Heterozygous CAPN3 missense variants causing autosomal-dominant calpainopathy in seven unrelated families.

AIMS: Recessive variants in CAPN3 gene are the cause of the commonest form of autosomal recessive limb girdle muscle dystrophy. However, two distinct in-frame deletions in CAPN3 (NM_000070.3:c.643_663del21 and c.598_621del15) and more recently, Gly445Arg and Arg572Pro substitutions have been linked to autosomal dominant (AD) forms of calpainopathy. We report 21 affected individuals from seven unrelated families presenting with an autosomal dominant form of muscular dystrophy associated with five different heterozygous missense variants in CAPN. METHODS: We have used massively parallel gene sequencing (MPS) to determine the genetic basis of a dominant form of limb girdle muscular dystrophy in affected individuals from seven unrelated families. RESULTS: The c.700G> A, [p.(Gly234Arg)], c.1327T> C [p.(Ser443Pro], c.1333G> A [p.(Gly445Arg)], c.1661A> C [p.(Tyr554Ser)] and c.1706T> C [p.(Phe569Ser)] CAPN3 variants were identified. Affected individuals presented in young adulthood with progressive proximal and axial weakness, waddling walking and scapular winging or with isolated hyperCKaemia. Muscle imaging showed fatty replacement of paraspinal muscles, variable degrees of involvement of the gluteal muscles, and the posterior compartment of the thigh and minor changes at the mid-leg level. Muscle biopsies revealed mild myopathic changes. Western blot analysis revealed a clear reduction in calpain 3 in skeletal muscle relative to controls. Protein modelling of these variants on the predicted structure of calpain 3 revealed that all variants are located in proximity to the calmodulin-binding site and are predicted to interfere with proteolytic activation. CONCLUSIONS: We expand the genotypic spectrum of CAPN3-associated muscular dystrophy due to autosomal dominant missense variants.

The quality of systematic reviews and other synthesis in the time of COVID-19.

COVID-19 research has been produced at an unprecedented rate and managing what is currently known is in part being accomplished through synthesis research. Here we evaluated how the need to rapidly produce syntheses has impacted the quality of the synthesis research. Thus, we sought to identify, evaluate and map the synthesis research on COVID-19 published up to 10 July 2020. A COVID-19 literature database was created using pre-specified COVID-19 search algorithms carried out in eight databases. We identified 863 citations considered to be synthesis research for evaluation in this project. Four-hundred and thirty-nine reviews were fully assessed with A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) and rated as very low-quality (n = 145), low-quality (n = 80), medium-quality (n = 208) and high-quality (n = 151). The quality of these reviews fell short of what is expected for synthesis research with key domains being left out of the typical methodology. The increase in risk of bias due to non-adherence to systematic review methodology is unknown and prevents the reader from assessing the validity of the review. The responsibility to assure the quality is held by both producers and publishers of synthesis research and our findings indicate there is a need to equip readers with the expertise to evaluate the review conduct before using it for decision-making purposes.

MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Methods for generating hypotheses in human enteric illness outbreak investigations: a scoping review of the evidence.

Enteric illness outbreaks are complex events, therefore, outbreak investigators use many different hypothesis generation methods depending on the situation. This scoping review was conducted to describe methods used to generate a hypothesis during enteric illness outbreak investigations. The search included five databases and grey literature for articles published between 1 January 2000 and 2 May 2015. Relevance screening and article characterisation were conducted by two independent reviewers using pretested forms. There were 903 outbreaks that described hypothesis generation methods and 33 papers which focused on the evaluation of hypothesis generation methods. Common hypothesis generation methods described are analytic studies (64.8%), descriptive epidemiology (33.7%), food or environmental sampling (32.8%) and facility inspections (27.9%). The least common methods included the use of a single interviewer (0.4%) and investigation of outliers (0.4%). Most studies reported using two or more methods to generate hypotheses (81.2%), with 29.2% of studies reporting using four or more. The use of multiple different hypothesis generation methods both within and between outbreaks highlights the complexity of enteric illness outbreak investigations. Future research should examine the effectiveness of each method and the contexts for which each is most effective in efficiently leading to source identification.

La Crosse virus: a scoping review of the global evidence.

