Epidemiology, linkage to care and natural history of women of childbearing age with chronic hepatitis B: A population-based study.

Pregnant women with chronic hepatitis B (CHB) are a priority population for hepatitis B care. Identification of HBV status prior to pregnancy would facilitate timely maternal interventions and perinatal care. In our study, we aimed to study the epidemiology of CHB among women of childbearing age (WoCBA, 18-49 years) in Alberta, Canada. We retrospectively analysed Alberta Analytics databases to study CHB epidemiology, natural history and care linkage among WoCBA in Alberta, between April 2012 and March 2021. A Poisson regression was conducted to estimate incidence of newly identified CHB cases and prevalence trends, whereas predictors of care linkage were determined using logistic regression. Age/sex-adjusted incidence of newly identified CHB among WoCBA between 2015 and 2020 was 36.2/100,000 person/years, highest among individuals aged 30-39 years. Incidence of newly identified CHB decreased from 52.6 to 18.2/100,000 between 2015 and 2020, but prevalence increased from 131.7 to 248.6/100,000 in the same period. Newly identified CHB incident cases (n = 2124) had lower survival rates than age/sex-matched Canadians, with a standardized mortality ratio of 5.7 (95% CI 2.6-11.0). Increasing age (years) at diagnosis (HR, 1.2; 95% CI 1.1-1.3) was independently associated with mortality. Comorbid hepatocellular carcinoma, anti-HBV treatment and year of diagnosis were not significantly associated with mortality. Of the 1927 women with 2436 hepatitis B surface antigen-positive pregnancies from 2012 to 2020, only 27.6% had recommended HBV assessment during pregnancy. Of those women meeting criteria for antiviral therapy to prevent mother-to-child transmission (MTCT), only 66.4% received treatment. Suboptimal management during pregnancy and overall lower survival rates highlight the need to address care linkage barriers in women of childbearing age living with CHB.

Within-herd transmission of Mycoplasma bovis infections after initial detection in dairy cows.

Mycoplasma bovis outbreaks in cattle, including pathogen spread between age groups, are not well understood. Our objective was to estimate within-herd transmission across adult dairy cows, youngstock, and calves. Results from 3 tests (PCR, ELISA, and culture) per cow and 2 tests (PCR and ELISA) per youngstock and calf were used in an age-stratified susceptible-infected-removed/recovered (SIR) model to estimate within-herd transmission parameters, pathways, and potential effects of farm management practices. A cohort of adult cows, youngstock, and calves on 20 Dutch dairy farms with a clinical outbreak of M. bovis in adult cows were sampled, with collection of blood, conjunctival fluid, and milk from cows, and blood and conjunctival fluid from calves and youngstock, 5 times over a time span of 12 wk. Any individual with at least one positive laboratory test was considered M. bovis-positive. Transmission dynamics were modeled using an age-stratified SIR model featuring 3 age strata. Associations with farm management practices were explored using Fisher's exact tests and Poisson regression. Estimated transmission parameters were highly variable among herds and cattle age groups. Notably, transmission from cows to cows, youngstock, or to calves was associated with R-values ranging from 1.0 to 80 secondarily infected cows per herd, 1.2 to 38 secondarily infected youngstock per herd, and 0.1 to 91 secondarily infected calves per herd, respectively. In case of transmission from youngstock to youngstock, calves or to cows, R-values were 0.7 to 96 secondarily infected youngstock per herd, 1.1 to 76 secondarily infected calves per herd, and 0.1 to 107 secondarily infected cows per herd. For transmission from calves to calves, youngstock or to cows, R-values were 0.5 to 60 secondarily infected calves per herd, 1.1 to 41 secondarily infected youngstock per herd, and 0.1 to 47 secondarily infected cows per herd. Among on-farm transmission pathways, cow-to-youngstock, cow-to-calf, and cow-to-cow were identified as most significant contributors, with calf-to-calf and calf-to-youngstock also having noteworthy roles. Youngstock-to-youngstock was also implicated, albeit to a lesser extent. Whereas the primary focus was a clinical outbreak of M. bovis among adult dairy cows, it was evident that transmission extended to calves and youngstock, contributing to overall spread. Factors influencing transmission and specific transmission pathways were associated with internal biosecurity (separate caretakers for various age groups, number of people involved), external biosecurity (contractors, external employees), as well as indirect transmission routes (number of feed and water stations).

Effects of bovine leukemia virus seropositivity and proviral load on milk, fat, and protein production of dairy cows.

