Novel role of cardiovascular MRI to contextualise tuberculous pericardial inflammation and oedema as predictors of constrictive pericarditis.

Tuberculosis (TB) and human immunodeficiency virus/acquired immunodeficiency syndrome have reached epidemic proportions, particularly affecting vulnerable populations in low- and middle-income countries of sub-Saharan Africa. TB pericarditis is the commonest cardiac manifestation of TB and is the leading cause of constrictive pericarditis, a reversible (by surgical pericardiectomy) cause of diastolic heart failure in endemic areas. Unpacking the complex mechanisms underpinning constrictive haemodynamics in TB pericarditis has proven challenging, leaving various basic and clinical research questions unanswered. Subsequently, risk stratification strategies for constrictive outcomes have remained unsatisfactory. Unique pericardial tissue characteristics, as identified on cardiovascular magnetic resonance imaging, enable us to stage and quantify pericardial inflammation and may assist in identifying patients at higher risk of tissue remodelling and pericardial constriction, as well as predict the degree of disease reversibility, tailor medical therapy, and determine the ideal timing for surgical pericardiectomy.

Issues in Medicine.

Rasmussen aneurysms are abnormalities of the pulmonary arterial system caused by tuberculosis (TB). They are associated with a highmortality rate when they cause life-threatening haemoptysis. High TB-prevalence regions have a large burden of TB-related haemoptysisbut often limited resources. This series of 25 patients who presented with life-threatening haemoptysis from current and/or previous TBwere found to have abnormal pulmonary arteries on computed tomography pulmonary angiogram (CTPA), which were judged to belikely contributors to their bleeding, either in isolation or with concomitant abnormal bronchial or systemic vasculature. These patientsunderwent transcatheter placement of Amplatzer vascular plugs in the feeder pulmonary artery. Bronchial and systemic lesions wereaddressed separately as needed. Immediate technical success was achieved in all patients, but four of them experienced intraoperativehaemoptysis related to dislodgement of the occluding platelet plug by the high-pressure automatic injector and wire. At 48 hours after theprocedure, 18 (72%) remained haemoptysis-free. Six of these experienced recurrence within 1 year of their procedure. Pulmonary arteryplacement of an Amplatzer vascular plug is a feasible option for treating bleeding Rasmussen aneurysms, but should be part of a combinedapproach to addressing suspected culprit vascular lesions in all intrathoracic vascular systems.

The utility of endobronchial ultrasound-guided transbronchial needle aspiration in a community with a high HIV and tuberculosis burden.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become the gold standard in diagnosing and performing nodal staging in patients with suspected lung cancer and diagnosing other malignant and benign diseases. Studies from countries with low tuberculosis (TB) incidence suggest that it has a sensitivity of 90 - 95% and a specificity of 100%. Objectives: To investigate the utility of EBUS-TBNA in a community with a high HIV and TB burden. Methods: We retrospectively reviewed all patients who underwent EBUS-TBNA to confirm a tissue diagnosis during a 2-year period from January 2017 - December 2018. Only patients with complete medical, pathology and radiology records and follow-up were included. Results: During the 2 years, a total of 201 patients underwent EBUS-TBNA. Some patients (n=19) had incomplete notes or follow-up and 104 cases were ultimately diagnosed with benign nodal disease. In the 182 patients who were ultimately included in the present study, EBUS-TBNA had a sensitivity of 95.1% (95% confidence interval (CI) 88.6 - 98.2), specificity of 100% (95% CI 94.20 - 100), positive predictive value (PPV) of 100.00% (95% CI 95.3 - 100) and negative predictive value (NPV) of 94.1% (95% CI 86.0 - 97.8) for all diagnoses. The overall diagnostic accuracy was 97.3% (95% CI 93.9 - 99.2). Out of the 64 patients who had lung cancer, EBUS-TBNA had a sensitivity of 95.2% (95% CI 86.7 - 99.0), specificity of 100% (95% CI 5.5 - 100), PPV of 100.0% and NPV of 58.3% (95% CI 31.7 - 80.9). The overall diagnostic accuracy for lung cancer was 95.5% (95% CI 87.2 - 99.1%). Conclusion: EBUS-TBNA has high diagnostic accuracy, even in a population with a high HIV and TB burden.