Urbanisation and climate change are altering the pattern of California serogroup viruses in North America. As La Crosse virus (LACV) is the most pathogenic of the California serogroup, it is important to identify changes in distribution, transmission and pathogenesis. A scoping review (ScR) was prioritised to summarise the global evidence on LACV. A comprehensive search strategy was used, identified references were screened for relevance and relevant articles were characterised. Each step was conducted by two independent reviewers using pre-tested forms. Analysis identified areas of research saturation and gaps. The ScR included 481 research articles that were mostly journal articles (78.2%) conducted in North America (90.9%) from 1969 to 2016. Most evidence focused on epidemiology (44.9%), virus characteristics (25.8%), transmission conditions (18.7%) and pathogenesis of LACV in hosts (18.3%). Fewer studies evaluated the accuracy of diagnostic tests (8.7%), the efficacy of treatments (3.5%), prevention and control strategies (3.1%), the economic burden of infection (0.6%) and social impact (0.2%) of LACV. None of the literature predicted the impact of climate change on LACV, nor were any cases reported in Canada. These findings are intended to guide research to close knowledge gaps and inform evidence-based decisions surrounding activities for the prevention and control of LACV.

The zoonotic potential of Mycobacterium avium ssp. paratuberculosis: a systematic review and meta-analyses of the evidence.

This systematic review-meta-analysis appraises and summarizes all the available research (128 papers) on the zoonotic potential of Mycobacterium avium ssp. paratuberculosis. The latter has been debated for a century due to pathogenic and clinical similarities between Johne's disease in ruminants and Crohn's disease (108 studies) in humans and recently for involvement in other human diseases; human immunodeficiency virus (HIV) infection (2), sarcoidosis (3), diabetes mellitus type 1 (T1DM) (7) and type 2 (3), multiple sclerosis (5) and Hashimoto's thyroiditis (2). Meta-analytical results indicated a significant positive association, consistently across different laboratory methods for Crohn's disease [odds ratio (OR) range 4·26-8·44], T1DM (OR range 2·91-9·95) and multiple sclerosis (OR range 6·5-7·99). The latter two and the thyroiditis hypothesis require further investigation to confirm the association. Meta-regression of Crohn's disease studies using DNA detection methods indicated that choice of primers and sampling frame (e.g. general population vs. hospital-based sample) explained a significant proportion of heterogeneity. Other epidemiological studies demonstrated a lack of association between high-risk occupations and development of Crohn's disease. Due to knowledge gaps in understanding the role of M. paratuberculosis in the development or progression of human disease, the evidence at present is not strong enough to inform the potential public health impact of M. paratuberculosis exposure.

A systematic review/meta-analysis of primary research investigating swine, pork or pork products as a source of zoonotic hepatitis E virus.

The objectives of our study were to identify and categorize primary research investigating swine/pork as a source of zoonotic hepatitis E virus (HEV) using the relatively new technique of scoping study, and to investigate the potential association between human exposure to swine/pork and HEV infection quantitatively using systematic review/meta-analysis methodology. From 1890 initially identified abstracts, 327 were considered for the review. Five study design types (cross-sectional, prevalence, genotyping, case-report and experimental transmission studies) were identified. A significant association between occupational exposure to swine and human HEV IgG seropositivity was reported in 10/13 cross-sectional studies. The association reported between pork consumption and HEV IgG seropositivity was inconsistent. The quantification of viral load in swine and retail pork, viral load required for infection in primates, cohort and case-control studies in humans, and formal risk assessment are recommended before specific public-health policy actions are taken.

The change in prevalence of Campylobacter on chicken carcasses during processing: a systematic review.

