Polypeptide variation encoded by the ovine transmembrane protein 154 gene (TMEM154) is associated with susceptibility to ovine lentivirus, the causative agent of Ovine Progressive Pneumonia (OPP) and ...Visna/Maedi. Our aim was to compare the four most prevalent TMEM154 haplotypes on the incidence of infection and ewe productivity during natural multiyear virus exposure. Prospective cohort studies were designed to test gene action and estimate effects of TMEM154 haplotypes encoding distinctive variant residues: K35 (“1”), I70 (“2”), ancestral (“3”), and A4del/M44 (“4”). Exposure consisted of co-mingling infected ewes at a rate greater than 30% with serological status evaluated every four months. For ewes with one or two copies of the highly susceptible haplotypes “2” and ”3”, the infection prevalence steadily increased to nearly 100% at 55 months. Haplotypes “2” and “3” were equally susceptible and dominant to haplotype “1”. A difference was not detected (p < 0.53) in the magnitude of effect with haplotype combinations of “1” and ”4”. The ewe infection prevalence with “1,1”; “1,4”; and “4,4” was 10% to 40% at 55 months. The latter suggested that two copies of the K35 amino acid substitution (“1”) were as effective as a homozygous TMEM154 “knockout” with the frame-shift deletion mutation (“4”) in reducing infection susceptibility. When considering ewe reproductive performance, a difference was not detected when comparing haplotypes “2”, and “3” to each other, or “1” and “4” to each other. Our study indicated that ewes with two copies of the severely truncated versions of TMEM154 (“4,4”) had normal lamb productivity. Without complete understanding of the natural function of TMEM154 our recommendations to producers interested in using TMEM154 selection to reduce their flock’s genetic predisposition to OPP are encouraged to increase the frequency of TMEM154 haplotype K35 (“1”) since it encodes a full-length protein with minimal difference to the ancestral polypeptide.
Abstract
The objective was to evaluate wool (Dorset and Rambouillet) and hair (Dorper, Katahdin, and White Dorper) breeds for their ability to complement Romanov germplasm in two distinct production ...systems by estimating direct sire and grandsire effects on lamb growth, survival, and ewe productivity traits. Rams of the five breeds (n = 75) were mated to Romanov ewes (n = 459) over a 3-yr period to produce five types of crossbred lambs (n = 2,739). Sire breed (P > 0.06) did not impact body weight or survival traits of the first-generation crossbred (F1) lambs. The productivity of retained crossbred ewes (n = 830) mated to Suffolk and Texel terminal sires was evaluated at 1, 2, and 3 yr of age in each production system. In the intensive production system, labor and harvested feed were provided for sheep that lambed in March in barns, and ewes were limited to rearing two lambs with additional lambs reared artificially. Ewes in the extensive production system lambed in May on pasture and were responsible for rearing all lambs born with no labor or supplemental feed provided before weaning. A total of 1,962 litters and 4,171 lambs from 2,229 exposures to two terminal sire breeds (Suffolk and Texel) were produced in the experiment. Crossbred ewes in the intensive production system were mated in October, resulting in larger litter sizes than crossbred ewes mated in December for the extensive production system. However, single- and twin-born lamb mortality was similar between the two systems that differed greatly in labor, feed, and facilities. Lambs produced in the intensive system received concentrate feed from an early age and were heavier at 24 wk of age than lambs produced in the extensive system. These outcomes resulted in greater 24-wk litter weight in the intensive than in the extensive system (P < 0.0001). Unexpectedly, the relative performance of crossbred types did not differ importantly between production systems. White Dorper × Romanov crossbred ewes had numerical advantages in productivity in each system; however, differences between ewe types were not significant. In the extensive system, without labor and shelter at lambing or supplemental feed until weaning, 3-yr-old crossbred ewes of all types averaged 1.78 lambs marketed per ewe lambing, and 40% of the ewes that gave birth to triplets weaned their entire litters. These results document that prolific sheep and extensive systems can be successfully combined if appropriate crossbred types are used.
