Design, Synthesis, and Biological Evaluation of a New Series of Carvedilol Derivatives That Protect Sensory Hair Cells from Aminoglycoside-Induced Damage by Blocking the Mechanoelectrical Transducer Channel.

Aminoglycosides (AGs) are broad-spectrum antibiotics used for the treatment of serious bacterial infections but have use-limiting side effects including irreversible hearing loss. Here, we assessed the otoprotective profile of carvedilol in mouse cochlear cultures and in vivo zebrafish assays and investigated its mechanism of protection which, we found, may be mediated by a block of the hair cell's mechanoelectrical transducer (MET) channel, the major entry route for the AGs. To understand the full otoprotective potential of carvedilol, a series of 18 analogues were prepared and evaluated for their effect against AG-induced damage as well as their affinity for the MET channel.

Optimising fluorescein diacetate sputum smear microscopy for assessing patients with pulmonary tuberculosis.

Background: Assessing Mycobacterium tuberculosis (TB) viability by fluorescein diacetate (FDA) microscopy can predict TB culture results, treatment response and infectiousness. However, diverse methods have been published. We aimed to optimise FDA microscopy, minimising sputum processing, biohazard and complexity for use in resource-constrained settings.

Extracorporeal membrane oxygenation (ECMO) and the acute respiratory distress syndrome (ARDS): a systematic review of pre-clinical models.

Objectives: Extracorporeal membrane oxygenation (ECMO) is an increasingly accepted means of supporting those with severe acute respiratory distress syndrome (ARDS). Given the high mortality associated with ARDS, numerous animal models have been developed to support translational research. Where ARDS is combined with ECMO, models are less well characterized.

Sepsis: Changing Definitions, Unchanging Treatment.

The recently revised Sepsis-3 definitions were based on criteria that were derived and validated in adult patient databases from high income countries. Both sepsis and septic shock continue to account for a substantial proportion of mortality globally, especially amongst children in low-and-middle income country settings. It is therefore urgent to develop and validate standardized criteria for sepsis that can be applied to pediatric populations in different settings, including in- and outside intensive care, both in high- and low/middle- income countries.

Neuron-Specific Enolase and Matrix Metalloproteinase 9 Signal Perioperative Silent Brain Infarction During or After Transcatheter Aortic Valve Implantation.

Magnetic resonance imaging (MRI) studies have consistently identified a high incidence of silent brain infarction (SBI) after cardiac intervention. The frequent occurrence, objective measurement and clinical sequelae of SBI have seen interest in their detection for both research and clinical purposes. However, MRI is expensive, time-consuming, unsafe in acutely-ill patients, and not always available, limiting its use as a routine screening tool.

Integrated morbidity mapping of lymphatic filariasis and podoconiosis cases in 20 co-endemic districts of Ethiopia.

Background: Lymphatic filariasis (LF) and podoconiosis are neglected tropical diseases (NTDs) that pose a significant physical, social and economic burden to endemic communities. Patients affected by the clinical conditions of LF (lymphoedema and hydrocoele) and podoconiosis (lymphoedema) need access to morbidity management and disability prevention (MMDP) services. Clear estimates of the number and location of these patients are essential to the efficient and equitable implementation of MMDP services for both diseases.

Lymphoedema management to prevent acute dermatolymphangioadenitis in podoconiosis in northern Ethiopia (GoLBeT): a pragmatic randomised controlled trial.

Background: Podoconiosis (also known as endemic, non-filarial elephantiasis) affects about 4 million subsistence farmers in tropical Africa. Poor awareness of the condition and inadequate evidence for the efficacy of treatment mean that no government in an endemic country yet offers lymphoedema management for patients with podoconiosis. Among patients with filarial lymphoedema, trials suggest that limb care is effective in reducing the most disabling sequelae: episodes of acute dermatolymphangioadenitis.

Pragmatism in practice: lessons learned during screening and enrollment for a randomised controlled trial in rural northern Ethiopia.

Background: We use the example of the Gojjam Lymphoedema Best Practice Trial (GoLBeT), a pragmatic trial in a remote rural setting in northern Ethiopia, to extract lessons relevant to other investigators balancing the demands of practicality and community acceptability with internal and external validity in clinical trials.

Methods: We explain in detail the preparation for the trial, its setting in northern Ethiopia, the identification and selection of patients (inclusion and exclusion criterion, identifying and screening of patients at home, enrollment of patients at the health centres and health posts), and randomisation.

Results: We describe the challenges met, together with strategies employed to overcome them.

A Comparative Analysis of Economic Cost of Podoconiosis and Leprosy on Affected Households in the Northwest Region of Cameroon.

Leprosy and podoconiosis (podo) are neglected tropical diseases that cause severe disfigurement and disability, and may lead to catastrophic health expenditure and hinder economic development of affected persons and households. This study compared economic costs of both diseases on affected households with unaffected neighboring households in the Northwest Region (N.W.

Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis.

