Ysbyty Ystrad Fawr

The production of cloned animals is, at present, an inefficient process. This study focused on the fetal losses that occur between Days 30-90 of gestation. Fetal and placental characteristics were studied from Days 30-90 of gestation using transrectal ultrasonography, maternal pregnancy specific protein b (PSPb) levels, and postslaughter collection of fetal tissue. Pregnancy rates at Day 30 were similar for recipient cows carrying nuclear transfer (NT) and control embryos (45% [54/120] vs. 58% [11/19]), although multiple NT embryos were often transferred into recipients. From Days 30-90, 82% of NT fetuses died, whereas all control pregnancies remained viable. Crown-rump (CR) length was less in those fetuses that were destined to die before Day 90, but no significant difference was found between the CR lengths of NT and control fetuses that survived to Day 90. Maternal PSPb levels at Days 30 and 50 of gestation were not predictive of fetal survival to Day 90. The placentas of six cloned and four control (in vivo or in vitro fertilized) bovine pregnancies were compared between Days 35 and 60 of gestation. Two cloned placentas showed rudimentary development, as indicated by flat, cuboidal trophoblastic epithelium and reduced vascularization, whereas two others possessed a reduced number of barely discernable cotyledonary areas. The remaining two cloned placentas were similar to the controls, although one contained hemorrhagic cotyledons. Poor viability of cloned fetuses during Days 35-60 was associated with either rudimentary or marginal chorioallantoic development. Our findings suggest that future research should focus on factors that promote placental and vascular growth and on fetomaternal interactions that promote placental attachment and villous formation.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

One thousand and sixty women aged 18 or over, randomly selected from a defined geographical area in South Wales, were interviewed at home about their urinary symptoms. Ninety-five per cent co-operated, of whom 45% admitted to some degree of incontinence. "Stress' incontinence was reported by 22% of women, "urge' incontinence by 10%, and both types combined--"complex'--by 14%. In most women urinary loss was both small and infrequent but 5% of all women experienced a loss sufficient to necessitate a change of clothes; in 2.6% such loss occurred daily. Over 3% of all women reported that incontinence interfered with their social or domestic life but only half of these had sought medical advice.

BACKGROUND: C-reactive protein (CRP) is a non-specific acute phase reactant elevated in infection or inflammation. Higher levels indicate more severe infection and have been used as an indicator of COVID-19 disease severity. However, the evidence for CRP as a prognostic marker is yet to be determined. The aim of this study is to examine the CRP response in patients hospitalized with COVID-19 and to determine the utility of CRP on admission for predicting inpatient mortality. METHODS: Data were collected between 27 February and 10 June 2020, incorporating two cohorts: the COPE (COVID-19 in Older People) study of 1564 adult patients with a diagnosis of COVID-19 admitted to 11 hospital sites (test cohort) and a later validation cohort of 271 patients. Admission CRP was investigated, and finite mixture models were fit to assess the likely underlying distribution. Further, different prognostic thresholds of CRP were analysed in a time-to-mortality Cox regression to determine a cut-off. Bootstrapping was used to compare model performance [Harrell's C statistic and Akaike information criterion (AIC)]. RESULTS: The test and validation cohort distribution of CRP was not affected by age, and mixture models indicated a bimodal distribution. A threshold cut-off of CRP ≥40 mg/L performed well to predict mortality (and performed similarly to treating CRP as a linear variable). CONCLUSIONS: The distributional characteristics of CRP indicated an optimal cut-off of ≥40 mg/L was associated with mortality. This threshold may assist clinicians in using CRP as an early trigger for enhanced observation, treatment decisions and advanced care planning.