Abstract
Extensive sheep systems have lower inputs (e.g., feed, labor, infrastructure) but, generally, lower outputs per ewe than intensively managed flocks. Average ewe prolificacy is low (< 1.1 ...lambs per ewe) across the United States and traditional expectation is that costs required to support larger litters will not be recovered due to greater lamb mortality. The Composite-IV (C-IV) is a 50% Romanov, 25% Katahdin, and 25% White Dorper hair sheep developed and selected for enhanced reproductive efficiency at the U.S. Meat Animal Research Center. Objectives of the current study were to compare productivity of C-IV ewes (N = 404) to Katahdin (N = 342) and Polypay (N = 390), two popular maternal composite breeds, in a lower-input system. Experimental ewes were exposed to either rams of their own breed or Texel rams for the first time at 7 mo of age and remained in the same mating system for up to 4 yr. Ewes lambed on pasture from May to June and were expected to rear their lambs in the absence of supplemental feed and with minimal intervention. The ewe age × breed interaction effect impacted all annually recorded traits (P < 0.01) including number and total weight of lamb marketed at 25 wk per ewe exposed to mating (LS25 and LW25, respectively). Within all ages, LS25 of C-IV was greater (1.2 to 1.63 lambs; P < 0.01) than Katahdin (0.71 to 1.17 lambs) and Polypay (0.68 to 1.26 lambs) which were similar. At 1, 2, and 3-yr of age, C-IV ewes had, on average, 12 to 17 kg greater LW25 (P ≤ 0.01) than other breeds. Polypay LW25 was similar to Katahdin at 1 yr of age, but 8 to 13 kg greater (P < 0.01) at older ages. At 4 yr of age, LW25 was similar for C-IV and Polypay (63 and 62 kg, respectively). Overall, Texel mating improved LW25 by 3 kg compared to purebred mating (P < 0.01). Twin litters were most common within mature ewes (> 1 yr) of all breeds (52% to 65%); however, the proportion of triplet litters was numerically greater for C-IV (13%) than Katahdin (1%) or Polypay (4%). The frequency of mature ewes that gave birth to and reared twins (75% to 82%) was high for all breeds. Most triplet-bearing mature C-IV ewes reared twins (43%) though many reared triplets (39%). Ewe reproductive efficiency can be enhanced in lower-input systems by utilizing additive breed effects and heterosis in a complimentary crossbreeding program. More research is needed to identify indicator traits associated with lamb survival and to derive appropriate levels of prolificacy to fit specific management constraints.
Ewe reproductive efficiency in a lower-input system was vastly improved over the current U.S. industry average by utilizing additive breed effects and heterosis in a complimentary crossbreeding program.
Lay Summary
Production systems across the U.S. sheep industry are diverse, ranging from intensive management to lower-input and extensive operations. Extensive flocks are more nutritionally reliant on grazing, have lower labor costs, and have limited housing for animals. Most extensively managed sheep operations in the United States are in the western states, where approximately 60% of lambs are born outside and with little intervention. Predation, recurrent drought, and limited nutritional value of forages are common in this region and are antagonistic to rearing multiple lambs. However, large breed differences in ewe maternal ability exist and can be utilized to improve lamb production through strategic crossbreeding. The Composite-IV is a sheep population developed at the U.S. Meat Animal Research Center and has been selected for enhanced reproductive efficiency in a lower-input system. Composite-IV ewes were evaluated alongside Katahdin and Polypay ewes, two other popular maternal sheep breeds, over 4 yr in a lower-input, pasture lambing system. Total number and weight of lamb marketed per ewe was greatest for Composite-IV, but all three breeds had much greater reproductive performance than the current U.S. average. Results highlight the importance of applying existing and novel genetic tools to optimize sheep performance for specific production systems.
Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and ...differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell's ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.
