in 2016). Between 2009 and 2016, the SMR for HIV-positive TB patients increased, from 9.0 to 19.6 in women, and 7.0 to 10.6 in men. In South Africa, case fatality during TB treatment is decreasing and further interventions to address specific risk factors for TB mortality are required. Young women (15-24-year-olds) with TB experience a disproportionate burden of mortality and interventions targeting this age-group are needed.

Early mortality in tuberculosis patients initially lost to follow up following diagnosis in provincial hospitals and primary health care facilities in Western Cape, South Africa.

In South Africa, low tuberculosis (TB) treatment coverage and high TB case fatality remain important challenges. Following TB diagnosis, patients must link with a primary health care (PHC) facility for initiation or continuation of antituberculosis treatment and TB registration. We aimed to evaluate mortality among TB patients who did not link to a TB treatment facility for TB treatment within 30 days of their TB diagnosis, i.e. who were "initial loss to follow-up (ILTFU)" in Cape Town, South Africa. We prospectively included all patients with a routine laboratory or clinical diagnosis of TB made at PHC or hospital level in Khayelitsha and Tygerberg sub-districts in Cape Town, using routine TB data from an integrated provincial health data centre between October 2018 and March 2020. Overall, 74% (10,208/13,736) of TB patients were diagnosed at PHC facilities and ILTFU was 20.0% (2,742/13,736). Of ILTFU patients, 17.1% (468/2,742) died, with 69.7% (326/468) of deaths occurring within 30 days of diagnosis. Most ILTFU deaths (85.5%; 400/468) occurred in patients diagnosed in hospital. Multivariable logistic regression identified increasing age, HIV positive status, and hospital-based TB diagnosis (higher in the absence of TB treatment initiation and being ILTFU) as predictors of mortality. Although hospitals account for a modest proportion of diagnosed TB patients they have high TB-associated mortality. A hospital-based TB diagnosis is a critical opportunity to identify those at high risk of early and overall mortality. Interventions to diagnose TB before hospital admission, improve linkage to TB treatment following diagnosis, and reduce mortality in hospital-diagnosed TB patients should be prioritised.

Health system determinants of tuberculosis mortality in South Africa: a causal loop model.

BACKGROUND: Tuberculosis (TB) is a major public health concern in South Africa and TB-related mortality remains unacceptably high. Numerous clinical studies have examined the direct causes of TB-related mortality, but its wider, systemic drivers are less well understood. Applying systems thinking, we aimed to identify factors underlying TB mortality in South Africa and describe their relationships. At a meeting organised by the 'Optimising TB Treatment Outcomes' task team of the National TB Think Tank, we drew on the wide expertise of attendees to identify factors underlying TB mortality in South Africa. We generated a causal loop diagram to illustrate how these factors relate to each other. RESULTS: Meeting attendees identified nine key variables: three 'drivers' (adequacy & availability of tools, implementation of guidelines, and the burden of bureaucracy); three 'links' (integration of health services, integration of data systems, and utilisation of prevention strategies); and three 'outcomes' (accessibility of services, patient empowerment, and socio-economic status). Through the development and refinement of the causal loop diagram, additional explanatory and linking variables were added and three important reinforcing loops identified. Loop 1, 'Leadership and management for outcomes' illustrated that poor leadership led to increased bureaucracy and reduced the accessibility of TB services, which increased TB-related mortality and reinforced poor leadership through patient empowerment. Loop 2, 'Prevention and structural determinants' describes the complex reinforcing loop between socio-economic status, patient empowerment, the poor uptake of TB and HIV prevention strategies and increasing TB mortality. Loop 3, 'System capacity' describes how fragmented leadership and limited resources compromise the workforce and the performance and accessibility of TB services, and how this negatively affects the demand for higher levels of stewardship. CONCLUSIONS: Strengthening leadership, reducing bureaucracy, improving integration across all levels of the system, increasing health care worker support, and using windows of opportunity to target points of leverage within the South African health system are needed to both strengthen the system and reduce TB mortality. Further refinement of this model may allow for the identification of additional areas of intervention.

Mortality in South African Children and Adolescents Routinely Treated for Tuberculosis.