BACKGROUND: Joint reminiscence groups, involving people with dementia and family carers together, are popular, but the evidence-base is limited. This study aimed to assess the effectiveness and cost-effectiveness of joint reminiscence groups as compared to usual care. METHODS: This multi-centre, pragmatic randomised controlled trial had two parallel arms: intervention group and usual-care control group. A restricted dynamic method of randomisation was used, with an overall allocation ratio of 1:1, restricted to ensure viable sized intervention groups. Assessments, blind to treatment allocation, were carried out at baseline, three months and ten months (primary end-point), usually in the person's home. Participants were recruited in eight centres, mainly through NHS Memory Clinics and NHS community mental health teams. Included participants were community resident people with mild to moderate dementia (DSM-IV), who had a relative or other care-giver in regular contact, to act as informant and willing and able to participate in intervention. 71% carers were spouses. 488 people with dementia (mean age 77.5)were randomised: 268 intervention, 220 control; 350 dyads completed the study (206 intervention, 144 control). The intervention evaluated was joint reminiscence groups (with up to 12 dyads) weekly for twelve weeks; monthly maintenance sessions for further seven months. Sessions followed a published treatment manual and were held in a variety of community settings. Two trained facilitators in each centre were supported by volunteers. Primary outcome measures were self-reported quality of life for the person with dementia (QoL-AD), psychological distress for the carer (General Health Questionnaire, GHQ-28). Secondary outcome measures included: autobiographical memory and activities of daily living for the person with dementia; carer stress for the carer; mood, relationship quality and service use and costs for both. RESULTS: The intention to treat analysis (ANCOVA) identified no differences in outcome between the intervention and control conditions on primary or secondary outcomes (self-reported QoL-AD mean difference 0.07 (-1.21 to 1.35), F = 0.48, p = 0.53). Carers of people with dementia allocated to the reminiscence intervention reported a significant increase in anxiety on a General Health Questionnaire-28 sub-scale at the ten month end-point (mean difference 1.25 (0.25 to 2.26), F = 8.28, p = 0.04). Compliance analyses suggested improved autobiographical memory, quality of life and relationship quality for people with dementia attending more reminiscence sessions, however carers attending more groups showed increased care-giving stress. Economic analyses from a public sector perspective indicated that joint reminiscence groups are unlikely to be cost-effective. There were no significant adverse effects attributed to the intervention. Potential limitations of the study include less than optimal attendance at the group sessions--only 57% of participants attended at least half of the intervention sessions over the 10 month period, and a higher rate of study withdrawal in the control group. CONCLUSIONS: This trial does not support the clinical effectiveness or cost-effectiveness of joint reminiscence groups. Possible beneficial effects for people with dementia who attend sessions as planned are offset by raised anxiety and stress in their carers. The reasons for these discrepant outcomes need to be explored further, and may necessitate reappraisal of the movement towards joint interventions. TRIAL REGISTRATION: ISRCTN Registry ISRCTN42430123.

BACKGROUND: Admission to the neonatal intensive care unit (NICU) is stressful for parents. Nurses often focus on maternal well-being and fail to acknowledge the stress of fathers. Research on fathers' psychological stress is limited. PURPOSE: A systematic review of the literature was completed to examine the extent of psychological stress and types of stressors in fathers with infants admitted to the NICU. METHODS/SEARCH STRATEGY: A search of Ovid MEDLINE, Cochrane Library, PsycINFO, CINAHL, and EMBASE was conducted to identify descriptive and observational studies reporting father-specific stress in the NICU. Studies using observational and descriptive designs, published in English, and reporting father-specific stress outcomes during a NICU admission were eligible for inclusion. Strengthening the Reporting of Observational Studies in Epidemiology guidelines were used for quality assessment. RESULTS: Fifteen studies met inclusion criteria. Fathers find the NICU environment stressful and are more stressed than fathers of full-term, healthy infants. Parental role alteration, infant appearance, NICU environment, and staff communication are stressors. IMPLICATIONS FOR PRACTICE/RESEARCH: By recognizing the extent and types of psychological stress in fathers, nurses can provide better support for fathers in their new role. Younger fathers and those with very low birth-weight premature infants may need additional support and resources. Future research on fathers' stress should include larger sample sizes, diverse populations, and tool development and evaluation.

The properties of a human monoclonal antibody to the thyrotropin receptor (TSHR) (M22) with the characteristics of patient sera thyroid stimulating autoantibodies is described. Similar concentrations (pmol/L) of M22 Fab and porcine TSH had similar stimulating effects on cyclic adenosine monophosphate (cAMP) production in TSHR-transfected Chinese hamster ovary cells whereas higher doses of intact M22 immunoglobulin G (IgG) were required to cause the same level of stimulation. Patient sera containing TSHR autoantibodies with TSH antagonist (blocking) activity inhibited M22 Fab and IgG stimulation in a similar way to their ability to block TSH stimulation. Thyroid-stimulating monoclonal antibodies (TSmAbs) produced in mice inhibited 125I-TSH binding and 125I-M22 Fab binding to the TSHR but the mouse TSmAbs were less effective inhibitors than M22. These competition studies emphasized the close relationship between the binding sites on the TSHR for TSH, TSHR autoantibodies with TSH agonist activity, and TSHR autoantibodies with TSH antagonist activity. Recombinant M22 Fab could be produced in Escherichia coli and the recombinant and hybridoma produced Fabs were similarly active in terms of inhibition of TSH binding and cAMP stimulation. The crystal structure of M22 Fab was determined to 1.65 A resolution and is that of a standard Fab although the hypervariable region of the heavy chain protrudes further from the framework than the hypervariable region of the light chain. The M22 antigen binding site is rich in aromatic residues and its surface is dominated by acidic patches on one side and basic patches on the other in agreement with an important role for charge-charge interactions in the TSHR-autoantibody interaction.