A systematic review was conducted to evaluate the change in prevalence of Campylobacter on chicken carcasses during processing. A structured literature search of 8 electronic databases using the key words for "Campylobacter," "chicken," and "processing" identified 1,734 unique citations. Abstracts were screened for relevance by 2 independent reviewers. Thirty-two studies described prevalence at more than one stage during processing and were included in this review. Of the studies that described the prevalence of Campylobacter on carcasses before and after specific stages of processing, the chilling stage had the greatest number of studies (9), followed by washing (6), defeathering (4), scalding (2), and evisceration (1). Studies that sampled before and after scalding or chilling, or both, showed that the prevalence of Campylobacter generally decreased immediately after the stage (scalding: 20.0 to 40.0% decrease; chilling: 100.0% decrease to 26.6% increase). The prevalence of Campylobacter increased after defeathering (10.0 to 72.0%) and evisceration (15.0%). The prevalence after washing was inconsistent among studies (23.0% decrease to 13.3% increase). Eleven studies reported the concentration of Campylobacter, as well as, or instead of, the prevalence. Studies that sampled before and after specific stages of processing showed that the concentration of Campylobacter decreased after scalding (minimum decrease of 1.3 cfu/g, maximum decrease of 2.9 cfu/mL), evisceration (0.3 cfu/g), washing (minimum 0.3 cfu/mL, maximum 1.1 cfu/mL), and chilling (minimum 0.2 cfu/g, maximum 1.7 cfu/carcass) and increased after defeathering (minimum 0.4 cfu/g, maximum 2.9 cfu/mL). Available evidence is sparse and suggests more data are needed to understand the magnitude and mechanism by which the prevalence and concentration of Campylobacter changes during processing. This understanding should help researchers and program developers identify the most likely points in processing to implement effective control efforts. For example, if contamination will occur during defeathering and likely during evisceration, critical control points postevisceration are likely to have a greater effect on the end product going to the consumer.

A new self-rating scale for detecting atypical or second-generation antipsychotic side effects.

We aimed to construct and assess a new self rating scale to detect the side effects of second generation antipsychotics. This scale was designed to allow a timely, sensitive and reliable method of gathering information on the number and severity of side effects an individual suffers from. The Glasgow Antipscyhotic Side-effect Scale (GASS) was developed after literature review, discussion with members of the mental health team and with service user feedback. Fifty indivudals taking second generation antipsychotics completed the GASS along with the Liverpool Univeristy Neuroleptic Side Effect Rating Scale, and one week later completed the GASS for a second time. Fifty comparison subjects also completed the GASS. The GASS was shown to have good discrimatory power and construct validity, along with good re-test reliablity, and is put forward as a short, helpful and valid clinical tool.

A scoping review of Lyme disease research relevant to public health.

Lyme disease (LD) is an emerging infectious disease in Canada associated with expansion of the geographic range of the tick vector Ixodes scapularis in eastern and central Canada. A scoping review of published research was prioritized to identify and characterize the scientific evidence concerning key aspects of LD to support public health efforts. Prior to initiation of this review, an expert advisory group was surveyed to solicit insight on priority topics and scope. A pre-tested search strategy implemented in eight databases (updated September 2016) captured relevant research. Pre-tested screening and data characterization forms were completed by two independent reviewers and descriptive analysis was conducted to identify topic areas with solid evidence and knowledge gaps. Of 19,353 records screened, 2,258 relevant articles were included in the review under the following six public health focus areas: a) surveillance/monitoring in North America (n=809); b) evaluation of diagnostic tests (n=736); c) risk factors (n=545); d) public health interventions (n=205); e) public knowledge, attitudes and/or perceptions in North America (n=202); and f) the economic burden of LD or cost-benefit of interventions (n=32). The majority of research investigated Borrelia burgdorferi (n=1,664), humans (n=1,154) and Ixodes scapularis (n=459). Sufficient research was identified for potential systematic reviews in four topic areas: a) accuracy of diagnostic tests; b) risk factors for human illness; c) efficacy of LD intervention strategies; and d) prevalence and/or incidence of LD in humans or B. burgdorferi sensu stricto in vertebrate reservoirs or ticks in North America. Future primary research could focus on closing knowledge gaps, such as the role of less studied vertebrate reservoirs in the transmission cycle. Results of this scoping review can be used to quickly identify and summarize relevant research pertaining to specific questions about LD or B. burgdorferi sensu lato in humans, vertebrate hosts or vectors, providing evidence-informed information within timelines that are conducive for public health decision-making.

Current evidence on the transmissibility of chronic wasting disease prions to humans-A systematic review.