The objective was to evaluate the effects of bovine leukemia virus (BLV) infection, as determined by BLV seropositivity and proviral load, on 305-d milk, fat, and protein production of dairy cows. A cross-sectional study was conducted among 1,712 cows from 9 dairy herds in Alberta, Canada. The BLV status was assessed using an antibody ELISA, whereas BLV proviral load in BLV-seropositive cattle was determined with quantitative PCR. Dairy Herd Improvement 305-d milk, fat, and protein production data were obtained for all enrolled cattle. Differences in these milk end points were assessed in 2 ways: first, by categorizing cows based on BLV serostatus (i.e., BLV positive or negative), and second, by categorizing based on BLV proviral load (i.e., BLV negative, low proviral load [LPL] BLV positive, and high proviral load [HPL] BLV positive). A mixed-effect multivariable linear regression model was used to assess differences in milk parameters. We found that BLV positivity, adjusted for parity and natural log-transformed somatic cell count (SCC), was not associated with reduction in 305-d milk, fat, or protein production. However, significant reductions in 305-d milk, fat, and protein yield occurred in HPL cows, but not in LPL cows, compared with BLV-negative cows, when adjusted for parity number and natural log-transformed SCC. In summary, BLV proviral load may predict effects of BLV infection on milk, fat, and protein production.

Comparative genomic analyses of Klebsiella pneumoniae K57 capsule serotypes isolated from bovine mastitis in China.

Klebsiella pneumoniae can cause severe clinical mastitis in dairy cows, with K. pneumoniae type K57 (K57-KP) being the most common capsular serotype. To identify virulence factors and antimicrobial-resistance (AMR) genes of K57-KP with varying virulence, Galleria mellonella (greater wax moth) larvae were infected as a screening model to characterize virulence of 90 K57-KP strains, with 10 and 11 strains defined as virulent or attenuated, respectively, based on larval survival rates. Next, virulence of these 21 isolates was subsequently confirmed in adhesion and lactate dehydrogenase release assays, using bovine mammary epithelial cells cultured in vitro. Finally, genes associated with virulence and AMR were characterize with whole-genome sequencing. These 21 K57-KP strains were designated into 16 sequence types based on multi-locus sequence typing and allocated in phylogenetic analysis based on single nucleotide polymorphisms. We found great genetic diversity among isolates. In addition, adhesion-associated genes (e.g., fimA, sfaA, and focA) aminoglycoside-resistance genes (aph(6)-Id, strAB) were associated with virulence. This study provided new knowledge regarding virulence of K57-KP associated with bovine mastitis, which may inform development of novel diagnostic tools and prevention strategies for bovine mastitis.

Adoption and decision factors regarding selective treatment of clinical mastitis on Canadian dairy farms.

As clinical mastitis (CM) treatments are responsible for a large portion of antimicrobial use on dairy farms, many selective CM treatment protocols have been developed and evaluated against a blanket treatment approach of CM cases. Selective treatment protocols use outcomes of diagnostic tests to exclude CM cases from antimicrobial treatment when they are unlikely to benefit. To tailor interventions to increase uptake of selective treatment strategies, a comprehension of current on-farm treatment practices and factors affecting treatment decisions is vital. Two questionnaires were conducted among 142 farms across 5 provinces participating in the Canadian Dairy Network for Antimicrobial Stewardship and Resistance in this cross-sectional study. Self-reported adoption of selective CM treatments by dairy farmers was 64%, with median of 82% of cows treated in those herds using selective treatment. Using logistic regression models, the odds to implement a selective CM treatment protocol increased with a decreasing average cow somatic cell count. No other associations were identified between use of a selective CM treatment protocol and farm characteristics (herd size, CM incidence, province, milking system, and housing system). Three subsets of farmers making cow-level CM treatment decisions were identified using a cluster analysis approach: those who based decisions almost exclusively on severity of clinical signs, those who used various udder health indicators, and farmers who also incorporated more general cow information such as production, age, and genetics. When somatic cell count was considered, the median threshold used for treating was >300,000 cells/mL at the last Dairy Herd Improvement test. Various thresholds were present among those considering CM case history. Veterinary laboratories were most frequently used for bacteriological testing. Test results were used to start, change, and stop treatments. Regardless of protocol, reasons for antimicrobial treatment withheld included cow being on a cull list, having a chronic intramammary infection, or being at end of lactation (i.e., close to dry off). If clinical signs persisted after treatment, farmers indicated that they would ask veterinarians for advice, stop treatment, or continue with the same or different antibiotics. Results of this study can be used to design interventions targeting judicious mastitis-related antimicrobial use, and aid discussions between veterinarians and dairy producers regarding CM-related antimicrobial use.

Frequency of isolation and phenotypic antimicrobial resistance of fecal Salmonella enterica recovered from dairy cattle in Canada.