Rapid Assembly of Infection-Resistant Coatings: Screening and Identification of Antimicrobial Peptides Works in Cooperation with an Antifouling Background.

Bacterial adhesion and the succeeding biofilm formation onto surfaces are responsible for implant- and device-associated infections. Bifunctional coatings integrating both nonfouling components and antimicrobial peptides (AMPs) are a promising approach to develop potent antibiofilm coatings. However, the current approaches and chemistry for such coatings are time-consuming and dependent on substrates and involve a multistep process. Also, the information is limited on the influence of the coating structure or its components on the antibiofilm activity of such AMP-based coatings. Here, we report a new strategy to rapidly assemble a stable, potent, and substrate-independent AMP-based antibiofilm coating in a nonfouling background. The coating structure allowed for the screening of AMPs in a relevant nonfouling background to identify optimal peptide combinations that work in cooperation to generate potent antibiofilm activity. The structure of the coating was changed by altering the organization of the hydrophilic polymer chains within the coatings. The coatings were thoroughly characterized using various surface analytical techniques and correlated with the efficiency to prevent biofilm formation against diverse bacteria. The coating method that allowed the conjugation of AMPs without altering the steric protection ability of hydrophilic polymer structure results in a bifunctional surface coating with excellent antibiofilm activity. In contrast, the conjugation of AMPs directly to the hydrophilic polymer chains resulted in a surface with poor antibiofilm activity and increased adhesion of bacteria. Using this coating approach, we further established a new screening method and identified a set of potent surface-tethered AMPs with high activity. The success of this new peptide screening and coating method is demonstrated using a clinically relevant mouse infection model to prevent catheter-associated urinary tract infection (CAUTI).

Self-Limiting Mussel Inspired Thin Antifouling Coating with Broad-Spectrum Resistance to Biofilm Formation to Prevent Catheter-Associated Infection in Mouse and Porcine Models.

Catheter-associated urinary tract infections (CAUTIs) are one of the most commonly occurring hospital-acquired infections. Current coating strategies to prevent catheter-associated biofilm formation are limited by their poor long-term efficiency and limited applicability to diverse materials. Here, the authors report a highly effective non-fouling coating with long-term biofilm prevention activity and is applicable to diverse catheters. The thin coating is lubricous, stable, highly uniform, and shows broad spectrum prevention of biofilm formation of nine different bacterial strains and prevents the migration of bacteria on catheter surface. The coating method is adapted to human-sized catheters (both intraluminal and extraluminal) and demonstrates long-term biofilm prevention activity over 30 days in challenging conditions. The coated catheters are tested in a mouse CAUTI model and demonstrate high efficiency in preventing bacterial colonization of both Gram-positive and Gram-negative bacteria. Furthermore, the coated human-sized Foley catheters are evaluated in a porcine CAUTI model and show consistent efficiency in reducing biofilm formation by Escherichia coli (E. coli) over 95%. The simplicity of the coating method, the ability to apply this coating on diverse materials, and the high efficiency in preventing bacterial adhesion increase the potential of this method for the development of next generation infection resistant medical devices.

Insights into the mechanism of action of two analogues of aurein 2.2.

The naturally occurring host defense peptide (HDP), aurein 2.2, secreted by the amphibian Litoria aurea, acts as a moderate antibacterial, affecting Gram positive bacteria such as Staphylococcus aureus by forming selective ion pores. In a quest to find more active analogues of aurein 2.2, peptides 73 and 77 were discovered. These peptides were rich in arginine and tryptophan and found to have MICs of 4 µg/mL. Here we examined what impact the increased charge from +2 to +3 and a slight increase in hydrophobic moment relative to aurein 2.2 had on the mechanism of action of these two analogues. Using a time-kill assay, both peptides 73 and 77 were found to kill bacteria more effectively than the parent peptide. Using solution CD and NMR, the peptides were found to not adopt a continuous α-helical structure, i.e. the analogues were not helical from residue 1-13 like the parent peptide. Results obtained from oriented CD (OCD), DiSC35 and pyranine assays and a gel retardation experiment showed that the peptides did not function by membrane perturbation and further showed that peptide 73 and 77 did not interact with DNA. Overall, the data were consistent with these peptides acting as cell penetrating peptides with intracellular targets, which did not appear to be DNA.

