Effect of ewe birth litter size and estimation of genetic parameters on ewe reproductive life traits.

Ewe lifetime productivity has economic implications for producers because shorter lifetime productivity results in less profit. Productive years of ewes from extensive, range-based systems of the United States West are generally less than ewes from more temperate regions of the United States. Accordingly, ewes from range-based systems, especially those employing shed-lambing strategies, have been selected for increased litter size to offset decreased lifetime productivity. However, the relationship of the ewe's birth litter size (ELSB) has not been considered a potential contributor to lifetime productivity. Longevity (number of productive years, n = 1 per population) and stayability (probability to survive to the next age; ages 2-7 years, n = 6 per population) were investigated to understand ELSB effects on productive life. Columbia, Polypay, Rambouillet, and Targhee breeds were used in this study. Across-breed (n = 11 550) and within-breed (Columbia, n = 4 398; Polypay, n = 4 534; Rambouillet, n = 5 922; Targhee, n = 6 482) analyses were used. Depending on the population, records spanned from 1950 to 2008, where ewe's birth year was included as a fixed effect in the animal model using restricted maximum likelihood estimation procedures. Fixed effects investigated included ELSB (single-, twin-, or triplet-born) and ewe breed (across-breed analyses only). Regardless of trait or population used, heritability ranged from 0.06 ± 0.02 to 0.34 ± 0.03, where stayability at younger ages had the highest estimates. The breed effect was significant in all across-breed analyses (0.0001 ≤ P ≤ 0.038; n = 7), where Polypay, a breed selected for accelerated lambing and increased fertility, averaged shorter productive life or had a lower probability of survival to the next age compared with other breeds (longevity: 0.009 ≤ P ≤ 0.223; stayability: 0.000 ≤ P ≤ 0.842). The ELSB was significant in 60% (n = 5) and 37% (n = 30) of longevity and stayability analyses, respectively. Except for Targhee, all analyses showed ewes born in smaller litter sizes were associated with longer productive lives or higher probability of surviving to the next age, particularly in across-breed analyses (e.g., longevity: single- vs twin-born ewes, P = 0.004; vs triplet-born ewes, P = 0.003). This study provides evidence that increasing prolificacy in ewes from extensive, range-based production systems may impact productive life. Due to the low heritability of these traits, additional investigation into modeling these traits with dominance effects and litter size needs to be conducted.

The relationship between parental adverse childhood experiences and the health, well-being and development outcomes of their children: a systematic review.

OBJECTIVES: A growing body of research is emerging regarding the relationship between parental adverse childhood experiences (ACEs) and negative health, well-being and developmental outcomes in their children. This systematic review seeks to understand the relationship between parental ACEs and the health, well-being and developmental outcomes of their children and whether the relationships differ according to the number and type of parental ACEs. STUDY DESIGN: Systematic review. METHOD: The review includes articles published between 2000 and 2021 from studies using quantitative longitudinal methods and multivariate analysis to investigate the relationship between parental ACEs and their offspring's outcomes. Relevant studies were identified through a systematic search of five databases and findings synthesised using a narrative synthesis. This review was registered on PROSPERO (CRD42021274068). RESULTS: Nineteen studies met the inclusion criteria and were included in the review. This resulted in a combined population sample of 124,043 parents and 128,400 children. Diversity in measurement of parental ACE exposure and in the type of ACEs measured within the studies precluded a meta-analysis. Offspring of parents exposed to ACEs had a higher risk of a range of negative health, well-being and developmental outcomes. This relationship differs according to the number and type of parental ACEs, with a positive relationship observed between the number of parental ACEs and the risk of negative health, well-being and development outcomes in their children. CONCLUSIONS: These findings indicate that screening for parental ACEs by health visitors, midwives and other health or social care staff may identify an at-risk population of infants, children and adolescents and improve child outcomes.

A review of custom implants for glenoid bone deficiency in reverse shoulder arthroplasty.