A number of prion diseases affect humans, including Creutzfeldt-Jakob disease; most of these are due to genetic mutations in the affected individual and occur sporadically, but some result from transmission of prion proteins from external sources. Of the known animal prion diseases, only bovine spongiform encephalopathy prions have been shown to be transmissible from animals to humans under non-experimental conditions. Chronic wasting disease (CWD) is a prion disease that affects cervids (e.g., deer and elk) in North America and isolated populations in Korea and Europe. Systematic review methodology was used to identify, select, critically appraise and analyse data from relevant research. Studies were evaluated for adherence to good conduct based on their study design following the Cochrane collaboration's approach to grading the quality of evidence and the strength of recommendations (GRADE). Twenty-three studies were included after screening 800 citations from the literature search and evaluating 78 full papers. Studies examined the transmissibility of CWD prions to humans using epidemiological study design, in vitro and in vivo experiments. Five epidemiological studies, two studies on macaques and seven studies on humanized transgenic mice provided no evidence to support the possibility of transmission of CWD prions to humans. Ongoing surveillance in the United States and Canada has not documented CWD transmission to humans. However, two studies on squirrel monkeys provided evidence that transmission of CWD prions resulting in prion disease is possible in these monkeys under experimental conditions and seven in vitro experiments provided evidence that CWD prions can convert human prion protein to a misfolded state. Therefore, future discovery of CWD transmission to humans cannot be entirely ruled out on the basis of current studies, particularly in the light of possible decades-long incubation periods for CWD prions in humans. It would be prudent to continue CWD research and epidemiologic surveillance, exercise caution when handling potentially contaminated material and explore CWD management opportunities.

The potential Public Health Impact of Mycobacterium avium ssp. paratuberculosis: Global Opinion Survey of Topic Specialists.

Global research knowledge has accumulated over the past few decades, and there is reasonable evidence for a positive association between Mycobacterium avium spp. paratuberculosis and Crohn's disease in humans, although its role as a human pathogen has not been entirely accepted. For this reason, management of public health risk due to M. paratuberculosis remains an important policy issue in agri-food public health arenas in many countries. Responsible authorities must decide whether existing mitigation strategies are sufficient to prevent or reduce human exposure to M. paratuberculosis. A Web-based questionnaire was administered to topic specialists to elicit empirical knowledge and opinion on the overall public health impact of M. paratuberculosis, the importance of various routes of human exposure to the pathogen, existing mitigation strategies and the need for future strategies. The questionnaire had four sections and consisted of 20 closed and five open questions. Topic specialists believed that M. paratuberculosis is likely a risk to human health (44.8%) and, given the paucity of available evidence, most frequently ranked it as a moderate public health issue (40.1%). A significant correlation was detected between topic specialists' commitment to M. paratuberculosis in terms of the number of years or proportion of work dedicated to this topic, and the likelihood of an extreme answer (high or low) to the above questions. Topic specialists identified contact with ruminants and dairy products as the most likely routes of exposure for humans. There was consensus on exposure routes for ruminants and what commodities to target in mitigation efforts. Described mandatory programmes mainly focused on culling diseased animals and voluntary on-farm prevention programmes. Despite ongoing difficulties in the identification of subclinical infections in animals, the topic specialists largely agreed that further enhancement of on-farm programmes in affected commodities by the agri-food industry (68.4%) and allocation of resources by governments to monitor the issue (92%) are most appropriate given the current state of evidence.

A scoping review of the role of wildlife in the transmission of bacterial pathogens and antimicrobial resistance to the food Chain.

Wildlife can contribute to environmental contamination with bacterial pathogens and their transfer to the human food chain. Global usage and frequent misuse of antimicrobials contribute to emergence of new antimicrobial resistant (AMR) strains of foodborne pathogens. We conducted a scoping review of published research to identify and characterize the evidence on wildlife's role in transmission of AMR and/or bacterial pathogens to the food chain. An advisory group (AG) of 13 North American experts from diverse disciplines was surveyed to solicit insight in the review scope, priority topics and research characteristics. A pre-tested search strategy was implemented in seven bibliographic databases (1990 to January 2013). Citations were relevance screened, and key characteristics on priority topics extracted independently by two reviewers. Analysis identified topic areas with solid evidence and main knowledge gaps. North America reported 30% of 866 relevant articles. The prevalence of five targeted bacterial pathogens and/or AMR in any pathogen in wildlife was reported in 582 articles. Transmission risk factors for selected bacteria or AMR in any bacteria were reported in 300. Interventions to control transmission were discussed in 124 articles and formally evaluated in 50. The majority of primary research investigated birds, cervids, rodents, feral pigs, opossums, E. coli (n = 329), Salmonella (n = 293) and Campylobacter (n = 124). An association between wildlife and transmission of bacterial pathogens and/or AMR to the food chain was supported in 122 studies. The scoping review identified a significant body of research on the role of wild birds in the prevalence and transmission of E. coli, Salmonella and Campylobacter. There was little research employing molecular methods contributing to the evidence concerning the importance and direction of transmission of wildlife/pathogen combinations. Given the advancements of these methods, future research should focus in this area to help prioritize future intervention studies and risk mitigation strategies.