Salmonellosis is one of the leading causes of gastrointestinal infections in humans. In Canada, it is estimated that approximately 87,500 cases of salmonellosis occur every year in humans, resulting in 17 deaths. In the United States, it is estimated that 26,500 hospitalizations and 420 deaths occur every year. In dairy cattle, infections caused by nontyphoidal Salmonella enterica can cause mild to severe disease, including enteritis, pneumonia, and septicemia. Our study objectives were to determine the proportion of fecal samples positive for Salmonella in dairy cattle in Canada and determine the resistance pattern of these isolates. We used data collected through the Canadian Dairy Network for Antimicrobial Stewardship and Resistance (CaDNetASR). Pooled fecal samples from preweaning calves, postweaning heifers, lactating cows, and manure storage were cultured for Salmonella, and the isolates were identified using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Antimicrobial susceptibilities were determined using the minimum inhibitory concentration test, and resistance interpretation was made according to the Clinical and Laboratory Standards Institute. A 2-level, multivariable logistic regression model was built to determine the probability of recovering Salmonella from a sample, accounting for province, year, and sample source. The proportion of farms with at least one positive sample were 12% (17/140), 19% (28/144), and 17% (24/144) for the sampling years 2019, 2020, and 2021, respectively. Out of the 113 Salmonella isolates, 23 different serovars were identified. The occurrence of Salmonella appeared to be clustered by farms and provinces. The most common serovars identified were Infantis (14%) and Typhimurium (14%). Overall, 21% (24/113) of the Salmonella isolates were resistant to at least one antimicrobial. Resistance to tetracycline was commonly observed (17%); however, very limited resistance to category I antimicrobials (categorization according to Health Canada that includes third-generation cephalosporins, fluoroquinolones, polymyxins, and carbapenems) was observed, with one isolate resistant to amoxicillin and clavulanic acid. The proportion of Salmonella isolates resistant to 2 and 3 antimicrobial classes was 3.5% and 8.8%, respectively. Our study provided valuable information on the proportion of fecal samples positive for Salmonella, the serovars identified, and the associated resistance patterns across CaDNetASR herds, at regional and national levels.

Global losses due to dairy cattle diseases: A comorbidity-adjusted economic analysis.

An economic simulation was carried out over 183 milk-producing countries to estimate the global economic impacts of 12 dairy cattle diseases and health conditions: mastitis (subclinical and clinical), lameness, paratuberculosis (Johne's disease), displaced abomasum, dystocia, metritis, milk fever, ovarian cysts, retained placenta, and ketosis (subclinical and clinical). Estimates of disease impacts on milk yield, fertility, and culling were collected from the literature, standardized, meta-analyzed using a variety of methods ranging from simple averaging to random-effects models, and adjusted for comorbidities to prevent overestimation. These comorbidity-adjusted disease impacts were then combined with a set of country-level lactational incidence and/or prevalence estimates, herd characteristics, and price estimates within a series of Monte Carlo simulations that estimated and valued the economic losses due to these diseases. It was estimated that total annual global losses are USD 65 billion (B). Subclinical ketosis, clinical mastitis, and subclinical mastitis were the costliest diseases modeled, resulting in mean annual global losses of approximately USD 18B, USD 13B, and USD 9B, respectively. Estimated global annual losses due to clinical ketosis, displaced abomasum, dystocia, lameness, metritis, milk fever, ovarian cysts, paratuberculosis, and retained placenta were estimated to be USD 0.2B, 0.6B, 0.6B, 6B, 5B, 0.6B, 4B, 4B, and 3B, respectively. Without adjustment for comorbidities, when statistical associations between diseases were disregarded, mean aggregate global losses would have been overestimated by 45%. Although annual losses were greatest in India (USD 12B), the USA (USD 8B), and China (USD 5B), depending on the measure of losses used (losses as a percent of GDP, losses per capita, losses as a percent of gross milk revenue), the relative economic burden of these dairy cattle diseases across countries varied markedly.

Herd-level prevalence of bovine leukemia virus, Salmonella Dublin and Neospora caninum in Alberta, Canada, dairy herds using ELISA on bulk tank milk samples.

