Anti-parasitic benzoxaboroles are ineffective against Theileria parva in vitro

East Coast Fever (ECF) is a disease affecting cattle in sub-Saharan Africa, caused by the tick-borne Apicomplexan pathogen Theileria parva. The disease is a major problem for cattle farmers in affected regions and there are few methods of control, including a complex infection and treatment vaccine, expensive chemotherapy, and the more widespread tick control through acaricides. New intervention strategies are, therefore, sorely needed. Benzoxaboroles are a versatile class of boron-heterocyclic compounds with demonstrable pharmacological activity against a diverse group of pathogens, including those related to T. parva. In this study, the in vitro efficacy of three benzoxaboroles against the intracellular schizont stage of T. parva was investigated using a flow cytometry approach. Of the benzoxaboroles tested, only one showed any potency, albeit only at high concentrations, even though there is high protein sequence similarity in the CPSF3 protein target compared to other protozoan pathogen species. This finding suggests that benzoxaboroles currently of interest for the treatment of African animal trypanosomiasis, toxoplasmosis, cryptosporidiosis and malaria may not be suitable for the treatment of ECF. We conclude that testing of further benzoxaborole compounds is needed to fully determine whether any lead compounds can be identified to target T. parva

E. coli O157 on Scottish cattle farms: evidence of local spread and persistence using repeat cross-sectional data

<b>Background</b><p></p> Escherichia coli (E. coli) O157 is a virulent zoonotic strain of enterohaemorrhagic E. coli. In Scotland (1998-2008) the annual reported rate of human infection is 4.4 per 100,000 population which is consistently higher than other regions of the UK and abroad. Cattle are the primary reservoir. Thus understanding infection dynamics in cattle is paramount to reducing human infections.<p></p> A large database was created for farms sampled in two cross-sectional surveys carried out in Scotland (1998 - 2004). A statistical model was generated to identify risk factors for the presence of E. coli O157 on farms. Specific hypotheses were tested regarding the presence of E. coli O157 on local farms and the farms previous status. Pulsed-field gel electrophoresis (PFGE) profiles were further examined to ascertain whether local spread or persistence of strains could be inferred.<p></p> <b>Results</b><p></p> The presence of an E. coli O157 positive local farm (average distance: 5.96km) in the Highlands, North East and South West, farm size and the number of cattle moved onto the farm 8 weeks prior to sampling were significant risk factors for the presence of E. coli O157 on farms. Previous status of a farm was not a significant predictor of current status (p = 0.398). Farms within the same sampling cluster were significantly more likely to be the same PFGE type (p < 0.001), implicating spread of strains between local farms. Isolates with identical PFGE types were observed to persist across the two surveys, including 3 that were identified on the same farm, suggesting an environmental reservoir. PFGE types that were persistent were more likely to have been observed in human clinical infections in Scotland (p < 0.001) from the same time frame.<p></p> <b>Conclusions</b><p></p> The results of this study demonstrate the spread of E. coli O157 between local farms and highlight the potential link between persistent cattle strains and human clinical infections in Scotland. This novel insight into the epidemiology of Scottish E. coli O157 paves the way for future research into the mechanisms of transmission which should help with the design of control measures to reduce E. coli O157 from livestock-related sources

How does the association of general and central adiposity with glycaemia and blood pressure differ by gender and area of residence in a Malawian population: a cross-sectional study.

BACKGROUND: In high-income settings, body mass index (BMI) and measures of central adiposity, such as waist-to-hip ratio (WHR) are associated with cardiometabolic risk, but evidence from low-income settings, particularly sub-Saharan Africa (SSA), is limited. We assessed whether there are differences between central and general adiposity in their associations with fasting glucose, diabetes, systolic and diastolic blood pressures and hypertension, and whether these associations differ with gender or rural/urban setting in Malawi. METHODS: We used data from a population-based study of 27 880 Malawian adults aged  ≥18 years, from both rural and urban areas. We used age-standardized z-scores of the means of BMI and WHR to directly compare their associations with glycaemic and blood pressure outcomes. RESULTS: Mean fasting glucose and blood pressure values and odds of hypertension increased linearly across fifths of BMI and WHR, with stronger associations with BMI. For both BMI and WHR, the associations with outcomes were stronger in urban versus rural residents. The association with diabetes was stronger in women than men, whereas for blood-pressure related outcomes a stronger association was seen in men. CONCLUSIONS: BMI is more strongly associated with cardiometabolic risk in SSA, and might be a more useful measure than WHR, in this population. The greater positive association of adiposity with cardiometabolic outcomes in urban residents (where rates of overweight/obesity are already high) highlights the particular importance of addressing obesity within urban SSA populations

Rationale, description and baseline findings of a community-based prospective cohort study of kidney function amongst the young rural population of Northwest Nicaragua.