Sensitivity of in vitro diagnostic dipstick tests to urinary protein.

Two commonly used brands of reagent strip (dipsticks) were evlauated for their sensitivity to Bence-Jones and seven other urinary proteins. Both brands showed significant differences in sensitivity to albumin, glycoprotein, ribonuclease and lysozyme; both were most sensitive to albumin and least sensitive to globulin. Furthermore, their comparative sensitivities to these proteins also differed markedly. These differences in sensitivity could lead to underestimation of protein content in urine specimens. Tests on urines from patients with multiple myeloma showed that a negative urinary dipstick test result did not rule out the presence of the disease.

Hypomagnesemia and hypocalcemia associated with protein-losing enteropathy in Yorkshire terriers: five cases (1992-1998).

OBJECTIVE: To determine clinical and laboratory findings associated with protein-losing enteropathy, hypomagnesemia, and hypocalcemia in Yorkshire Terriers. DESIGN: Retrospective study. ANIMALS: 5 purebred or crossbred Yorkshire Terriers with protein-losing enteropathy, hypomagnesemia, and hypocalcemia. PROCEDURE: Medical records were reviewed for dogs with protein-losing enteropathy, hypomagnesemia, and hypocalcemia. RESULTS: Of 8 dogs with these signs, 5 had Yorkshire Terrier breeding. Common findings were diarrhea, abdominal effusion, leukocytosis, neutrophilia, hypocalcemia (ionized calcium), hypomagnesemia, hypoproteinemia, hypoalbuminemia, hypocholesterolemia, and increased serum activity of aspartate aminotransferase. CONCLUSIONS AND CLINICAL RELEVANCE: Yorkshire Terriers are at increased risk for development of protein-losing enteropathy with hypomagnesemia and decreased ionized calcium concentration. Hypomagnesemia and hypocalcemia may have a related pathogenesis involving intestinal loss, malabsorption, and abnormalities of vitamin D and parathyroid hormone metabolism. Serum electrolyte replacement may be required to avoid neurologic and metabolic problems.

Direct blood pressure monitoring.

Veterinary care has continued to advance by implementing more of the equipment and techniques that are commonly used in human medicine. This includes the placement of arterial catheters and pulmonary artery catheters and continuous monitoring of arterial pressure, central venous pressure, and pulmonary artery pressure. This article describes the technique for placement of appropriate catheters, the equipment that is needed, and the waveforms that are obtained when measuring direct arterial pressures, central venous pressures, and pulmonary arterial pressures.

Approach to the patient in respiratory distress.

Respiratory distress is a very common presenting complaint in emergency practice. It is essential that the clinician rapidly determine the underlying cause of the clinical signs using physical examination findings and nonstressful diagnostic tests. Oxygen therapy will often stabilize a patient, allowing for a more complete physical examination and diagnostics, including thoracocentesis, thoracic radiographs, and blood collection for laboratory analysis. The disease processes that cause respiratory distress can be grouped according to anatomic location: the airways, pulmonary parenchyma, pleural space, or thoracic wall. The choice of diagnostic and therapeutic techniques will be dependent on the suspected anatomic origin of disease. Techniques useful in diagnosing airway disorders include oral examination, cervical and thoracic radiographs, fluoroscopy, and bronchoscopy. Therapeutic techniques include intubation and tracheostomy. For parenchymal disease, thoracic radiographs, echocardiography, ultrasound of the thorax, and transtracheal or endotracheal wash can be useful. When the disease process is in the pleural space, thoracocentesis can be both diagnostic and therapeutic. Chest tube placement may be necessary for continuous removal of air or fluid from the pleural space. Monitoring of the respiratory patient can involve serial physical examination, pulse oximetry, and arterial blood gas analysis. It is essential to minimize stress on patients with respiratory distress because decompensation can occur easily, leading to respiratory arrest.

Critical care nutrition: routes of feeding.

Nutrition is an integral part of the management of the critically ill patient. Nutritional support can be provided by either parenteral or enteral routes. Whenever possible, enteral nutrition is the method of choice, as it reduces complication rates and improves outcome. Potential choices for enteral feeding include nasoesophageal, esophagostomy, gastrostomy, jejunostomy, and transpyloric feeding tubes. The modes of parenteral and enteral nutrition are reviewed individually, including indications and selection of appropriate routes of feeding, methods of tube placement, and benefits and risks associated with each feeding approach.