Endemic infectious diseases remain a major challenge for dairy producers worldwide. For effective disease control programs, up-to-date prevalence estimates are of utmost importance. The objective of this study was to estimate the herd-level prevalence of bovine leukemia virus (BLV), Salmonella Dublin, and Neospora caninum in dairy herds in Alberta, Canada using a serial cross-sectional study design. Bulk tank milk samples from all Alberta dairy farms were collected 4 times, in December 2021 (n = 489), April 2022 (n = 487), July 2022 (n = 487), and October 2022 (n = 480), and tested for antibodies against BLV, S. Dublin, and N. caninum using ELISAs. Herd-level apparent prevalence was calculated as positive samples divided by total tested samples at each time point. A mixed effect modified Poisson regression model was employed to assess the association of prevalence with region, herd size, herd type, and type of milking system. Apparent prevalence of BLV was 89.4, 88.7, 86.9 and 86.9% in December, April, July, and October, respectively, whereas for S. Dublin apparent prevalence was 11.2, 6.6, 8.6, and 8.5%, and for N. caninum apparent prevalence was 18.2, 7.4, 7.8, and 15.0%. For BLV, S. Dublin and N. caninum, a total of 91.7, 15.6, and 28.1% of herds, respectively, were positive at least once, whereas 82.5, 3.6, and 3.0% of herds were ELISA-positive at all 4 times. Compared with the north region, central Alberta had a high prevalence (prevalence ratio (PR) = 1.13) of BLV-antibody positive herds, whereas south Alberta had a high prevalence (PR = 2.56) of herds positive for S. Dublin antibodies. Furthermore, central (PR = 0.52) and south regions (PR = 0.46) had low prevalence of N. caninum-positive herds compared with the north. Hutterite colony herds were more frequently BLV-positive (PR = 1.13) but less frequently N. caninum-positive (PR = 0.47). Large herds (>7,200 L/day milk delivered ∼ > 250 cows) were 1.1 times more often BLV-positive, whereas small herds (≤3,600 L/day milk delivered ∼ ≤ 125 cows) were 3.2 times more often N. caninum-positive. For S. Dublin, Hutterite-colony herds were less frequently (PR = 0.07) positive than non-colony herds only in medium and large stratum but not in small stratum. Moreover, larger herds were more frequently (PR = 2.20) S. Dublin-positive than smaller herds only in non-colony stratum but not in colony stratum. Moreover, N. caninum prevalence was 1.6 times higher on farms with conventional milking systems compared with farms with an automated milking system. These results provide up-to-date information of the prevalence of these infections that will inform investigations of within-herd prevalence of these infections and help in devising evidence-based disease control strategies.

MicroRNA miR-223 modulates NLRP3 and Keap1, mitigating lipopolysaccharide-induced inflammation and oxidative stress in bovine mammary epithelial cells and murine mammary glands.

Bovine mastitis, the most prevalent and costly disease in dairy cows worldwide, decreases milk quality and quantity, and increases cow culling. However, involvement of microRNAs (miRNAs) in mastitis is not well characterized. The objective was to determine the role of microRNA-223 (miR-223) in regulation of the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome and kelch like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) oxidative stress pathway in mastitis models induced by lipopolysaccharide (LPS) treatment of immortalized bovine mammary epithelial cells (bMECs) and murine mammary glands. In bMECs cultured in vitro, LPS-induced inflammation downregulated bta-miR-223; the latter interacted directly with the 3' untranslated region (3' UTR) of NLRP3 and Keap1. Overexpression of bta-miR-223 in bMECs decreased LPS and Adenosine 5'-triphosphate (ATP)-induced NLRP3 and its mediation of caspase 1 and IL-1ß, and inhibited LPS-induced Keap1 and Nrf2 mediated oxidative stress, whereas inhibition of bta-miR-223 had opposite effects. In an in vivo murine model of LPS-induced mastitis, increased miR-223 mitigated pathology in the murine mammary gland, whereas decreased miR-223 increased inflammatory changes and oxidative stress. In conclusion, bta-miR-223 mitigated inflammation and oxidative injury by downregulating the NLRP3 inflammasome and Keap1/Nrf2 signaling pathway. This study implicated bta-miR-223 in regulation of inflammatory responses, with potential as a novel target for treating bovine mastitis and other diseases.

Incidence, susceptibility and outcomes of candidemia in adults living in Calgary, Alberta, Canada (2010-2018).

BACKGROUND: Candidemia is increasing in frequency and is associated with high mortality. We sought to determine the burden of illness, the population it affects and its resistance profile in our region. METHODS: The Calgary Zone (CZ) provides all care for residents of Calgary and surrounding communities (~ 1.69 million) via five tertiary hospitals each served by a common single laboratory for acute care microbiology. All adult patients in the CZ with at least one Candida spp.-positive blood culture between January 1, 2010, and December 31, 2018, were identified using microbiological data from Calgary Lab Services, the laboratory that processes > 95% of all blood culture samples in the CZ, were reviewed for the study. RESULTS: The overall annual incidence of candidemia among individuals living in the CZ was 3.8 per 100,000 persons (Median age 61 years (IQR 48-72) and 221/455 (47.4%) were female). C. albicans was the most common species (50.6%), followed by C. glabrata, (24.0%). No other species accounted for more than 7% of cases. Overall mortality at 30, 90, and 365 days was 32.2, 40.1, and 48.1% respectively. Mortality rate did not differ by Candida species. Of individuals who developed candidemia, more than 50% died within the next year. No new resistance pattern has emerged in the most common Candida species in Calgary, Alberta. CONCLUSIONS: In Calgary, Alberta, the incidence of candidemia has not increased in the last decade. C. albicans was the most common species and it remains susceptible to fluconazole.