The contributions of micro RNAs (miRNAs) to rheumatoid arthritis (RA) are beginning to be uncovered during the last decade. Many studies in efforts to use miRNAs as biomarkers in disease diagnosis, prognosis, and treatment are ongoing.We conducted a systematic literature review to reveal the role of miRNAs in the pathogenesis of RA in order to inform future research.We analyzed all the literature which is searched by keywords "microRNA" and "arthritis" in PubMed from December 2007 to June 2015, and the references cited by the articles searched were also considered.Relevant literature focusing on the field of miRNAs and RA was identified. The searching process was conducted by 5 independent investigators. The experts in the field of miRNAs and Rheumatology were involved in the process of analyzing.Relevant literature was analyzed according to the objective of this review and the availability of full text.The crucial role of miRNAs in maintaining immune and inflammatory responses is revealed. In addition, it is now clear that miRNAs are implicated in the development of RA synovial phenotype including synovial hyperplasia and joint destruction. Intriguingly, the biomedical application of several miRNAs may result in the effects of "double-edged sword." Moreover, there appears to have a feedback loop for expression of some miRNAs related to disease activity in inflammatory milieu of rheumatoid joint.This review underscores the potential importance of miRNAs to diagnosis, prognosis, and treatment of RA. Further investigations are required to identify the unique miRNAs signatures in RA and characterize the mechanisms mediated by miRNAs in the pathology of RA.

Thyrotrophin receptor antibodies (TRAb) exist as stimulating or blocking antibodies in the serum (neutral TRAb have been identified recently). The clinical features of GD occur when stimulating TRAb predominate. But the relationship of TRAb to clinical phenotype and outcome is not clear when current assay methods are used. Therefore no consensus exists about its utility in diagnosing and predicting outcome in GD. The most commonly used TRAb assays, measure thyroid binding inhibiting immunoglobulins (TBII or "receptor assays") and don't differentiate between stimulating and blocking antibodies. However, the more expensive, technically demanding and less freely available "biological assays" differentiate between them by their ability to stimulate cyclic AMP or failure to do so. Failure to differentiate between TRAb types and its heterogeneous molecular and functional properties has limited TBII use to GD diagnosis and differentiating from other forms of thyrotoxicosis. The current 2nd-3rd generation receptor assays are highly sensitive and specific when used for this purpose. TRAb assays should also be done in appropriate pregnant women. Current data do not support its use in outcome prediction as there is a significant variability of assay methodology, population characteristics and study design in published data, resulting in a lack of consensus.

Multiparous Holstein cows ( n = 45) were assigned at calving to one of four diets arranged in a 2 2 factorial design. The two main factors were dietary concentration (dry matter basis) of 1 ) degradable intake protein (11.1 or 15.7%) and 2 ) supplemental fat (Ca salts of long-chain fatty acids; 0 or 2.2%). Soybean meal and urea were replaced with less degradable protein meals (corn gluten meal, meat and bone meal, fish meal, and blood meal). During the first 9 wk postpartum, cows fed diets containing the greater concentration of highly degradable protein demonstrated less follicular development on their ovaries, were delayed in their first luteal activity postpartum (25.2 vs. 38.6 d), accumulated less luteal tissue (<15 vs. >70 mm), and had lower plasma progesterone accumulated over time. The supplementation of Ca salts of long-chain fatty acids to the 15.7% degradable protein diet doubled the number of corpora lutea, reduced time to first rise in progesterone by 6 d, doubled the number of normal luteal phases, and restored the pattern of accumulated plasma progesterone concentrations to a pattern that was similar to that induced by other diets. Cows were synchronized to estrus and inseminated at approximately 65 d postpartum. Pregnancy rate was increased from 52.3 to 86.4% when fat was supplemented. Cows fed fat tended to have more corpora lutea and a larger corpus luteum and accumulated more plasma progesterone than did cows not fed fat. Diets containing excess degradable protein or Ca salts of long-chain fatty acids influenced ovarian structures and reproductive performance.

The results of a study looking into the association between thyroid status and depression in the postpartum period were reanalysed to explore the psychometric properties of the rating scales employed. The performance of the Edinburgh Postnatal Depression Scale was found to be superior to that of the Hospital Anxiety and Depression Scale in identifying RDC-defined depression, and on a par with the observer-rated Hamilton Rating Scale for Depression, which it also matched for sensitivity to change in mood state over time. The anxiety subscale of the Hospital Anxiety and Depression Scale performed well, reflecting the fact that anxiety represents a prominent symptom in postnatal depression.