BACKGROUND: An epidemic of Mesoamerican Nephropathy (MeN) is killing thousands of agricultural workers along the Pacific coast of Central America, but the natural history and aetiology of the disease remain poorly understood. We have recently commenced a community-based longitudinal study to investigate Chronic Kidney Disease (CKD) in Nicaragua. Although logistically challenging, study designs of this type have the potential to provide important insights that other study designs cannot. In this paper we discuss the rationale for conducting this study and summarize the findings of the baseline visit. METHODS: The baseline visit of the community-based cohort study was conducted in 9 communities in the North Western Nicaragua in October and November 2014. All of the young men, and a random sample of young women (aged 18-30) without a pre-existing diagnosis of CKD were invited to participate. Glomerular filtration rate (eGFR) was estimated with CKD-EPI equation, along with clinical measurements, questionnaires, biological and environmental samples to evaluate participants' exposures to proposed risk factors for MeN. RESULTS: We identified 520 young adults (286 males and 234 females) in the 9 different communities. Of these, 16 males with self-reported CKD and 5 females with diagnoses of either diabetes or hypertension were excluded from the study population. All remaining 270 men and 90 women, selected at random, were then invited to participate in the study; 350 (97%) agreed to participate. At baseline, 29 (11%) men and 1 (1%) woman had an eGFR <90 mL/min/1.73 m2. CONCLUSION: Conducting a community based study of this type requires active the involvement of communities and commitment from local leaders. Furthermore, a research team with strong links to the area and broad understanding of the context of the problem being studied is essential. The key findings will arise from follow-up, but it is striking that 5% of males under aged 30 had to be excluded because of pre-existing kidney disease, and that despite doing so 11% of males had an eGFR <90 mL/min/1.73 m2 at baseline

Clinical profile of predefined asthma phenotypes in a large cohort of UK primary care patients (Clinical Practice Research Datalink).

BACKGROUND: Distinct asthma phenotypes have previously been suggested, including benign asthma, atopic asthma and obese non-eosinophilic asthma. This study aims to establish if these phenotypes can be identified using data recorded in primary care clinical records and reports on patient characteristics and exacerbation frequency. METHODS: A population-based cohort study identified 193,999 asthma patients in UK primary care from 2007 to 2017. We used linked primary and secondary care data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics. Patients were classified into predefined phenotypes or included in an asthma "not otherwise specified" (NOS) group. We used negative binomial regression to calculate the exacerbation rates and adjusted rate ratios. Rate ratios were further stratified by asthma treatment step. RESULTS: In our cohort, 3.9% of patients were categorized as benign asthma, 28.6% atopic asthma and 4.8% obese non-eosinophilic asthma. About 62.7% of patients were asthma NOS, including asthma NOS without treatment (10.4%), only on short-acting beta agonist (6.1%) and on maintenance treatment (46.2%). Crude severe exacerbation rates per 1,000 person-years were lowest for benign asthma (106.8 [95% CI: 101.2-112.3]) and highest for obese non-eosinophilic asthma (469.0 [451.7-486.2]). Incidence rate ratios for all phenotype groups decreased when stratified by treatment step but remained raised compared to benign asthma. CONCLUSION: Established phenotypes can be identified in a general asthma population, although many patients did not fit into the specific phenotypes which we studied. Phenotyping patients and knowledge of asthma treatment step could help anticipate clinical course and therefore could aid clinical management but is only possible in a minority of primary care patients based on current phenotypes and electronic health records (EHRs)

No evidence that herpes zoster is associated with increased risk of dementia diagnosis.