Experiences and attitudes towards evidence-informed policy-making among research and policy stakeholders in the Canadian agri-food public health sector.

Policy-makers working at the interface of agri-food and public health often deal with complex and cross-cutting issues that have broad health impacts and socio-economic implications. They have a responsibility to ensure that policy-making based on these issues is accountable and informed by the best available scientific evidence. We conducted a qualitative descriptive study of agri-food public health policy-makers and research and policy analysts in Ontario, Canada, to understand their perspectives on how the policy-making process is currently informed by scientific evidence and how to facilitate this process. Five focus groups of 3-7 participants and five-one-to-one interviews were held in 2012 with participants from federal and provincial government departments and industry organizations in the agri-food public health sector. We conducted a thematic analysis of the focus group and interview transcripts to identify overarching themes. Participants indicated that the following six key principles are necessary to enable and demonstrate evidence-informed policy-making (EIPM) in this sector: (i) establish and clarify the policy objectives and context; (ii) support policy-making with credible scientific evidence from different sources; (iii) integrate scientific evidence with other diverse policy inputs (e.g. economics, local applicability and stakeholder interests); (iv) ensure that scientific evidence is communicated by research and policy stakeholders in relevant and user-friendly formats; (V) create and foster interdisciplinary relationships and networks across research and policy communities; and (VI) enhance organizational capacity and individual skills for EIPM. Ongoing and planned efforts in these areas, a supportive culture, and additional education and training in both research and policy realms are important to facilitate evidence-informed policy-making in this sector. Future research should explore these findings further in other countries and contexts.

A systematic review-meta-analysis of primary research investigating the effect of selected alternative treatments on gastrointestinal nematodes in sheep under field conditions.

Selected alternative treatments for preventing or controlling gastrointestinal nematodes (GIN) in sheep under field conditions were evaluated using a systematic review-meta-analysis methodology. Forty-three publications reporting 51 studies (21 controlled studies (CS) and 30 challenge studies (ChS)) and 85 unique treatment comparisons were included in the review. The alternative treatment categories were nutraceuticals (28 studies), breeding for genetic resistance (12), nutritional manipulation (6), homeopathies (2), administration of copper oxide wire particles (2), and biological control (1). Random effect meta-analyses (MA) and meta-regression were performed with the natural logarithm of the difference in means (lnMD) between the control and treatment groups, for fecal egg counts per gram of wet feces (FEC), worm counts (WC) or fecal egg counts per gram of dry matter (FECDM) as the outcome. Treatment effect estimates (lnMD) were back-transformed to their count ratios (CR), a relative measure of effect for controlled versus treated groups, for presentation of results. Significant heterogeneity was observed for both CS and ChS that evaluated nutraceuticals, genetic resistance and nutrition treatments. MA of ChS that investigated nutraceuticals resulted in a significant overall CR of 1.62 (P<0.01) and 1.64 (P<0.01) for FEC and FECDM, respectively and a marginal significant CR of 1.14 (P=0.06) for WC, all favoring the treated groups. MA of CS and ChS that investigated genetic resistance resulted in a significant overall CR of 5.89 and 15.42, respectively (P<0.01), again favoring treated groups. MA of CS that investigated homeopathies with FEC as an outcome were homogenous (I(2)=0.0%) and resulted in a non-significant pooled CR of 1.61. ChS investigating copper oxide wire particle treatments and WC as an outcome, were homogenous (I(2)=0.0%) and had a marginally significant pooled CR of 1.68 (P=0.06). Publication bias was observed for ChS with WC outcomes, indicating that small size studies reporting non-significant CR, were less likely to be published than similar studies that found a significant CR. In a meta-regression, randomization (6.2%) and study size (29.2%) were the main factors contributing to the total variation when the outcome was FEC, and none of the variables contributed to between study heterogeneity. When the outcome was WC, type of treatment was the only significant covariate, explaining 6% of the heterogeneity and 38.5% of the total variation. The methodological soundness and reporting of primary research in the selected studies were low. Our results indicate that from the studied alternative treatments, nutraceuticals and use of genetically resistant sheep might be more promising for control of GINs in sheep.