The aetiology of severe community-acquired pneumonia requiring intensive care unit admission in the Western Cape Province, South Africa.

BACKGROUND: Community-acquired pneumonia (CAP) is a common condition, with mortality increasing in patients who require intensive care unit (ICU) admission. A better understanding of the current aetiology of severe CAP will aid clinicians in requesting appropriate diagnostic tests and initiating appropriate empiric antimicrobials. OBJECTIVES: To assess the comorbidities, aetiology and mortality associated with severe CAP in a tertiary ICU in Cape Town, South Africa. METHODS: We retrospectively analysed a prospective registry of all adults admitted to the medical intensive care unit at Tygerberg Hospital with severe CAP over a 1-year period. RESULTS: We identified 74 patients (mean (SD) age 40.0 (15.5) years; 44 females). The patients had a mean (SD) APACHE II score of 21.4 (7.9), and the mean ICU stay was 6.6 days. Of the 74 patients, 16 (21.6%) died in ICU. Non-survivors had a higher mean (SD) APACHE II score than survivors (28.3 (6.8) v. 19.4 (7.1); p<0.001). Mycobacterium tuberculosis (n=16; 21.6%) was the single most common agent identified, followed by Pseudomonas aeruginosa (n=9; 12.2%). All P. aeruginosa isolates were sensitive to first-line treatment. No organism was identified in 32 patients (43.2%). CONCLUSION: M. tuberculosis was the single most common agent identified in patients presenting with CAP. The mortality of CAP requiring invasive ventilation was relatively low, with a strong association between mortality and a higher APACHE II score.

SLE pachymeningitis and multiple cranial nerve palsies: a case report and review of the literature.

Hypertrophic pachymeningitis (HP) is a relatively uncommon disease associated with focal or diffuse thickening of the dura mater secondary to underlying chronic inflammation. The link between systemic lupus erythematosus (SLE) and hypertrophic pachymeningitis (HP) is extremely rare, with only six other cases reported in the literature. We, however, report the first case of SLE pachymeningitis presenting with multiple cranial nerve palsies. The patient showed good response to steroids and cyclophosphamide therapy. One should maintain a high index of suspicion to make the diagnosis in patients with SLE presenting with neurological dysfunction. Prompt therapy prevents long-term neurological sequelae.

Aurein-Derived Antimicrobial Peptides Formulated with Pegylated Phospholipid Micelles to Target Methicillin-Resistant Staphylococcus aureus Skin Infections.

Antimicrobial peptides have been the focus of considerable research; however, issues associated with toxicity and aggregation have the potential to limit clinical applications. Here, a derivative of a truncated version of aurein 2.2 (aurein 2.2Δ3), namely peptide 73, was investigated, along with its d-amino acid counterpart (D-73) and a retro-inverso version (RI-73). A version that incorporated a cysteine residue to the C-terminus (73c) was also generated, as this form is required to covalently attach antimicrobial peptides to polymers (e.g., polyethylene glycol (PEG) or hyperbranched polyglycerol (HPG)). The antimicrobial activity of the 73-derived peptides was enhanced 2- to 8-fold, and all the derivatives eradicated preformed Staphylococcus aureus biofilms. Formulation of the peptides with compatible polyethylene glycol (PEG)-modified phospholipid micelles alleviated toxicity toward human cells and reduced aggregation. When evaluated in vivo, the unformulated d-enantiomers aggregated when injected under the skin of mice, but micelle encapsulated peptides were well absorbed. Pegylated micelle formulated peptides were investigated for their potential as therapeutic agents for treating high-density infections in a murine cutaneous abscess model. Formulated peptide 73 reduced abscess size by 36% and bacterial loads by 2.2-fold compared to the parent peptide aurein 2.2Δ3. Micelle encapsulated peptides 73c and D-73 exhibited superior activity, further reducing abscess sizes by 85% and 63% and lowering bacterial loads by 510- and 9-fold compared to peptide 73.

