Lupus myocarditis: review of current diagnostic modalities and their application in clinical practice.

Lupus myocarditis (LM) is a potentially fatal manifestation of SLE, occurring in 5-10% of patients. Clinical manifestations may vary from an unexplained tachycardia to fulminant congestive cardiac failure (CCF). With no single clinical or imaging modality being diagnostic, a rational and practical approach to the patient presenting with possible LM is essential. Markers of myocyte injury (including troponin I and creatine kinase) may be unelevated and do not exclude a diagnosis of LM. Findings on ECG are non-specific but remain essential to exclude other causes of CCF such as an acute coronary syndrome or conduction disorders. Echocardiographic modalities including wall motion abnormalities and speckle tracking echocardiography may demonstrate regional and/or global left ventricular dysfunction and is more sensitive than conventional echocardiography, especially early in the course of LM. Cardiac magnetic resonance imaging (CMRI) is regarded as the non-invasive diagnostic modality of choice in myocarditis. While more sensitive and specific than echocardiography, CMRI has certain limitations in the context of SLE, including technical challenges in acutely unwell and uncooperative patients, contraindications to gadolinium use in the context of renal impairment (including lupus nephritis) and limited literature regarding the application of recommended diagnostic CMRI criteria in SLE. Both echocardiography as well as CMRI may detect subclinical myocardial dysfunction and/or injury of which the clinical significance remains uncertain. Considering these challenges, a combined decision-making approach by rheumatologists and cardiologists interpreting diagnostic test results within the clinical context of the patient is essential to ensure an accurate, early diagnosis of LM.

Bad company? The pericardium microbiome in people investigated for tuberculosis pericarditis in an HIV-prevalent setting.

Background: The microbiome likely plays a role in tuberculosis (TB) pathogenesis. We evaluated the site-of-disease microbiome and predicted metagenome in people with presumptive tuberculous pericarditis, a major cause of mortality, and explored for the first time, the interaction between its association with C-reactive protein (CRP), a potential diagnostic biomarker and the site-of-disease microbiome in extrapulmonary TB. Methods: People with effusions requiring diagnostic pericardiocentesis (n=139) provided background sampling controls and pericardial fluid (PF) for 16S rRNA gene sequencing analysed using QIIME2 and PICRUSt2. Blood was collected to measure CRP. Results: PF from people with definite (dTB, n=91), probable (pTB, n=25), and non- (nTB, n=23) tuberculous pericarditis differed in ß-diversity. dTBs were, vs. nTBs, Mycobacterium-, Lacticigenium-, and Kocuria- enriched. Within dTBs, HIV-positives were Mycobacterium-, Bifidobacterium- , Methylobacterium- , and Leptothrix -enriched vs. HIV-negatives and HIV-positive dTBs on ART were Mycobacterium - and Bifidobacterium -depleted vs. those not on ART. Compared to nTBs, dTBs exhibited short-chain fatty acid (SCFA) and mycobacterial metabolism microbial pathway enrichment. People with additional non-pericardial involvement had differentially PF taxa (e.g., Mycobacterium -enrichment and Streptococcus -depletion associated with pulmonary infiltrates). Mycobacterium reads were in 34% (31/91), 8% (2/25) and 17% (4/23) of dTBs, pTBs, and nTBs, respectively. ß-diversity differed between patients with CRP above vs. below the median value ( Pseudomonas -depleted). There was no correlation between enriched taxa in dTBs and CRP. Conclusions: PF is compositionally distinct based on TB status, HIV (and ART) status and dTBs are enriched in SCFA-associated taxa. The clinical significance of these findings, including mycobacterial reads in nTBs and pTBs, requires evaluation.

Access to novel anti-diabetic agents in resource limited settings: A brief commentary.

The prevalence of diabetes mellitus is increasing in resource limited settings. Simultaneously, there has been an increase in the number of novel therapies for the management of diabetes mellitus. However, use of novel antidiabetic therapies is limited because of major market access challenges in resource limited settings. Niching products to those patients with the highest absolute risk for major adverse cardiovascular outcomes, and thus most likely to benefit from the therapy, are less likely to have negative budget impact for funders. To improve access, and reduce morbidity and mortality, requires alignment amongst key stakeholders including patient advocacy groups, health care professional councils, national departments of health, the pharmaceutical industry, treasury and finance departments.

Optimal dosing of gliclazide-A model-based approach.