Rationale: Platelets may interact with the immune system in tuberculosis (TB) to regulate human inflammatory responses that lead to morbidity and spread of infection.

Objectives: To identify a functional role of platelets in the innate inflammatory and matrix-degrading response in TB.

Methods: Markers of platelet activation were examined in plasma from 50 patients with TB before treatment and 50 control subjects.

Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death.

Aminoglycoside antibiotics are used to treat life-threatening bacterial infections but can cause deafness due to hair cell death in the inner ear. Compounds have been described that protect zebrafish lateral line hair cells from aminoglycosides, but few are effective in the cochlea. As the aminoglycosides interact with several ion channels, including the mechanoelectrical transducer (MET) channels by which they can enter hair cells, we screened 160 ion-channel modulators, seeking compounds that protect cochlear outer hair cells (OHCs) from aminoglycoside-induced death in vitro.

Histological Examination in Obtaining a Diagnosis in Patients with Lymphadenopathy in Lima, Peru.

The differential diagnosis for lymphadenopathy is wide and clinical presentations overlap, making obtaining an accurate diagnosis challenging. We sought to characterize the clinical and radiological characteristics, histological findings, and diagnoses for a cohort of patients with lymphadenopathy of unknown etiology. 121 Peruvian adults with lymphadenopathy underwent lymph node biopsy for microbiological and histopathological evaluation.

Left Ventricular Global Strain Analysis by Two-Dimensional Speckle-Tracking Echocardiography: The Learning Curve.

Background: The application of left ventricular (LV) global strain by speckle-tracking is becoming more widespread, with the potential for incorporation into routine clinical echocardiography in selected patients. There are no guidelines or recommendations for the training requirements to achieve competency. The aim of this study was to determine the learning curve for global strain analysis and determine the number of studies that are required for independent reporting.

Association between infection with Helicobacter pylori and atopy in young Ethiopian children: A longitudinal study.

Background: Epidemiological evidence from developed countries indicates that Helicobacter pylori infection correlates with a reduced risk of atopy and allergic disorders; however, limited data are available from low-income countries.

Objective: We examined associations between H. pylori infection in early childhood and atopy and reported allergic disorders at the age of 6.

A metabolomic analytical approach permits identification of urinary biomarkers for Plasmodium falciparum infection: a case-control study.

Background: Currently available diagnostic techniques of Plasmodium falciparum infection are not optimal for non-invasive, population-based screening for malaria. It was hypothesized that a mass spectrometry-based metabolomics approach could identify urinary biomarkers of falciparum malaria.

Methods: The study used a case-control design, with cases consisting of 21 adults in central Ethiopia with a diagnosis of P.

Health beliefs of school-age rural children in podoconiosis-affected families: A qualitative study in Southern Ethiopia.

Background: Several studies have suggested investigation of health beliefs in children to be an important pre-condition for primary prevention of disease. However, little effort has been made to understand these in the context of podoconiosis. This study therefore aimed to explore the health beliefs of school-age rural children in podoconiosis-affected families.

Sputum Microscopy With Fluorescein Diacetate Predicts Tuberculosis Infectiousness.

Background: Sputum from patients with tuberculosis contains subpopulations of metabolically active and inactive Mycobacterium tuberculosis with unknown implications for infectiousness.

Methods: We assessed sputum microscopy with fluorescein diacetate (FDA, evaluating M. tuberculosis metabolic activity) for predicting infectiousness.

Haemolytic activity of soil from areas of varying podoconiosis endemicity in Ethiopia.

Background: Podoconiosis, non-filarial elephantiasis, is a non-infectious disease found in tropical regions such as Ethiopia, localized in highland areas with volcanic soils cultivated by barefoot subsistence farmers. It is thought that soil particles can pass through the soles of the feet and taken up by the lymphatic system, leading to the characteristic chronic oedema of the lower legs that becomes disfiguring and disabling over time.

Methods: The close association of the disease with volcanic soils led us to investigate the characteristics of soil samples in an endemic area in Ethiopia to identify the potential causal constituents.

TST positivity in household contacts of tuberculosis patients: a case-contact study in Malawi.

Background: Screening household contacts of active tuberculosis (TB) patients is recommended for TB control. Due to resource constraints this rarely occurs in lower income countries. Demographic and clinical features of index cases may influence the likelihood of onwards TB transmission.

Laboratory-based and office-based risk scores and charts to predict 10-year risk of cardiovascular disease in 182 countries: a pooled analysis of prospective cohorts and health surveys.

Background: Worldwide implementation of risk-based cardiovascular disease (CVD) prevention requires risk prediction tools that are contemporarily recalibrated for the target country and can be used where laboratory measurements are unavailable. We present two cardiovascular risk scores, with and without laboratory-based measurements, and the corresponding risk charts for 182 countries to predict 10-year risk of fatal and non-fatal CVD in adults aged 40-74 years.

Methods: Based on our previous laboratory-based prediction model (Globorisk), we used data from eight prospective studies to estimate coefficients of the risk equations using proportional hazard regressions.