Objective
To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset.
Methods
Daily practice ...data from the worldwide METEOR registry were used. Patients (7912) were stratified into three age-groups (age at disease diagnosis <45 years, 45–65 years, >65 years). Initial treatment was compared between the different age-groups. With Cox regression analyses the effect of age-group on time-to-switch from first to second treatment was investigated, and with linear mixed models differences in response to treatment (DAS and HAQ) between the age-groups were assessed, after correction for potential confounders.
Results
The >65 years age-group included more men, and more seronegative RA with somewhat higher inflammatory markers. Initial treatment choices differed only slightly between the age-groups, and the time-to-switch from initial treatment to the next was similar. DAS and HAQ improvement were dependent on the age-group, reflected by a significant interaction between age-group and outcome. The stratified analysis showed a difference of −0.02 and −0.05 DAS points and, −0.01 and 0.02 HAQ points per month in the <45 and 45–65 years age-groups as compared with the >65 year age group, a difference that did not seem clinically relevant.
Conclusion
In this international study on worldwide clinical practice, patients with RA onset >65 years include more men and seronegative arthritis, and were initially treated slightly differently than younger patients. We observed no clinically relevant differences in timing of a next treatment step, or response to treatment measured by DAS and HAQ.
People with cancer are at increased risk of hospitalisation and death following infection with SARS-CoV-2. Therefore, we aimed to conduct one of the first evaluations of vaccine effectiveness against ...breakthrough SARS-CoV-2 infections in patients with cancer at a population level.
In this population-based test-negative case-control study of the UK Coronavirus Cancer Evaluation Project (UKCCEP), we extracted data from the UKCCEP registry on all SARS-CoV-2 PCR test results (from the Second Generation Surveillance System), vaccination records (from the National Immunisation Management Service), patient demographics, and cancer records from England, UK, from Dec 8, 2020, to Oct 15, 2021. Adults (aged ≥18 years) with cancer in the UKCCEP registry were identified via Public Health England's Rapid Cancer Registration Dataset between Jan 1, 2018, and April 30, 2021, and comprised the cancer cohort. We constructed a control population cohort from adults with PCR tests in the UKCCEP registry who were not contained within the Rapid Cancer Registration Dataset. The coprimary endpoints were overall vaccine effectiveness against breakthrough infections after the second dose (positive PCR COVID-19 test) and vaccine effectiveness against breakthrough infections at 3–6 months after the second dose in the cancer cohort and control population.
The cancer cohort comprised 377 194 individuals, of whom 42 882 had breakthrough SARS-CoV-2 infections. The control population consisted of 28 010 955 individuals, of whom 5 748 708 had SARS-CoV-2 breakthrough infections. Overall vaccine effectiveness was 69·8% (95% CI 69·8–69·9) in the control population and 65·5% (65·1–65·9) in the cancer cohort. Vaccine effectiveness at 3–6 months was lower in the cancer cohort (47·0%, 46·3–47·6) than in the control population (61·4%, 61·4–61·5).
COVID-19 vaccination is effective for individuals with cancer, conferring varying levels of protection against breakthrough infections. However, vaccine effectiveness is lower in patients with cancer than in the general population. COVID-19 vaccination for patients with cancer should be used in conjunction with non-pharmacological strategies and community-based antiviral treatment programmes to reduce the risk that COVID-19 poses to patients with cancer.
University of Oxford, University of Southampton, University of Birmingham, Department of Health and Social Care, and Blood Cancer UK.