OBJECTIVE: To investigate whether herpes zoster (HZ) was associated with subsequent increased risk of dementia diagnosis. METHODS: We conducted a historical cohort study using primary care electronic health records from the Clinical Practice Research Datalink in the United Kingdom. Individuals with incident HZ aged ≥40 years from 2000 to 2017 were matched with up to four individuals without HZ by age, sex, primary care practise and calendar time. The primary outcome was a new diagnosis of all-cause dementia. We used the Cox proportional hazards regression adjusting for demographic, lifestyle and clinical confounders to assess any association between HZ and dementia. We investigated interactions with sex, frailty index and antiviral treatment and conducted various sensitivity analyses. RESULTS: The cohort comprised 177,144 individuals with HZ and 706,901 matched unexposed individuals (median age 65 years (IQR 55.1-75.0), 40% male) followed for a median duration of 4.6 years (IQR 2.0-8.1). In total, 26,585 (3%) patients had an incident dementia diagnosis recorded and 113,056 patients died (12.8%). HZ was associated with a small reduction in dementia diagnosis (adjusted HR 0.92 (95% CI 0.89-0.95)), occurring predominantly in frail individuals and females. For patients who were fit (578,115, 65%), no association was seen (adjusted HR 0.97, 95% CI 0.92-1.02). There was no association between HZ and a composite outcome of dementia or death (adjusted HR 1.00, 95% CI 0.99-1.02). Dementia risk did not vary by prescription of antiviral agents. Sensitivity analyses showed consistent results. INTERPRETATION: HZ was not associated with increased dementia diagnosis in a UK primary care-based cohort

The benefit of evolving multidisciplinary care in ALS: a diagnostic cohort survival comparison

BACKGROUND Care for people with amyotrophic lateral sclerosis (ALS) has altered at King's College Hospital over the last 20 years. The clinic has been a multidisciplinary, specialist, tertiary referral centre since 1995 with a large team with integrated palliative and respiratory care since 2006. We hypothesised that these changes would improve survival. METHODS In this retrospective observational study, patients diagnosed with El Escorial definite, probable and possible ALS between 1995-1998 and 2008-2011 were followed up. The primary outcome measure was a chi-square test for the proportion of each cohort surviving. Kaplan-Meier survival analysis and Cox multivariate regression were secondary analyses. RESULTS There was low reporting of some interventions. Five hundred and forty-seven people were included. Survival between the cohorts was significantly different (p = 0.022) with a higher proportion surviving during 2008-2011. Survival time was 21.6 (95% CI 19.2-24.0) months in the 2008-2011 cohort compared to 19.2 years (15.6-21.6) in the 1995-1998 cohort (log rank p = 0.018). Four hundred and ninety-three cases were included in the Cox regression. Diagnostic cohort was a significant predictor variable (HR 0.79 (0.64-0.97) p = 0.023). CONCLUSIONS These results support the hypothesis that integrated specialist clinics with multidisciplinary input improve survival in ALS

Decline in Kidney Function among Apparently Healthy Young Adults at Risk of Mesoamerican Nephropathy.

Background Epidemic levels of CKD of undetermined cause, termed Mesoamerican nephropathy in Central America, have been found in low- and middle-income countries. We investigated the natural history of, and factors associated with, loss of kidney function in a population at high risk for this disease.Methods We conducted a 2-year prospective, longitudinal study with follow-up every 6 months in nine rural communities in northwestern Nicaragua and included all men (n=263) and a random sample of women (n=87) ages 18-30 years old without self-reported CKD, diabetes, or hypertension. We used growth mixture modeling to identify subgroups of eGFR trajectory and weighted multinomial logistic regression to examine associations with proposed risk factors.Results Among men, we identified three subpopulations of eGFR trajectory (mean baseline eGFR; mean eGFR change over follow-up): 81% remained stable (116 ml/min per 1.73 m2; -0.6 ml/min per 1.73 m2 per year), 9.5% experienced rapid decline despite normal baseline function (112 ml/min per 1.73 m2; -18.2 ml/min per 1.73 m2 per year), and 9.5% had baseline dysfunction (58 ml/min per 1.73 m2; -3.8 ml/min per 1.73 m2 per year). Among women: 96.6% remained stable (121 ml/min per 1.73 m2; -0.6 ml/min per 1.73 m2 per year), and 3.4% experienced rapid decline (132 ml/min per 1.73 m2; -14.6 ml/min per 1.73 m2 per year; n=3 women). Among men, outdoor and agricultural work and lack of shade availability during work breaks, reported at baseline, were associated with rapid decline.Conclusions Although Mesoamerican nephropathy is associated with agricultural work, other factors may also contribute to this disease