Outdoor access practices in the Canadian dairy industry.

Dairy cows are highly motivated to access pasture and have a partial preference for alternative forms of outdoor access (e.g., deep-bedded outdoor sand or wood-chip packs). In addition, Canadians value the provision of outdoor access to dairy cows as they perceive it as important for good cow welfare. In contrast to Europe, Oceania, and the United States, little data exist on the use of outdoor access on Canadian dairy farms. Therefore, our objective was to assess current outdoor access practices for dairy cows in Canada. An online questionnaire was used to determine housing and outdoor access practices for lactating cows, dry cows, pregnant heifers, and weaned, nonpregnant heifers on Canadian dairy farms. The questionnaire was distributed by the 10 provincial milk boards between November 2020 and August 2021, resulting in an 8.9% response rate (n = 903 completed questionnaires). In total, 75% (n = 675) of respondents provided some form of outdoor access to at least 1 cattle class on their farm. Pasture was the most frequently used form of outdoor access for all cattle classes. Based on a weighted average, a total of 29% and 48% of Canadian dairy farms provided lactating and dry cows, respectively, access to pasture; for youngstock, these numbers were 48% and 27% for pregnant heifers and weaned, nonpregnant heifers, respectively. Herd size (for each cow class), indoor housing system, and region were all associated with the provision of pasture. Farms with larger lactating herds less often provided access to pasture; larger herd sizes in terms of weaned, nonpregnant heifers, pregnant heifers, and dry cows were also associated with a lower likelihood of access to pasture. Farms using indoor bedded pack housing for their lactating cows more often provided pasture to this cattle class than farms with freestall or tiestall housing; this likelihood did not differ between farms with tie or freestall housing for this cattle class. Dry cows or pregnant heifers housed in a tiestall were more often provided pasture than freestall-housed dry cows or pregnant heifers. Housing type for weaned, nonpregnant heifers was not associated with the likelihood of pasture provision. Farms in British Columbia or on Canada's East Coast (i.e., Nova Scotia, New Brunswick, and Prince Edward Island) more often provided lactating cows pasture compared with farms in other regions. For the other 3 cattle classes, farms on the East Coast of Canada more often provided pasture than farms in other parts of Canada. These results will inform future decisions regarding outdoor access for Canadian dairy cattle and may also aid in identifying future areas of research. For example, our results may aid in designing housing systems that facilitate outdoor access in larger herds and in areas that are subject to more extreme weather conditions.

Contextualized understandings of dairy farmers' perspectives on antimicrobial use and regulation in Alberta, Canada.

Antimicrobial resistance (AMR) has been largely attributed to antimicrobial use (AMU). To achieve judicious AMU, much research and many policies focus on knowledge translation and behavioral change mechanisms. To address knowledge gaps in contextual drivers of decisions made by dairy farmers concerning AMU, we conducted ethnographic fieldwork to investigate one community's understanding of AMU, AMR, and associated regulations in the dairy industry in Alberta, Canada. This included participation in on-farm activities and observations of relevant interactions on dairy farms in central Alberta for 4 mo. Interviews were conducted with 25 dairy farmers. The interviews were analyzed using thematic analysis and yielded several key findings. Many dairy farmers in this sample: (1) value their autonomy and hope to maintain agency regarding AMU; (2) have shared cultural and immigrant identities which may inform their perspectives of future AMU regulation as it relates to their farming autonomy; (3) feel that certain AMU policies implemented in other contexts would be impractical in Alberta and would constrain their freedom to make what they perceive to be the best animal welfare decisions; (4) believe that their knowledge and experience are undervalued by consumers and policy makers; (5) are concerned that the public does not have a complex understanding of dairy farming and, consequently, worry that AMU policy will be based on misguided consumer concerns; and (6) are variably skeptical of a link between AMU in dairy cattle and AMR in humans due to their strict adherence to milk safety protocols that is driven by their genuine care for the integrity of the product. A better understanding of the sociocultural and political-economic infrastructure that supports such perceptions is warranted and should inform efforts to improve AMU stewardship and future policies regarding AMU.

Antimicrobial and teat sealant use and selection criteria at dry-off on Canadian dairy farms.