Population divergence can occur due to mechanisms associated with geographic isolation and/or due to selection associated with different ecological niches. Much of the evidence for selection‐driven ...speciation has come from studies of specialist insect herbivores that use different host plant species; however, the influence of host plant use on population divergence of generalist herbivores remains poorly understood. We tested how diet breadth, host plant species and geographic distance influence population divergence of the fall webworm (Hyphantria cunea; FW). FW is a broadly distributed, extreme generalist herbivore consisting of two morphotypes that have been argued to represent two different species: black‐headed and red‐headed. We characterized the differentiation of FW populations at two geographic scales. We first analysed the influence of host plant and geographic distance on genetic divergence across a broad continental scale for both colour types. We further analysed the influence of host plant, diet breadth and geographic distance on divergence at a finer geographic scale focusing on red‐headed FW in Colorado. We found clear genetic and morphological distinction between red‐ and black‐headed FW, and Colorado FW formed a genetic cluster distinct from other locations. Although both geographic distance and host plant use were correlated with genetic distance, geographic distance accounted for up to 3× more variation in genetic distance than did host plant use. As a rare study investigating the genetic structure of a widespread generalist herbivore over a broad geographic range (up to 3,000 km), our study supports a strong role for geographic isolation in divergence in this system.
People living with cancer and haematological malignancies are at an increased risk of hospitalisation and death following infection with acute respiratory syndrome coronavirus 2. Coronavirus third ...dose vaccine boosters are proposed to boost waning immune responses in immunocompromised individuals and increase coronavirus protection; however, their effectiveness has not yet been systematically evaluated.
This study is a population-scale real-world evaluation of the United Kingdom’s third dose vaccine booster programme for cancer patients from 8th December 2020 to 7th December 2021. The cancer cohort comprises individuals from Public Health England’s national cancer dataset, excluding individuals less than 18 years. A test-negative case-control design was used to assess the third dose booster vaccine effectiveness. Multivariable logistic regression models were fitted to compare risk in the cancer cohort relative to the general population.
The cancer cohort comprised of 2,258,553 tests from 361,098 individuals. Third dose boosters were evaluated by reference to 87,039,743 polymerase chain reaction coronavirus tests. Vaccine effectiveness against breakthrough infections, symptomatic infections, coronavirus hospitalisation and death in cancer patients were 59.1%, 62.8%, 80.5% and 94.5%, respectively. Lower vaccine effectiveness was associated with a cancer diagnosis within 12 months, lymphoma, recent systemic anti-cancer therapy (SACT) or radiotherapy. Patients with lymphoma had low levels of protection from symptomatic disease. In spite of third dose boosters, following multivariable adjustment, individuals with cancer remain at an increased risk of coronavirus hospitalisation and death compared to the population control (OR 3.38, 3.01, respectively. p < 0.001 for both).
Third dose boosters are effective for most individuals with cancer, increasing protection from coronavirus. However, their effectiveness is heterogenous and lower than the general population. Many patients with cancer will remain at the increased risk of coronavirus infections even after 3 doses. In the case of patients with lymphoma, there is a particularly strong disparity of vaccine effectiveness against breakthrough infection and severe disease. Breakthrough infections will disrupt cancer care and treatment with potentially adverse consequences on survival outcomes. The data support the role of vaccine boosters in preventing severe disease, and further pharmacological intervention to prevent transmission and aid viral clearance to limit the disruption of cancer care as the delivery of care continues to evolve during the coronavirus pandemic.
•Largest population evaluation of third dose SARS-CoV-2 disease (COVID-19) vaccination in patients with cancer.•Vaccine effectiveness against COVID-19 infections, hospitalisation and death assessed.•Lower vaccine effectiveness associated with recent systemic anti-cancer therapy.•Patients with lymphoma had low levels of vaccine protection from symptomatic COVID-19.•Patients with cancer remain at a higher risk of severe COVID-19 hospitalisation and death.