Gliclazide was approved as a treatment for type 2 diabetes in an era before model-based drug development, and consequently, the recommended doses were not optimised with modern methods. To investigate various dosing regimens of gliclazide, we used publicly available data to characterise the dose-response relationship using pharmacometric models. A literature search identified 21 published gliclazide pharmacokinetic (PK) studies with full profiles. These were digitised, and a PK model was developed for immediate- (IR) and modified-release (MR) formulations. Data from a gliclazide dose-ranging study of postprandial glucose were used to characterise the concentration-response relationship using the integrated glucose-insulin model. Simulations from the full model showed that the maximum effect was 44% of the patients achieving HbA1c <7%, with 11% experiencing glucose <3 mmol/L and the most sensitive patients (i.e., 5% most extreme) experiencing 35 min of hypoglycaemia. Simulations revealed that the recommended IR dose (320 mg) was appropriate with no efficacy gain with increased dose. However, the recommended dose for the MR formulation may be increased to 270 mg, with more patients achieving HbA1c goals (i.e., HbA1c <7%) without a hypoglycaemic risk higher than the resulting risk from the recommended IR dose.

Image-guided percutaneous biopsy and pathological diagnosis in atypical tuberculous spondylitis: a case series and clinical outcomes.

Background: Tuberculous spondylitis can be difficult to distinguish from alternative spinal pathologies such as malignancy, particularly if the imaging features are not typical. Biopsy and histopathological analysis are facilitative to the early and accurate diagnosis of atypical tuberculous spondylitis and the clinical management. The purpose of this study is to describe some of the atypical imaging features of tuberculous spondylitis diagnosed by image-guided percutaneous biopsy, as well as associated treatment outcomes. Methods: We performed a retrospective analysis of all patients diagnosed with tuberculous spondylitis after image-guided percutaneous biopsy at The Third Affiliated Hospital of Southern Medical University between 2013 and 2020. Of the patients identified, those with atypical imaging features were selected for case review. All patients were given anti-tuberculous medication treatment with or without surgery. The imaging features, histological and microbiological results, and clinical presentations and outcomes were evaluated. Neurological function was evaluated according to the Frankel grading system. The clinical outcomes were evaluated by Visual Analogic Scale (VAS) scores for pain, imaging [X-ray, computed tomography (CT), and magnetic resonance imaging (MRI)] results, and laboratory examinations. Comparison of VAS scores was made by Student t-test. Results: Of the 102 patients identified with tuberculous spondylitis between 2013 and 2020, eight patients (two females and six males) with a mean age of 41.6 years (range, 18-61 years) demonstrated atypical imaging findings, including central vertebral body lesion, multiple skip vertebral lesions, extradural mass lesion and anterior subperiosteal lesion. All eight patients received anti-tuberculous medication treatment, and six underwent surgery. One patient developed a pleural effusion after debridement of the thoracic lesion. The mean follow-up period was 16.2 months (6-37 months). The VAS scores before treatment and at the final follow-up showed significant differences (7.25±1.49 and 0.0±0.0, respectively, P<0.01). Improved neurological function were observed in all patients. Solid fusion and osteogenic osteosclerosis were observed at the final follow-up, and no recurrence was observed in any cases. Conclusions: All eight patients had a good prognosis. Image-guided biopsy and histopathological analysis are helpful for the early diagnosis of tuberculous spondylitis, especially when imaging features are not typical for this condition.

Post-tuberculous lung disease: should we be using Theophylline?

Tuberculosis affects 10 million people and over 320,000 South Africans every year. A significant proportion of patients treated for tuberculosis develop post-tuberculous lung disease (PTBLD), a disease of chronic respiratory impairment for which there is a lack of affordable treatment options. PTBLD a heterogenous disorder that shares phenotypical features with chronic obstructive lung disease, bronchiectasis, lung fibrosis and destruction as well as pulmonary hypertension. There remains a paucity of proven pharmacotherapy for the management of PTBLD. Theophylline, a widely available and affordable medicine that has largely fell out of favour in high-income settings due to its toxicity and narrow therapeutic index, may be repositioned for the treatment of PTBLD. In this review, we unpack the potential role of theophylline in the management of PTBLD by reviewing the evidence for its bronchodilatory, anti-inflammatory and potential pleotrophic effects.

Real-world evidence and product development: Opportunities, challenges and risk mitigation.

Real-world evidence (RWE) is derived from real-world data (RWD) sources including electronic health records, claims data, registries (disease, product) and pragmatic clinical trials. The importance of RWE derived from RWD has been once again demonstrated during the coronavirus disease 2019 (COVID-19) pandemic, as it can improve patient care by complementing information obtained from traditional clinical trial programs. Additionally, RWE can generate insights into disease mechanisms, epidemiology, patient flows in and out of healthcare systems, and drivers and barriers to optimal clinical care in real-world settings. Identifying unmet medical needs is crucial as it often can inform which investigational new drugs enter clinical trial testing, and RWE studies from hospital settings have contributed substantial progress here. RWE can also optimize the design of clinical studies, inform benefit risk assessments and use networks of pragmatic studies to help with clinical trial feasibilities and eventual trial initiation. The challenges of RWD include data quality, reproducibility and accuracy which may affect validity. RWD and RWE must be fit for purpose and one must be cognizant of inherent biases.