Infections with antimicrobial resistant pathogens are a major threat to human and animal health worldwide. Further, reduction of livestock-associated antimicrobial use (AMU) is often identified as an area of focus. Selective dry cow therapy (DCT) warrants consideration as an important way to decrease AMU on Canadian dairy farms. In addition, teat sealants (TS) are a nonantimicrobial alternative for prevention of intramammary infection during the dry period. Therefore, objectives of this study were to determine how antimicrobials and TS are used at dry-off on Canadian dairy farms to determine selective DCT uptake and enacted selection protocols. It was expected that these data will provide a baseline understanding of DCT practices and highlight areas for future intervention to further reduce AMU. An observational study was conducted utilizing 2 in-person questionnaires conducted between July 2019 and September 2021 on 144 participating dairy farms in 5 Canadian provinces (British Columbia = 30, Alberta = 30, Ontario = 31, Québec = 29, and Nova Scotia = 24). Overall, 45 farms (31%) reported adopting selective DCT, 95 (66%) enacted blanket DCT, and 4 (3%) did not provide antimicrobial DCT. Farms enacting selective DCT had approximately 50% less intramammary antimicrobials used at dry-off compared with blanket DCT farms. Cow somatic cell count history was the most common criterion for selective DCT decision-making, followed by previous clinical mastitis history, bacteriological culture, and milk production. A slight majority of farms (56%) applied TS to all cows at dry-off, whereas 17 farms (12%) used TS selectively, and 46 farms (32%) did not use TS. Larger herds more often used TS, and farms with an automatic milking system more often used TS selectively than applied to all cows. Results highlighted the variability in antimicrobial treatment and TS use protocols at dry-off on Canadian dairy farms, and the potential for further antimicrobial reduction with increased adoption of selective DCT.

Underlying genetic architecture of resistance to mastitis in dairy cattle: A systematic review and gene prioritization analysis of genome-wide association studies.

Mastitis, the most frequent disease in dairy cattle. Resistance to mastitis is a complex, polygenic trait controlled by several genes, each with small effects. Genome-wide association studies have been widely used to identify genomic variants associated with complex traits, including resistance to mastitis, to elucidate the underlying genetic architecture of the trait. However, no systematic review and gene prioritization analysis have been conducted to date on GWAS results for resistance to mastitis in dairy cattle. Hence, the objective was to perform a systematic review and gene prioritization analysis of GWAS studies to identify potential functional candidate genes associated with resistance to mastitis-related traits in dairy cattle. Four electronic databases were searched from inception to December 2020, supplemented with multiple sources of gray literature, to identify eligible articles. Annotation for genes and quantitative trait loci (QTL), and QTL enrichment analysis were conducted using GALLO. Gene prioritization analysis was performed by a guilty-by-association approach using GUILDify and ToppGene. From 52 articles included within this systematic review, 30 articles were used for further functional analyses. Gene and QTL annotation resulted in 9,125 and 43,646 unique genes and QTL, respectively, from 39 studies. In general, overlapping of genes across studies was very low (mean ± SD = 0.02% ± 0.07%). Most annotated genes were associated with somatic cell count-related traits and the Holstein breed. Within all annotated genes, 74 genes were shared among Holstein, Jersey, and Ayrshire breeds. Approximately 7.5% of annotated QTL were related to QTL class "health." Within the health QTL class, 2.6 and 2.2% of QTL were associated with clinical mastitis and somatic cell count-related traits. Enrichment analysis of QTL demonstrated that many enriched QTL were associated with somatic cell score located in Bos taurus autosomes 5, 6, 16, and 20. The prioritization analysis resulted in 427 significant genes after multiple test correction (false discovery rate of 5%) from 26 studies. Most prioritized genes were located in Bos taurus autosomes 19 and 7, and most top-ranked genes were from the cytokine superfamily (e.g., chemokines, interleukins, transforming growth factors, and tumor necrosis factor genes). Although most prioritized genes (397) were associated with somatic cell count-related traits, only 54 genes were associated with clinical mastitis-related traits. Twenty-four genes (ABCC9, ACHE, ADCYAP1, ARC, BCL2L1, CDKN1A, EPO, GABBR2, GDNF, GNRHR, IKBKE, JAG1, KCNJ8, KCNQ1, LIFR, MC3R, MYOZ3, NFKB1, OSMR, PPP3CA, PRLR, SHARPIN, SLC1A3, and TNFRSF25) were reported for both somatic cell count and clinical mastitis-related traits. Prioritized genes were mainly associated with immune response, regulation of secretion, locomotion, cell proliferation, and development. In conclusion, this study provided a fine-mapping of previously identified genomic regions associated with resistance to mastitis and identified key functional candidate genes for resistance to mastitis, which can be used to develop enhanced genomic strategies to combat mastitis by increasing mastitis resistance through genetic selection.

Invited review: Selective treatment of clinical mastitis in dairy cattle.