ObjectivesTo study whether there is an association between body mass index (BMI) category and survival of various tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients in a ...real-life longitudinal international registry.MethodsData from 5230 patients with RA starting treatment with any TNFi were selected from the METEOR registry. Patients were divided into six BMI categories: 3.7% underweight, BMI<18.5 kg/m2; 46% normal weight, BMI 18.5–25 kg/m2; 32% pre-obesity, BMI 25–30 kg/m2; 13% obesity class I, BMI 30–35 kg/m2; 3.4% obesity class II, BMI 35–40 kg/m2; and 1.6% obesity class III, BMI >40 kg/m2. Time on treatment in the different BMI categories was compared for all TNFi combined and for the infliximab, adalimumab and etanercept separately, using Kaplan–Meier curves and Cox regression analyses. Cox regression analyses were adjusted for potential confounders, with follow-up censored at 5000 days.ResultsPatients in obesity class II (HR 1.28, 95% CI 1.06 to 1.54) and III (HR 1.67, 95% CI 1.29 to 2.18) and underweight patients (HR 1.30, 95% CI 1.07 to 1.58) showed statistically significantly shorter TNFi survival than normal weight patients. The effect in underweight patients was strongest for infliximab (HR 1.82, 95% CI 1.20 to 2.76), the effect in overweight patients was strongest for infliximab (category II (HR 1.49, 95% CI 0.98 to 2.26); category III (HR 1.46, 95% CI 0.79 to 2.71)) and etanercept (category II (HR 1.27 95% CI 0.98 to 1.65); category III (HR 1.79, 95% CI 1.25 to 2.55)). No significant effect modification from reported pain was found.ConclusionBoth underweight and overweight patients discontinued TNFi treatment earlier than normal weight patients, without evidence of reported pain as the main determinant. It remains uncertain what determines TNFi survival in individual patients.
Abstract Economic selection indexes provide the best method to achieve genetic gain for multiple traits simultaneously. Hair sheep enterprises, particularly in environments with substantial ...gastrointestinal nematode challenge, may benefit from incorporating parasite resistance in a selection index. However, obtaining the relative economic value (REV) for parasite resistance is challenging; information on its impact on productivity is incomplete, as are the costs of treatment given anthelmintic resistance. The National Sheep Improvement Program (NSIP) currently provides producers with an index designed to increase total weight of lamb weaned per ewe lambing (TW). Our objective was to assess the effects of including fecal egg count, an indicator of parasite resistance, as an additional goal trait. Including the benchmark scenario with TW as its sole objective, 10 indexes were constructed using standard index theory. Post-weaning fecal egg count (PFEC) was added to this breeding objective with a REV of -1 and the REV for TW was varied from +1 to +5 at +0.5 increments. Weaning weight, number of lambs born and weaned, and PFEC were the selection criteria, modelled as either phenotypes or estimated breeding values (EBV). Phenotypes and EBV were simulated for 1,000 lambs by Cholesky decomposition and used to generate index scores. Ten replicates were run and the top 3% of males and 26% of females were retained on index scores. Annual responses in the goal traits were estimated. Responses in PFEC were expressed as a percentage, assuming a mean PFEC of 2,089 eggs/g as in NSIP. Concordances with those selected in the benchmark scenario were determined. Using EBV as selection criteria, TW increased by 1.7 kg/yr in the benchmark scenario (Table 1). However, unfavorably, PFEC increased by 2.3%/yr. When phenotypic criteria were used, TW increased by 0.5 kg/yr, and PFEC by 0.3%/yr. Once added to the breeding objective, PFEC decreased regardless of the REV of TW. However, response in TW also reduced, although less so as its REV increased. With EBV as the criteria, the REV of +3 for TW appeared preferable: PFEC reduced by 7.1%/yr with 98% of the response in TW retained. With phenotypic selection criteria, PFEC reduced by 5.2%/yr with 94% of the response in TW retained. With +3 REV for TW and EBV as the selection criteria, on average 65% and 82% of males and females, respectively, were chosen in common with the benchmark. When phenotypic criteria were used, those percentages were 60% and 80%, respectively. Implementing a more holistic index with REV of +3 for TW and -1 for PFEC would result in reasonable responses in both traits. However, producers will need to decide if reduced gains in TW is acceptable to improve parasite resistance in a hair sheep breeding program.
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