Reverse Total Shoulder Arthroplasty is being increasingly performed, with indications in both elective and trauma settings. Accordingly, there are an increasing number of revision cases where glenoid bone loss is a concern. There are well recognised surgical techniques for dealing with mild to moderate glenoid wear, including eccentric reaming and impaction grafting. In cases of severe wear or uncontained glenoid defects these may not be suitable, and the surgeon may look to a customised implant to deal with such bone loss. There are several implant manufacturers who currently market and produce patient specific instrumentation and customised glenoid baseplates to achieve the best possible fixation in cases of severe bone loss. This article outlines some examples of custom implants currently available to surgeons, and the process by which they may be procured and used. Implant and surgical considerations, and key aspects of surgical technique are also covered. Literature on outcomes and complications following custom shoulder arthroplasty shows promising results, but at present is limited to relatively small case series with no long-term outcome data.

Dopaminergic Modulation of Dynamic Emotion Perception.

Emotion recognition abilities are fundamental to our everyday social interaction. A large number of clinical populations show impairments in this domain, with emotion recognition atypicalities being particularly prevalent among disorders exhibiting a dopamine system disruption (e.g., Parkinson's disease). Although this suggests a role for dopamine in emotion recognition, studies employing dopamine manipulation in healthy volunteers have exhibited mixed neural findings and no behavioral modulation. Interestingly, while a dependence of dopaminergic drug effects on individual baseline dopamine function has been well established in other cognitive domains, the emotion recognition literature so far has failed to account for these possible interindividual differences. The present within-subjects study therefore tested the effects of the dopamine D2 antagonist haloperidol on emotion recognition from dynamic, whole-body stimuli while accounting for interindividual differences in baseline dopamine. A total of 33 healthy male and female adults rated emotional point-light walkers (PLWs) once after ingestion of 2.5 mg haloperidol and once after placebo. To evaluate potential mechanistic pathways of the dopaminergic modulation of emotion recognition, participants also performed motoric and counting-based indices of temporal processing. Confirming our hypotheses, effects of haloperidol on emotion recognition depended on baseline dopamine function, where individuals with low baseline dopamine showed enhanced, and those with high baseline dopamine decreased emotion recognition. Drug effects on emotion recognition were related to drug effects on movement-based and explicit timing mechanisms, indicating possible mediating effects of temporal processing. Results highlight the need for future studies to account for baseline dopamine and suggest putative mechanisms underlying the dopaminergic modulation of emotion recognition.SIGNIFICANCE STATEMENT A high prevalence of emotion recognition difficulties among clinical conditions where the dopamine system is affected suggests an involvement of dopamine in emotion recognition processes. However, previous psychopharmacological studies seeking to confirm this role in healthy volunteers thus far have failed to establish whether dopamine affects emotion recognition and lack mechanistic insights. The present study uncovered effects of dopamine on emotion recognition in healthy individuals by controlling for interindividual differences in baseline dopamine function and investigated potential mechanistic pathways via which dopamine may modulate emotion recognition. Our findings suggest that dopamine may influence emotion recognition via its effects on temporal processing, providing new directions for future research on typical and atypical emotion recognition.

Renal medullary carcinoma and its association with sickle cell trait: a case report and literature review.

Renal medullary carcinoma (rmc) is a rare and aggressive renal malignancy that usually presents at an advanced stage, has a poor prognosis, and is associated with sickle cell trait. We present a case of rmc including radiologic and pathology findings, treatment, and outcome. A review of the literature is also presented, with an emphasis on the association of rmc with sickle cell trait, which was an unknown diagnosis in our patient preoperatively.

Equal North: how can we reduce health inequalities in the North of England? A prioritization exercise with researchers, policymakers and practitioners.

