Safety and Efficacy of the East Coast Fever Muguga Cocktail Vaccine:A Systematic Review

Immunisation of livestock with high quality vaccines is considered an essential approach to controlling many animal diseases. The only currently available commercial vaccine to protect cattle from East Coast fever (ECF), a tick-borne disease caused by Theileria parva, is an unconventional “infection and treatment method” (ITM) involving administration of a combination of live T. parva isolates, referred to as the “Muguga cocktail”, and simultaneous treatment with long-acting oxytetracycline. Veterinary vaccine research and development typically involves studies designed to demonstrate vaccine quality, safety, and efficacy; however, as there were no such purpose-designed registration studies conducted for the Muguga cocktail, evidence for safety and efficacy is solely based on that which is available in the clinical literature. An extensive systematic review was conducted to analyse the evidence available in the literature in order to establish the safety and efficacy of the Muguga cocktail vaccine. A combination of meta-analyses and narrative summaries was conducted. A total of 61 studies met the criteria to be included in the systematic review. The majority of studies demonstrated or reported in favour of the vaccine with regards to safety and efficacy of the Muguga cocktail vaccine. Proximity to buffalo often resulted in reduced vaccine efficacy, and reports of shed and transmission of vaccine components affected the overall interpretation of safety. Better understanding of control options for this devastating livestock disease is important for policymakers and livestock keepers, enabling them to make informed decisions with regards to the health of their animals and their livelihoods

Feasibility of a randomized controlled trial of functional strength training for people between six months and five years after stroke: FeSTivaLS trial

Background: Functional Strength Training (FST) could enhance recovery late after stroke. The aim of this study was to evaluate the feasibility of a subsequent fully powered, randomized controlled trial. Methods: The study was designed as a randomized, observer-blind trial. Both interventions were provided for up to one hour a day, four days a week, for six weeks. Evaluation points were before randomization (baseline), after six weeks intervention (outcome), and six weeks thereafter (follow-up). The study took place in participants’ own homes. Participants (n = 52) were a mean of 24.4 months after stroke with a mean age of 68.3 years with 67.3% male. All had difficulty using their paretic upper (UL) and lower limb (LL). Participants were allocated to FST-UL or FST-LL by an independent randomization service. The outcome measures were recruitment rate, attrition rate, practicality of recruitment strategies, occurrence of adverse reactions, acceptability of FST, and estimation of sample size for a subsequent trial. Primary clinical efficacy outcomes were the Action Research Arm Test (ARAT) and the Functional Ambulation Categories (FAC). Analysis was conducted using descriptive statistics and thematic analysis of participants’ views of FST. A power calculation used estimates of clinical efficacy variance to estimate sample size for a subsequent trial. Results: The screening process identified 1,127 stroke survivors of whom 52 (4.6%) were recruited. The recruitment rate was higher for referral from community therapists than for systematic identification of people discharged from an acute stroke unit. The attrition rate was 15.5% at the outcome and follow-up time-points. None of the participants experienced an adverse reaction. The participants who remained in the study at outcome had received 68% of the total possible amount of therapy. Participants reported that their experience of FST provided a sense of purpose and involvement and increased their confidence in performing activities. The power calculation provides estimation that 150 participants in each group will be required for a subsequent clinical trial. Conclusions: This study found that a subsequent clinical trial was feasible with modifications to the recruitment strategy to be used

Systematic map of reproductive performance of female cattle in Africa

This protocol uses the Systematic Review Protocol for Animal Intervention Studies by Syrcle (www.syrcle.nl)This is a protocol for undertaking a systematic review of reproductive performance of female cattle in Africa. The objective of the review is to prepare a systematic evidence map of ruminant reproduction. The map will help to define the current state of ruminant reproduction in different production systems and ecosystems, and will identify current trends, barriers to improvements, and potential solutions

Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition

ATR is an attractive target in cancer therapy because it signals replication stress and DNA lesions for repair and to S/G2 checkpoints. Cancer-specific defects in the DNA damage response (DDR) may render cancer cells vulnerable to ATR inhibition alone. We determined the cytotoxicity of the ATR inhibitor VE-821 in isogenically matched cells with DDR imbalance. Cell cycle arrest, DNA damage accumulation and repair were determined following VE-821 exposure. Defects in homologous recombination repair (HRR: ATM, BRCA2 and XRCC3) and base excision repair (BER: XRCC1) conferred sensitivity to VE-821. Surprisingly, the loss of different components of the trimeric non-homologous end-joining (NHEJ) protein DNA-PK had opposing effects. Loss of the DNA-binding component, Ku80, caused hypersensitivity to VE-821, but loss of its partner catalytic subunit, DNA-PKcs, did not. Unexpectedly, VE-821 was particularly cytotoxic to human and hamster cells expressing high levels of DNA-PKcs. High DNA-PKcs was associated with replicative stress and activation of the DDR. VE-821 suppressed HRR, determined by RAD51 focus formation, to a greater extent in cells with high DNA-PKcs. Defects in HRR and BER and high DNA-PKcs expression, that are common in cancer, confer sensitivity to ATR inhibitor monotherapy and may be developed as predictive biomarkers for personalised medicine