Treatment of clinical mastitis (CM) and use of antimicrobials for dry cow therapy are responsible for the majority of animal-defined daily doses of antimicrobial use (AMU) on dairy farms. However, advancements made in the last decade have enabled excluding nonsevere CM cases from antimicrobial treatment that have a high probability of cure without antimicrobials (no bacterial causes or gram-negative, excluding Klebsiella spp.) and cases with a low bacteriological cure rate (chronic cases). These advancements include availability of rapid diagnostic tests and improved udder health management practices, which reduced the incidence and infection pressure of contagious CM pathogens. This review informed an evidence-based protocol for selective CM treatment decisions based on a combination of rapid diagnostic test results, review of somatic cell count and CM records, and elucidated consequences in terms of udder health, AMU, and farm economics. Relatively fast identification of the causative agent is the most important factor in selective CM treatment protocols. Many reported studies did not indicate detrimental udder health consequences (e.g., reduced clinical or bacteriological cures, increased somatic cell count, increased culling rate, or increased recurrence of CM later in lactation) after initiating selective CM treatment protocols using on-farm testing. The magnitude of AMU reduction following a selective CM treatment protocol implementation depended on the causal pathogen distribution and protocol characteristics. Uptake of selective treatment of nonsevere CM cases differs across regions and is dependent on management systems and adoption of udder health programs. No economic losses or animal welfare issues are expected when adopting a selective versus blanket CM treatment protocol. Therefore, selective CM treatment of nonsevere cases can be a practical tool to aid AMU reduction on dairy farms.

Selective treatment of nonsevere clinical mastitis does not adversely affect cure, somatic cell count, milk yield, recurrence, or culling: A systematic review and meta-analysis.

Treatment of clinical mastitis (CM) contributes to antimicrobial use on dairy farms. Selective treatment of CM based on bacterial diagnosis can reduce antimicrobial use, as not all cases of CM will benefit from antimicrobial treatment, e.g., mild and moderate gram-negative infections. However, impacts of selective CM treatment on udder health and culling are not fully understood. A systematic search identified 13 studies that compared selective versus blanket CM treatment protocols. Reported outcomes were synthesized with random-effects models and presented as risk ratios or mean differences. Selective CM treatment protocol was not inferior to blanket CM treatment protocol for the outcome bacteriological cure. Noninferiority margins could not be established for the outcomes clinical cure, new intramammary infection, somatic cell count, milk yield, recurrence, or culling. However, no differences were detected between selective and blanket CM treatment protocols using traditional analyses, apart from a not clinically relevant increase in interval from treatment to clinical cure (0.4 d) in the selective group and higher proportion of clinical cure at 14 d in the selective group. The latter occurred in studies co-administering nonsteroidal anti-inflammatories only in the selective group. Bias could not be ruled out in most studies due to suboptimal randomization, although this would likely only affect subjective outcomes such as clinical cure. Hence, findings were supported by a high or moderate certainty of evidence for all outcome measures except clinical cure. In conclusion, this review supported the assertion that a selective CM treatment protocol can be adopted without adversely influencing bacteriological and clinical cure, somatic cell count, milk yield, and incidence of recurrence or culling.

Multi-Omics Integration and Network Analysis Reveal Potential Hub Genes and Genetic Mechanisms Regulating Bovine Mastitis.

Mastitis, inflammation of the mammary gland, is the most prevalent disease in dairy cattle that has a potential impact on profitability and animal welfare. Specifically designed multi-omics studies can be used to prioritize candidate genes and identify biomarkers and the molecular mechanisms underlying mastitis in dairy cattle. Hence, the present study aimed to explore the genetic basis of bovine mastitis by integrating microarray and RNA-Seq data containing healthy and mastitic samples in comparative transcriptome analysis with the results of published genome-wide association studies (GWAS) using a literature mining approach. The integration of different information sources resulted in the identification of 33 common and relevant genes associated with bovine mastitis. Among these, seven genes-CXCR1, HCK, IL1RN, MMP9, S100A9, GRO1, and SOCS3-were identified as the hub genes (highly connected genes) for mastitis susceptibility and resistance, and were subjected to protein-protein interaction (PPI) network and gene regulatory network construction. Gene ontology annotation and enrichment analysis revealed 23, 7, and 4 GO terms related to mastitis in the biological process, molecular function, and cellular component categories, respectively. Moreover, the main metabolic-signalling pathways responsible for the regulation of immune or inflammatory responses were significantly enriched in cytokine-cytokine-receptor interaction, the IL-17 signaling pathway, viral protein interaction with cytokines and cytokine receptors, and the chemokine signaling pathway. Consequently, the identification of these genes, pathways, and their respective functions could contribute to a better understanding of the genetics and mechanisms regulating mastitis and can be considered a starting point for future studies on bovine mastitis.

Tenofovir disoproxil fumarate therapy to prevent hepatitis B virus vertical transmission-A review of maternal and infant outcomes.