BACKGROUND: The Equal North network was developed to take forward the implications of the Due North report of the Independent Inquiry into Health Equity. The aim of this exercise was to identify how to reduce health inequalities in the north of England. METHODS: Workshops (15 groups) and a Delphi survey (3 rounds, 368 members) were used to consult expert opinion and achieve consensus. Round 1 answered open questions around priorities for action; Round 2 used a 5-point Likert scale to rate items; Round 3 responses were re-rated alongside a median response to each item. In total, 10 workshops were conducted after the Delphi survey to triangulate the data. RESULTS: In Round 1, responses from 253 participants generated 39 items used in Round 2 (rated by 144 participants). Results from Round 3 (76 participants) indicate that poverty/implications of austerity (4.87 m, IQR 0) remained the priority issue, with long-term unemployment (4.8 m, IQR 0) and mental health (4.7 m, IQR 1) second and third priorities. Workshop 3 did not diverge from findings in Round 1. CONCLUSIONS: Practice professionals and academics agreed that reducing health inequalities in the North of England requires prioritizing research that tackles structural determinants concerning poverty, the implications of austerity measures and unemployment.

Review of epidemiology, clinical presentation, diagnosis, and treatment of common primary psychiatric causes of cutaneous disease.

Approximately half of all patients presenting to dermatologists exhibit signs and symptoms of psychiatric conditions that are either primary or secondary to cutaneous disease. Because patients typically resist psychiatric consult, dermatologists often are on the front line in evaluating and treating these patients. Accordingly, distinguishing the specific underlying or resulting psychiatric condition is essential for effective treatment. The etiology, epidemiology, clinical presentation, diagnosis, and first-line treatment of specific primary psychiatric causes of dermatologic conditions, including delusional infestation, Morgellons syndrome, olfactory reference syndrome, body dysmorphic disorder, excoriation disorder, trichotillomania, and dermatitis artefacta are discussed here, followed by a discussion of the recommended treatment approach with an overview of the different first-line therapies discussed in this review, specifically cognitive behavioral therapy, atypical antipsychotics, selective serotonin reuptake inhibitors, and tricyclic antidepressants. Included is a guide for dermatologists to use while prescribing these medications.

Ancestral whole-genome duplication in the marine chelicerate horseshoe crabs.

This corrects the article DOI: 10.1038/hdy.2015.89.

Distance of translation as a predictor of failure of fixation in paediatric supracondylar fractures.

Introduction This study investigates the influence of incomplete reduction of supracondylar fractures on the incidence of loss of reduction requiring reoperation Materials and methods A review of 107 consecutive patients presenting with supracondylar fractures treated with closed reduction and Kirschner wire stabilisation, between January 2011 and March 2013, was conducted. The mean age was 5 years (range 10 months to 12 years). Pre-, intra- and postoperative radiographs were reviewed. All patients who had failure of fixation requiring revision surgery were identified. Results Ninety-nine patients had an initial adequate radiographic reduction. Of these, one (1%) required revision surgery. Eight patients had an initial incomplete radiographic reduction and, of these, six (75%) required revision surgery (P < 0.0001). Discussion Supracondylar fractures treated with closed reduction and K wire stabilisation require adequate intraoperative reduction. Incomplete reduction should not be accepted, as despite the bones potential to remodel, the risk of further loss of reduction is high, requiring reoperation.

Cerebellar Cathodal Transcranial Direct Stimulation and Performance on a Verb Generation Task: A Replication Study.

The role of the cerebellum in cognitive processing is increasingly recognized but still poorly understood. A recent study in this field applied cerebellar Transcranial Direct Current Stimulation (c-tDCS) to the right cerebellum to investigate the role of prefrontal-cerebellar loops in language aspects of cognition. Results showed that the improvement in participants' verbal response times on a verb generation task was facilitated immediately after cathodal c-tDCS, compared to anodal or sham c-tDCS. The primary aim of the present study is to replicate these findings and additionally to investigate possible longer term effects. A crossover within-subject design was used, comparing cathodal and sham c-tDCS. The experiment consisted of two visits with an interval of one week. Our results show no direct contribution of cathodal c-tDCS over the cerebellum to language task performance. However, one week later, the group receiving cathodal c-tDCS in the first visit show less improvement and increased variability in their verbal response times during the second visit, compared to the group receiving sham c-tDCS in the first visit. These findings suggest a potential negative effect of c-tDCS and warrant further investigation into long term effects of c-tDCS before undertaking clinical studies with poststroke patients with aphasia.