Antigenic diversity in Theileria parva populations from sympatric cattle and African buffalo analysed using long read sequencing

East Coast fever (ECF) in cattle is caused by the Apicomplexan protozoan parasite , transmitted by the three-host tick . The African buffalo () is the natural host for but does not suffer disease, whereas ECF is often fatal in cattle. The genetic relationship between populations circulating in cattle and buffalo is poorly understood, and has not been studied in sympatric buffalo and cattle. This study aimed to determine the genetic diversity of populations in cattle and buffalo, in an area where livestock co-exist with buffalo adjacent to the Serengeti National Park, Tanzania. Three antigens (Tp1, Tp4, and Tp16), known to be recognized by CD8 and CD4 T cells in immunized cattle, were used to characterize genetic diversity of in cattle ( = 126) and buffalo samples ( = 22). Long read (PacBio) sequencing was used to generate full or near-full length allelic sequences. Patterns of diversity were similar across all three antigens, with allelic diversity being significantly greater in buffalo-derived parasites compared to cattle-derived (e.g., for Tp1 median cattle allele count was 9, and 81.5 for buffalo), with very few alleles shared between species (8 of 651 alleles were shared for Tp1). Most alleles were unique to buffalo with a smaller proportion unique to cattle (412 buffalo unique vs. 231 cattle-unique for Tp1). There were indications of population substructuring, with one allelic cluster of Tp1 representing alleles found in both cattle and buffalo (including the TpM reference genome allele), and another containing predominantly only alleles deriving from buffalo. These data illustrate the complex interplay between populations in buffalo and cattle, revealing the significant genetic diversity in the buffalo population, the limited sharing of parasite genotypes between the host species, and highlight that a subpopulation of is maintained by transmission within cattle. The data indicate that fuller understanding of buffalo population dynamics is needed, as only a comprehensive appreciation of the population genetics of populations will enable assessment of buffalo-derived infection risk in cattle, and how this may impact upon control measures such as vaccination

Identification of genes important for cutaneous function revealed by a large scale reverse genetic screen in the mouse.

The skin is a highly regenerative organ which plays critical roles in protecting the body and sensing its environment. Consequently, morbidity and mortality associated with skin defects represent a significant health issue. To identify genes important in skin development and homeostasis, we have applied a high throughput, multi-parameter phenotype screen to the conditional targeted mutant mice generated by the Wellcome Trust Sanger Institute's Mouse Genetics Project (Sanger-MGP). A total of 562 different mouse lines were subjected to a variety of tests assessing cutaneous expression, macroscopic clinical disease, histological change, hair follicle cycling, and aberrant marker expression. Cutaneous lesions were associated with mutations in 23 different genes. Many of these were not previously associated with skin disease in the organ (Mysm1, Vangl1, Trpc4ap, Nom1, Sparc, Farp2, and Prkab1), while others were ascribed new cutaneous functions on the basis of the screening approach (Krt76, Lrig1, Myo5a, Nsun2, and Nf1). The integration of these skin specific screening protocols into the Sanger-MGP primary phenotyping pipelines marks the largest reported reverse genetic screen undertaken in any organ and defines approaches to maximise the productivity of future projects of this nature, while flagging genes for further characterisation

NuSTAR Hard X-ray Survey of the Galactic Center Region I: Hard X-ray Morphology and Spectroscopy of the Diffuse Emission