Hepatitis B virus (HBV) is a global health problem. Vertical transmission of HBV from HBV surface antigen (HBsAg)-positive mothers to their infants is the most common cause of HBV infection worldwide. The use of passive-active immunoprophylaxis is >90% effective in reducing the risk of vertical transmission, but immunoprophylaxis failure can occur in infants born to mothers with high viraemia. Thus, it is recommended that pregnant women with HBV-DNA level >200 000 IU/ml receive nucleos(t)ide analogue (NA) treatment [i.e. tenofovir disoproxil fumarate (TDF), lamivudine or telbivudine] during third trimester to prevent infant immunoprophylaxis failure. TDF is recommended as the first-line therapy based on available data on efficacy, safety and resistance profile. However, maternal immunological reconstitution following parturition can increase immune-mediated flares to viral antigens that is potentially exacerbated following TDF withdrawal. In this article, we review available data on the efficacy and safety of TDF administration to prevent HBV mother-to-child transmission. We also discuss changes in maternal viral markers [i.e. HBV-DNA, HBV e antigen and HBsAg] and alanine aminotransferase during follow-up post-partum in mothers received NA to prevent HBV vertical transmission.

Associations of the COVID-19 pandemic with the reported incidence of important endemic infectious disease agents and syndromes in Pakistan.

BACKGROUND: Persons in Pakistan have suffered from various infectious diseases over the years, each impacted by various factors including climate change, seasonality, geopolitics, and resource availability. The COVID-19 pandemic is another complicating factor, with changes in the reported incidence of endemic infectious diseases and related syndromes under surveillance. METHODS: We assessed the monthly incidence of eight important infectious diseases/syndromes: acute upper respiratory infection (AURI), viral hepatitis, malaria, pneumonia, diarrhea, typhoid fever, measles, and neonatal tetanus (NNT), before and after the onset of the COVID-19 pandemic. Administrative health data of monthly reported cases of these diseases/syndromes from all five provinces/regions of Pakistan for a 3-year interval (March 2018-February 2021) were analyzed using an interrupted time series approach. Reported monthly incidence for each infectious disease agent or syndrome and COVID-19 were subjected to time series visualization. Spearman's rank correlation coefficient between each infectious disease/syndrome and COVID-19 was calculated and median case numbers of each disease before and after the onset of the COVID-19 pandemic were compared using a Wilcoxon signed-rank test. Subsequently, a generalized linear negative binomial regression model was developed to determine the association between reported cases of each disease and COVID-19. RESULTS: In late February 2020, concurrent with the start of COVID-19, in all provinces, there were decreases in the reported incidence of the following diseases: AURI, pneumonia, hepatitis, diarrhea, typhoid, and measles. In contrast, the incidence of COVID was negatively associated with the reported incidence of NNT only in Punjab and Sindh, but not in Khyber Pakhtunkhwa (KPK), Balochistan, or Azad Jammu & Kashmir (AJK) & Gilgit Baltistan (GB). Similarly, COVID-19 was associated with a lowered incidence of malaria in Punjab, Sindh, and AJK & GB, but not in KPK and Balochistan. CONCLUSIONS: COVID-19 was associated with a decreased reported incidence of most infectious diseases/syndromes studied in most provinces of Pakistan. However, exceptions included NNT in KPK, Balochistan and AJK & GB, and malaria in KPK and Balochistan. This general trend was attributed to a combination of resource diversion, misdiagnosis, misclassification, misinformation, and seasonal patterns of each disease.

Economic premiums associated with Mycobacterium avium ssp. paratuberculosis-negative replacement purchases in major dairy-producing regions.

Johne's disease, or paratuberculosis, is an infectious disorder of the intestines that can affect domestic and wild ruminants that is caused by an infection with Mycobacterium avium ssp. paratuberculosis (MAP). Although the economic losses due to Johne's disease in dairy cattle herds and the benefits and costs of various potential control practices have been estimated before, little is known about the economic value of purchasing MAP-negative dairy replacements in major dairy-producing regions. This study used Markov Chain Monte Carlo simulation techniques to compare 2 sets of MAP-negative and MAP-positive herds across a comprehensive selection of regions: herds purchasing MAP-negative replacement animals and herds purchasing replacement animals with unknown MAP infection status. The economic benefits per MAP-negative replacement purchased were then estimated over a 10-yr horizon, and the additional value of MAP-negative replacements when compared with unknown status replacements were calculated as a percentage premium of the average aggregated dairy replacement price in each region. An average benefit of US$76 per MAP-negative replacement purchase was estimated in major dairy-producing regions, equivalent to a premium of 13%, with higher premiums in regions characterized by below-average replacement prices and on-average farm-gate prices. It was also estimated that the greatest benefits from MAP-negative replacement purchases are associated with MAP-negative herds that successfully remain uninfected.