Cerebellar tDCS does not improve performance in probabilistic classification learning.

In this study, the role of the cerebellum in a cognitive learning task using transcranial direct current stimulation (tDCS) was investigated. Using a weather prediction task, subjects had to learn the probabilistic associations between a stimulus (a combination of cards) and an outcome (sun or rain). This task is a variant of a probabilistic classification learning task, for which it has been reported that prefrontal tDCS enhances performance. Using a between-subject design, all 30 subjects learned to improve their performance with increasing accuracies and shortened response times over a series of 500 trials. Subjects also became more confident in their prediction during the experiment. However, no differences in performance and learning were observed between subjects receiving sham stimulation (n = 10) or anodal stimulation (2 mA for 20 min) over either the right cerebellum (n = 10) or the left prefrontal cortex (n = 10). This suggests that stimulating the brain with cerebellar tDCS does not readily influence probabilistic classification performances, probably due to the rather complex nature of this cognitive task.

Ocean forcing of glacier retreat in the western Antarctic Peninsula.

In recent decades, hundreds of glaciers draining the Antarctic Peninsula (63° to 70°S) have undergone systematic and progressive change. These changes are widely attributed to rapid increases in regional surface air temperature, but it is now clear that this cannot be the sole driver. Here, we identify a strong correspondence between mid-depth ocean temperatures and glacier-front changes along the ~1000-kilometer western coastline. In the south, glaciers that terminate in warm Circumpolar Deep Water have undergone considerable retreat, whereas those in the far northwest, which terminate in cooler waters, have not. Furthermore, a mid-ocean warming since the 1990s in the south is coincident with widespread acceleration of glacier retreat. We conclude that changes in ocean-induced melting are the primary cause of retreat for glaciers in this region.

Ancestral whole-genome duplication in the marine chelicerate horseshoe crabs.

Whole-genome duplication (WGD) results in new genomic resources that can be exploited by evolution for rewiring genetic regulatory networks in organisms. In metazoans, WGD occurred before the last common ancestor of vertebrates, and has been postulated as a major evolutionary force that contributed to their speciation and diversification of morphological structures. Here, we have sequenced genomes from three of the four extant species of horseshoe crabs-Carcinoscorpius rotundicauda, Limulus polyphemus and Tachypleus tridentatus. Phylogenetic and sequence analyses of their Hox and other homeobox genes, which encode crucial transcription factors and have been used as indicators of WGD in animals, strongly suggests that WGD happened before the last common ancestor of these marine chelicerates >135 million years ago. Signatures of subfunctionalisation of paralogues of Hox genes are revealed in the appendages of two species of horseshoe crabs. Further, residual homeobox pseudogenes are observed in the three lineages. The existence of WGD in the horseshoe crabs, noted for relative morphological stasis over geological time, suggests that genomic diversity need not always be reflected phenotypically, in contrast to the suggested situation in vertebrates. This study provides evidence of ancient WGD in the ecdysozoan lineage, and reveals new opportunities for studying genomic and regulatory evolution after WGD in the Metazoa.

A novel RIPK4-IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes.