PCSK9 Inhibitors: From Nature's Lessons to Clinical Utility.

BACKGROUND: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of non-statin lipid lowering therapy that reduce LDL-cholesterol by 50 - 60%. PCSK9 inhibitors decrease LDL-cholesterol by preventing intracellular degradation of LDL receptors; subsequently, a greater number of LDL-receptors are available on the cell surface to extract circulating LDL. OBJECTIVE: To describe the origins of PCSK9 inhibitors and their current use in clinical practice. METHODS: We performed a narrative review of the PCSK9 inhibitor class of drugs. RESULTS: Current data indicate that PCSK9 inhibitors effectively reduce LDL-cholesterol and are well tolerated and safe. PCSK9 inhibitors have also been shown to reduce cardiovascular event rates in patients with stable atherosclerotic cardiovascular disease and in patients with a recent (up to one year) acute coronary syndrome. Given the costs, chronicity of the treatment and the potential budget impact, PCSK9 inhibitors are often limited to patients with the highest absolute risk for major adverse cardiovascular events despite optimal treatment with high-intensity statin and ezetimibe. CONCLUSION: PCSK9 inhibitors have a favorable safety, efficacy and tolerability profile. Postmarketing safety surveillance and real-world studies are needed to further support the long-term safety profile of this class of medicine.

Management of adult patients with type 1 diabetes mellitus in Africa: A post-hoc cohort analysis of 12 African countries participating in the International Diabetes Management Practices Study (Wave 7).

There is a paucity of information on real world management of African adult patients with type 1 diabetes mellitus (T1DM). We aimed to describe a cohort of African adults with T1DM.The International Diabetes Management Practices Study is an observational survey conducted from 2005 to 2017. Data were collected in seven individual waves from countries in Asia, Africa, East Europe, and Latin America. Wave 7 was conducted from 2016 to 2017 and the African cohort included 12 countries. Questionnaires were administered to clinicians and patients. Analyses were mainly descriptive. Logistic regressions were performed to identify predictive factors for glycaemic control.A total of 788 patients were enrolled in the study. HbA1c values were available for 712 patients; only 16.6% had HbA1c values <7%. A total of 196 (24.9%) reported being hospitalized in the preceding year, with the most common reasons being diabetic ketoacidosis (58.1%, 93/160) and hypoglycaemia (31.1%; 52/167). Over half of the patients (55.4%) stated that the cost of test strips limited regular glycemic monitoring; a minority of patients (15%, 120/788) received structured diabetes education. Predictors of HbA1c <7% included patients receiving diabetes education (odds ratio [OR] [95% confidence interval, CI] = 2.707 [1.157-6.335] P = .022), following a healthy diet and exercise plan (OR [95% CI] = 2.253 [1.206-4.209], P < .001) and self-managing (monitoring glucose levels and adjusting insulin accordingly) (OR [95% CI] 2.508 [1.500-4.191] P < .001).African adults with T1DM have suboptimal glycemic control with almost one-quarter reporting hospitalization within the preceding year. Most patients felt comfortable with self-adjustment of insulin dose but said that the cost of test strips was the main factor that limited regular monitoring. Reducing direct costs of testing strips and insulin, and improving education will address major challenges within these settings.

Risk Factors for Incident Diabetes in a Cohort Taking First-Line Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy.

Efavirenz is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) in first-line antiretroviral therapy (ART) regimens in low- and middle-income countries, where the prevalence of diabetes is increasing. Randomized control trials have shown mild increases in plasma glucose in participants in the efavirenz arms, but no association has been reported with overt diabetes. We explored the association between efavirenz exposure and incident diabetes in a large Southern African cohort commencing NNRTI-based first-line ART. Our cohort included HIV-infected adults starting NNRTI-based ART in a private sector HIV disease management program from January 2002 to December 2011. Incident diabetes was identified by the initiation of diabetes treatment. Patients with prevalent diabetes were excluded. We included 56,298 patients with 113,297 patient-years of follow-up (PYFU) on first-line ART. The crude incidence of diabetes was 13.24 per 1000 PYFU. Treatment with efavirenz rather than nevirapine was associated with increased risk of developing diabetes (hazard ratio 1.27 (95% confidence interval (CI): 1.10-1.46)) in a multivariate analysis adjusting for age, sex, body mass index, baseline CD4 count, viral load, NRTI backbone, and exposure to other diabetogenic medicines. Zidovudine and stavudine exposure were also associated with an increased risk of developing diabetes. We found that treatment with efavirenz, as well as stavudine and zidovudine, increased the risk of incident diabetes. Interventions to detect and prevent diabetes should be implemented in ART programs, and use of antiretrovirals with lower risk of metabolic complications should be encouraged.