BACKGROUND: In South Africa, tuberculosis (TB) is a leading cause of death among those <20 years of age. We describe changes in TB mortality among children and adolescents in South Africa over a 13-year period, identify risk factors for mortality, and estimate excess TB-related mortality. METHODS: Retrospective analysis of all patients <20 years of age routinely recorded in the national electronic drug-susceptible TB treatment register (2004-2016). We developed a multivariable Cox regression model for predictors of mortality and used estimates of mortality among the general population to calculate standardized mortality ratios (SMRs). RESULTS: Between 2004 and 2016, 729 463 children and adolescents were recorded on TB treatment; 84.0% had treatment outcomes and 2.5% (18 539) died during TB treatment. The case fatality ratio decreased from 3.3% in 2007 to 1.9% in 2016. In the multivariable Cox regression model, ages 0 to 4, 10 to 14, and 15 to 19 years (compared with ages 5 to 9 years) were associated with increased risk of mortality, as was HIV infection, previous TB treatment, and extrapulmonary involvement. The SMR of 15 to 19-year-old female patients was more than double that of male patients the same age (55.3 vs 26.2). Among 10 to 14-year-olds and those who were HIV-positive, SMRs increased over time. CONCLUSIONS: Mortality in South African children and adolescents treated for TB is declining but remains considerable, with 2% dying during 2016. Adolescents (10 to 19 years) and those people living with HIV have the highest risk of mortality and the greatest SMRs. Interventions to reduce mortality during TB treatment, specifically targeting those at highest risk, are urgently needed.

The Impact of the Evolving Human Immunodeficiency Virus Response on the Epidemiology of Tuberculosis in South African Children and Adolescents.

BACKGROUND: Few studies have evaluated tuberculosis control in children and adolescents. We used routine tuberculosis surveillance data to quantify age- and human immunodeficiency virus (HIV)-stratified trends over time and investigate the relationship between tuberculosis, HIV, age, and sex. METHODS: All children and adolescents (0-19 years) routinely treated for drug-susceptible tuberculosis in South Africa and recorded in a de-duplicated national electronic tuberculosis treatment register (2004-2016) were included. Age- and HIV-stratified tuberculosis case notification rates (CNRs) were calculated in four age bands: 0-4, 5-9, 10-14, and 15-19 years. The association between HIV infection, age, and sex in children and adolescents with tuberculosis was evaluated using multivariable logistic regression. RESULTS: Of 719 400 children and adolescents included, 339 112 (47%) were 0-4 year olds. The overall tuberculosis CNR for 0-19 year olds declined by 54% between 2009 and 2016 (incidence rate ratio [IRR] = 0.46; 95% confidence interval [CI], .45-.47). Trends varied by age and HIV, with the smallest reductions (2013-2016) in HIV-positive 0-4 year olds (IRR = 0.90; 95% CI, .85-.95) and both HIV-positive (IRR = .84; 95% CI, .80-.88) and HIV-negative (IRR = 0.89; 95% CI, .86-.92) 15-19 year olds. Compared with 0- to 4-year-old males, odds of HIV coinfection among 15-19 year olds were nearly twice as high in females (adjusted odds ratio [aOR] = 2.49; 95% CI, 2.38-2.60) than in males (aOR = 1.35; 95% CI, 1.29-1.42). CONCLUSIONS: South Africa's national response to the HIV epidemic has made a substantial contribution to the observed declining trends in tuberculosis CNRs in children and adolescents. The slow decline of tuberculosis CNRs in adolescents and young HIV-positive children is concerning. Understanding how tuberculosis affects children and adolescents beyond conventional age bands and by sex can inform targeted tuberculosis control strategies.

Parvimonas micra, Peptostreptococcus stomatis, Fusobacterium nucleatum and Akkermansia muciniphila as a four-bacteria biomarker panel of colorectal cancer.

Dysbiosis of the gut microbiome has been associated with the pathogenesis of colorectal cancer (CRC). We profiled the microbiome of gut mucosal tissues from 18 CRC patients and 18 non-CRC controls of the UKM Medical Centre (UKMMC), Kuala Lumpur, Malaysia. The results were then validated using a species-specific quantitative PCR in 40 CRC and 20 non-CRC tissues samples from the UMBI-UKMMC Biobank. Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus stomatis and Akkermansia muciniphila were found to be over-represented in our CRC patients compared to non-CRC controls. These four bacteria markers distinguished CRC from controls (AUROC = 0.925) in our validation cohort. We identified bacteria species significantly associated (cut-off value of > 5 fold abundance) with various CRC demographics such as ethnicity, gender and CRC staging; however, due to small sample size of the discovery cohort, these results could not be further verified in our validation cohort. In summary, Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus stomatis and Akkermansia muciniphila were enriched in our local CRC patients. Nevertheless, the roles of these bacteria in CRC initiation and progression remains to be investigated.