Receptor-interacting protein kinase 4 (RIPK4)-deficient mice have epidermal defects and fusion of all external orifices. These are similar to Bartsocas-Papas syndrome and popliteal pterygium syndrome (PPS) in humans, for which causative mutations have been documented in the RIPK4 and IRF6 (interferon regulatory factor 6) gene, respectively. Although genetically distinct, these syndromes share the anomalies of marked pterygia, syndactyly, clefting and hypoplastic genitalia. Despite the strong resemblance of these two syndromes, no molecular connection between the transcription factor IRF6 and the kinase RIPK4 was known and the mechanism underlying the phenotype was unclear. Here we describe that RIPK4 deficiency in mice causes epithelial fusions associated with abnormal periderm development and aberrant ectopic localization of E-cadherin on the apical membrane of the outer peridermal cell layers. In Xenopus, RIPK4 depletion causes the absence of ectodermal epiboly and concomitant gastrulation defects that phenocopy ectopic expression of dominant-negative IRF6. We found that IRF6 controls RIPK4 expression and that wild-type, but not kinase-dead, RIPK4 can complement the gastrulation defect in Xenopus caused by IRF6 malfunctioning. In contrast to the mouse, we observed only minor effects on cadherin membrane expression in Xenopus RIPK4 morphants. However, gastrulation defects were associated with a virtual absence of cortical actin in the ectodermal cells that face the blastocoel cavity and this was phenocopied in embryos expressing dominant-negative IRF6. A role for RIPK4 in actin cytoskeleton organization was also revealed in mouse epidermis and in human epithelial HaCaT cells. In conclusion, we showed that in mice RIPK4 is implicated in cortical actin organization and in E-cadherin localization or function, which can explain the characteristic epithelial fusions observed in PPSs. In addition, we provide a novel molecular link between IRF6 and RIPK4 that unifies the different PPSs to a common molecular pathway.

Analytical and clinical challenges in a patient with concurrent type 1 diabetes, subcutaneous insulin resistance and insulin autoimmune syndrome.

UNLABELLED: A lean 15-year-old girl was diagnosed with type 1 diabetes based on symptomatic hyperglycaemia and positive anti-islet cell antibodies. Glycaemia was initially stabilised on twice-daily mixed insulin. After 11 months from the time of diagnosis, she complained of hyperglycaemia and ketosis alternating with hypoglycaemia. This progressively worsened until prolonged hospital admission was required for treatment of refractory hypoglycaemia. A high titre of anti-insulin antibodies was detected associated with a very low recovery of immunoreactive (free) insulin from plasma after precipitation with polyethylene glycol, suggesting the presence of insulin in bound complexes. Insulin autoimmune syndrome was diagnosed and metabolic fluctuations were initially managed supportively. However, due to poor glucose control, immunosuppressive therapy was initiated first with steroids and plasmapheresis and later with anti-CD20 antibody therapy (Rituximab). This treatment was associated with a gradual disappearance of anti-insulin antibodies and her underlying type 1 diabetes has subsequently been successfully managed with an insulin pump. LEARNING POINTS: Anti-insulin antibodies may result in low levels of free insulin.Polyclonal anti-insulin antibodies can interfere with the pharmacological action of administered insulin, resulting in hypoglycaemia and insulin resistance, due to varying affinities and capacities.In this patient, rituximab administration was associated with a gradual disappearance of anti-insulin antibodies.It is hypothesised that this patient had subcutaneous insulin resistance (SIR) caused by insulin capture at the tissue level, either by antibodies or by sequestration.A prolonged tissue resistance protocol may be more appropriate in patients with immune-mediated SIR syndrome.

Deep brain stimulation for tremor resulting from acquired brain injury.

OBJECTIVES: To evaluate the efficacy of deep brain stimulation (DBS) in the treatment of tremor resulting from acquired brain injury (ABI). METHODS: A series of eight consecutive patients with post-ABI tremor were treated with DBS of the ventro-oralis posterior (VOP)/zona incerta (ZI) region, and subsequently underwent blinded assessments using Bain's tremor severity scale. RESULTS: VOP/ZI DBS produced a mean reduction in tremor severity of 80.75% based on Bain's tremor severity scale, with significant reductions in all five component tremor subscores: rest, postural, kinetic, proximal and distal. No adverse neurological complications were reported, although one patient experienced exacerbation of pre-existing gait ataxia. CONCLUSION: VOP/ZI stimulation is demonstrated here to be an effective and safe approach for the treatment of post-ABI tremor in the largest series published at the time of writing.