We present the first sub-arcminute images of the Galactic Center above 10 keV, obtained with NuSTAR. NuSTAR resolves the hard X-ray source IGR J17456-2901 into non-thermal X-ray filaments, molecular clouds, point sources and a previously unknown central component of hard X-ray emission (CHXE). NuSTAR detects four non-thermal X-ray filaments, extending the detection of their power-law spectra with $\Gamma\sim1.3$-$2.3$ up to ~50 keV. A morphological and spectral study of the filaments suggests that their origin may be heterogeneous, where previous studies suggested a common origin in young pulsar wind nebulae (PWNe). NuSTAR detects non-thermal X-ray continuum emission spatially correlated with the 6.4 keV Fe K$\alpha$ fluorescence line emission associated with two Sgr A molecular clouds: MC1 and the Bridge. Broad-band X-ray spectral analysis with a Monte-Carlo based X-ray reflection model self-consistently determined their intrinsic column density ($\sim10^{23}$ cm$^{-2}$), primary X-ray spectra (power-laws with $\Gamma\sim2$) and set a lower limit of the X-ray luminosity of Sgr A* flare illuminating the Sgr A clouds to $L_X \stackrel{>}{\sim} 10^{38}$ erg s$^{-1}$. Above ~20 keV, hard X-ray emission in the central 10 pc region around Sgr A* consists of the candidate PWN G359.95-0.04 and the CHXE, possibly resulting from an unresolved population of massive CVs with white dwarf masses $M_{\rm WD} \sim 0.9 M_{\odot}$. Spectral energy distribution analysis suggests that G359.95-0.04 is likely the hard X-ray counterpart of the ultra-high gamma-ray source HESS J1745-290, strongly favoring a leptonic origin of the GC TeV emission.Comment: 27 pages. Accepted for publication in the Astrophysical Journa

Reducing Calf Mortality in Ethiopia

SIMPLE SUMMARY: Disease and death of young livestock cause financial and production difficulties to farmers around the world. High rates of disease and death occur in various production systems in Ethiopia, hampering livestock production, reducing incomes, and damaging livelihoods. Over the last 10 years, studies carried out in Ethiopia have reported death and disease incidence rates in young livestock as high as 31% and 67%, respectively. Diarrhea and respiratory infections are the two leading causes of disease and death in calves in all production systems. In this paper, we describe findings from the experience of the Young Stock Mortality Reduction Consortium. This unique group produced important information on the main causes of disease and death in Ethiopia and created activities for small-scale farmers to address these problems. We found that several diseases caused diarrhea and respiratory infections in young calves in Ethiopia. Improving farmer knowledge and behaviors with respect to basic livestock management led to considerable reductions in young livestock disease and death and has the potential to help improve livestock productivity and human livelihoods in Ethiopia. ABSTRACT: Morbidity and mortality of young stock present economic and production challenges to livestock producers globally. In Ethiopia, calf morbidity and mortality rates, particularly due to diarrhea and respiratory disease, are high, limiting production, incomes, and the ability of farmers to improve their livelihoods. In this paper, we present findings from the combined experience of the Young Stock Mortality Reduction Consortium, which conducted epidemiological and intervention testing in calves across three production systems. This innovative alliance identified Cryptosporidium parvum and E. Coli K99 as the most common causes of diarrhea in pastoral and peri-urban calves; Strongyloides spp. as the most common fecal parasite in mixed crop–livestock and peri-urban calves; and bovine adenovirus, parainfluenza virus-3, and bovine respiratory syncytial virus as the most common respiratory pathogens in peri-urban calves. Furthermore, by improving producer knowledge with respect to fundamental livestock husbandry, feeding, housing, and neonatal care practices, calf mortality risk across production systems was reduced by 31.4 to 71.4% compared to baseline (between 10.5 and 32.1%), whereas risk of diarrhea was reduced by 52.6–75.3% (baseline between 11.4 and 30.4%) and risk of respiratory disease was reduced by 23.6–80.8% (baseline between 3.3 and 16.3%). These findings have informed scaling strategies and can potentially contribute to improved livestock productivity and human livelihoods in Ethiopia

A study of the effectiveness of a detergent-based California mastitis test (CMT), using Ethiopian and Nigerian domestic detergents, for the detection of high somatic cell counts in milk and their reliability compared to the commercial UK CMT [version 2; peer review: 2 approved]

Background:  The California mastitis test (CMT) is a simple cow-side indicator of the somatic cell count (SCC) in milk, providing a useful tool in identifying cases of subclinical mastitis in cattle. Mastitis, and in particular subclinical mastitis, is a major concern in Ethiopia and Nigeria, yet detection is challenging due to cost and access to commercial CMT reagents. Methods: Commercially available domestic detergents from Ethiopia and Nigeria were compared (n = 3 for each country) with the UK commercial CMT reagent in their ability to detect high SCC (>400,000 cells/ml milk).  Sensitivity and specificity of the CMT test were calculated for the different detergents and positive and negative predictive values were established. Results:  The average sensitivities of the tests ranged from 28-75% for the Ethiopian detergents and 68-80% for the Nigerian detergents, compared to 76% for the UK domestic detergent.  Test specificities were 84-98%, 93-97% and 96%, respectively. Conclusions:  Overall, the detergents demonstrated higher specificity than sensitivity.  Nigerian detergents performed better than the Ethiopian products, however, the study identified suitable domestic detergents from both Ethiopia and Nigeria, comparable to the UK commercial CMT reagent, and we recommend their use as alternative CMT reagents for livestock-keepers to aid in cost-effective diagnosis of mastitis