Atrialized right ventricular myxoma in a patient with Ebstein's anomaly.

Ebstein's anomaly is a rare entity affecting around 1 in 200,000 live births and accounts for less than 1% of congenital heart diseases. Ebstein's anomaly with an associated right-sided myxoma is extremely rare, with only one other case report found in the literature. Previous reports have also noted cases of Ebstein's anomaly associated with left-sided myxomas. We describe a female patient with, to our knowledge, the first case of a histopathologically confirmed right ventricular myxoma in the setting of Ebstein's anomaly.

50 years of tuberculosis control in India: progress, pitfalls and the way forward.

India established the National Tuberculosis Control Project (NTCP) 50 years ago and re-designed it as Revised NTCP (RNTCP) 19 years ago. Tuberculosis (TB) control was beset with obstacles-BCG vaccination was found ineffective in TB control in 1979; human immunodeficiency virus began spreading in India since 1984 with TB as the commonest opportunistic disease; multi-drug resistance was found to be prevalent since 1992. The World Health Organization declared TB as global emergency in 1993. Yet, RNTCP was extended to the whole nation very slowly, taking 13 years from inception. The first objective of RNTCP, namely 85% treatment success has been achieved and case-fatality had dropped by 90%;. Still, TB burden continues to remain huge; about half the cases are not getting registered under RNTCP; pediatric TB is neglected; TB drains national economy of US$ 23 billion annually. Therefore, TB control is in urgent need of re-design and re-invigoration, with additional inputs and system re-organization to cover all such gaps. We highlight the need for Public Health infrastructure under which all vertical disease control projects such as RNTCP should be synergized for better efficiency and for establishing Public Health Surveillance for collecting denominator-based data on incidence and prevalence to guide course corrections. India ought to spend 3 to 5 times more on TB control than at present. Control needs clear epidemiologic definition and measurable parameters for monitoring the level of control over time. TB control is both a measure of, and a means to, socioeconomic development.

Biomembrane interactions reveal the mechanism of action of surface-immobilized host defense IDR-1010 peptide.

Dissecting the mechanism of action of surface-tethered antimicrobial and immunomodulatory peptides is critical to the design of optimized anti-infection coatings on biomedical devices. To address this, we compared the biomembrane interactions of host defense peptide IDR-1010cys (1) in free form, (2) as a soluble polymer conjugate, and (3) with one end tethered to a solid support with model bacterial and mammalian lipid membranes. Our results show that IDR-1010cys in all three distinct forms interacted with bacterial and mammalian lipid vesicles, but the extent of the interactions as monitored by the induction of secondary structure varied. The enhanced interaction of surface-tethered peptides is well correlated with their very good antimicrobial activities. Our results demonstrate that there may be a difference in the mechanism of action of surface-tethered versus free IDR-1010cys.

Building on the success of the Expanded Programme on Immunization: enhancing the focus on disease prevention and control.

The Expanded Programme on Immunization (EPI) has succeeded in establishing a vaccine delivery system in all low and middle income (LMI) countries. Because EPI has focused on immunization delivery, its major outcome is measured in many countries only as vaccine coverage, not as disease reduction, the real goal of EPI. Monitoring disease reduction requires real-time case-based disease surveillance and appropriate interventions, for which a functional public health infrastructure is needed. If the highest priority for assessing impact of EPI shifts to disease prevention and control from vaccine coverage, the programme may be transformed to one of control of childhood communicable diseases (CCCD), with the potential of expanding the range of diseases of children and adults for control and of integrating all other current vertical (single disease) control efforts with it. EPI provides the essential platform on which CCCD can be built to create a public health infrastructure.