The role of ALFY in selective autophagy.

Autophagy, a highly conserved lysosomal degradation pathway, was initially characterized as a bulk degradation system induced in response to starvation. In recent years, autophagy has emerged also as a highly selective pathway, targeting various cargoes such as aggregated proteins and damaged organelles for degradation. The key factors involved in selective autophagy are autophagy receptors and adaptor proteins, which connect the cargo to the core autophagy machinery. In this review, we discuss the current knowledge about the only mammalian adaptor protein identified thus far, autophagy-linked FYVE protein (ALFY). ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. We also comment on the possible role of ALFY in the context of disease.

Delayed and differential effects of the economic crisis in Sweden in the 1990s on health-related exclusion from the labour market: a health equity assessment.

UNLABELLED: Many OECD countries are currently experiencing economic crisis and introducing counter-measures with unknown effects. To learn from previous experience, we explored whether there were delayed or differential effects of the Swedish recession in the 1990s and the government's response to it for people with limiting longstanding illness or disability (LLSI) from different socioeconomic groups (SEGs), by policy analysis and secondary data analysis of the Swedish Survey of Living Conditions (ULF) from 1978 to 2005. The government policy response involved cutting public expenditure, privatising some services and measures to boost private sector employment. There was a decline in overall employment rates from the early 1990s, particularly among men and women with LLSI and in lower SEGs. Public sector employment declined from 53 to 40 percent among women and from 23 to 14 percent among men. Private sector employment increased modestly for women (from 31 percent to 37 percent), and stayed stable at 59-60 percent among men. Following economic recovery, employment rates continued to decline among men and women with LLSI from manual SEGs, while the employment levels increased among most healthy men and women. There was a concomitant increase in rates of LLSI, sickness absence and rates of disability pension particularly among women in lower SEGs. CONCLUSION: The policy response to the 1990s economic crisis in Sweden had differential consequences, hitting the employment of women in the public sector, especially women with both LLSI and low socioeconomic status. The observed increase in disability pension rates, particularly among women with LLSI in lower SEGs, may be a delayed effect of the policy response to the economic crisis.

Bilateral pisotriquetral loose bodies.

Case reports detailing diagnosis and effective treatment of pisotriquetral loose bodies are scarce. This article describes an even rarer case of bilateral pisotriquetral joint loose bodies, explores the relative diagnostic roles of magnetic resonance imaging versus computed tomography, and outlines effective strategies used for the management of this condition drawn from the literature and our own experience.

Evaluation of pharmacodynamic biomarkers in a Phase 1a trial of dulanermin (rhApo2L/TRAIL) in patients with advanced tumours.

BACKGROUND: Dulanermin (rhApo2L/TRAIL) induces apoptosis by binding to death receptors DR4 and DR5, leading to caspase activation and subsequent cell death. A Phase1a trial evaluated the safety and tolerability of dulanermin in patients with advanced tumours. One aim was to develop and validate pharmacodynamic biomarkers to monitor dulanermin activity in patient serum. METHODS: We optimised assays to measure the cell-death markers caspase 3/7, cytokeratin 18 and genomic DNA in serum. Mice bearing Colo205 xenografts were treated with dulanermin and sera were collected and assayed for apoptotic markers. Upon validating these assays, we monitored apoptotic markers in patients who received dulanermin. RESULTS: We detected transient increases in apoptotic markers in mouse sera 8-24 h after dulanermin treatment. This increase was dose-dependent and correlated with active caspase 3 detected by IHC in Colo205 tumours. A statistically significant increase in serum caspase 3/7 was detected in cohorts of colorectal and sarcoma patients 24 h after receiving dulanermin dosed above 4 mg kg(-1). CONCLUSION: Owing to limited responses in the Phase 1a study, the changes in circulating cell-death markers were not evaluable. Future studies with dulanermin are needed to determine the utility of these assays with respect to providing evidence of activity or predicting overall response.