CONTEXT: Sequential conversion of Hashimoto's thyroiditis (HT) to Graves' disease (GD) is uncommon. Distinct immune paradigms, paucity of functioning tissue in long-standing HT, and infrequent conversion of blocking (TBAb) to stimulating (TSAb) thyrotrophin receptor antibody (TRAb) may account for this. Molecular and crystal structure analysis helps delineate TSH receptor (TSHR)/TRAb interactions in detail. Such 'fingerprinting' helps determine the behaviour and characteristics of TRAb in longitudinal studies. PATIENT: An 80-year-old woman taking thyroxine for long-standing HT became hyperthyroid. This persisted despite thyroxine withdrawal - free T3 was 7·3 pmol/l (2·6-5·7) and TSH < 0·01 mU/l (0·2-4·5) and TRAb highly positive. She had a goitre (ultrasound - HT), pretibial myxoedema, with mild inactive Graves' orbitopathy. She had RAI treatment and is on thyroxine replacement. MEASUREMENTS AND RESULTS: Blood samples at presentation (A) and 1 year (B) showed high TSAb and TPOAb activity but no TBAb. Experiments involving TSHR mutations confirmed that (i) TRAb had stable characteristics over 1 year; (ii) TSHR mutation R255D caused complete inhibition and (iii) R109A caused marked reduction of cAMP production by M22 (TSHR-stimulating human monoclonal antibody) and A and B; (iv) mutations R80A, E107A and K129A while affecting M22 had little effect on A and B. CONCLUSIONS: The reasons for an immunological paradigm shift in this elderly woman remain speculative. We believe that de-novo TSAb synthesis occurred converting her long-standing HT to GD although the mechanisms responsible remain unexplained. TRAb analysis confirmed stable autoantibody characteristics over 1 year and variable effects of TSHR mutations on TRAb and M22 function.

Involving people in health research is increasingly recognised as being important to make sure that research is focused more on the needs of people who use health services. At present, ideas about what should be researched most often comes from researchers and/or health professionals like doctors and nurses rather than people with a lived experience of mental illness. In this study, we will talk with this group of people from across Wales to explore what they think research into their health services should focus on. The findings from this work will help to influence the work of the National Centre for Mental Health Research Partnership Group; as well as` researchers and health professionals and others who concentrate on mental health research. The Research group is a partnership between people with a lived experience of mental ill health and professionals with an interest in mental ill health. The group plan to take forward the ideas that came from this research and some of the ideas have already been used to increase funding in the area of mental health research. Background This paper is the result of continued collaboration between members of the Service User and Carer Research Partnership, based in Wales and supported by the National Centre for Mental Health, Health and Care Research Wales, and Hafal. The aim of this study was to explore the research priorities of people with experience of mental health services which include people with a lived experience of mental ill health, their carers, and professionals. Method A nominal group technique was used to gather data. A one-day workshop ‘Getting Involved in Research: Priority Setting’ was held to gather the ideas and suggestions for research priorities from people who have experience of mental health services. Results Twenty-five participants attended the workshop. 5 were mental health professionals, 20 had a lived experience of mental ill health, (of which 3 were also carers). 11 were male and 14 were female. 120 research ideas were generated across 6 ‘Ideas Generating Workstations’. Participants took part in a 3 stage vote to narrow down the ideas to 2 main research priorities. Conclusion The two main research priority areas that were identified:

BACKGROUND AND OBJECTIVES: The value and practice of thyroid radionuclide imaging in the diagnosis and management of hyperthyroidism is unsettled. Our objectives were to determine the influence of thyroid uptake and scintigraphy on the diagnosis of hyperthyroidism and the prediction of outcome following radioiodine therapy. PATIENTS AND DESIGN: We reviewed records and scintigraphic studies on 881 hyperthyroid patients carried out between 2000 and 2007. The agreement between the clinical and scintigraphic diagnosis was evaluated by kappa statistics. We determined the relationship between 4-h (123)I uptake and the outcome of (131)I treatment in 626 patients. A multiple logistic regression model was used to determine variables influencing treatment outcome in 1 year. RESULTS: The diagnostic categories were Graves' disease (GD, n = 383), toxic multinodular goitre (n = 253), solitary toxic nodule (n = 164) and Graves' disease coexisting with nodules (n = 81). The mean age of the patients was 58 +/- 17, (M:F 160:721). There was good agreement between clinical and scintigraph diagnosis (K = 0.60, 95% CI 0.57-0.64, P < 0.001); and they were correctly matched in 74%; mismatched in 6% and indeterminate in 20% of patients. Treatment outcome was not associated with scintigraph diagnosis (P = 0.98) or radioiodine uptake at 4 h (P = 0.2). The use of antithyroid medications before treatment predicted treatment failure (odds ratio 2.0, 95% CI 1.2-3.6, P = 0.01). CONCLUSION: Thyroid scintigraphy and uptake studies did not influence diagnosis or treatment outcomes in most cases of hyperthyroidism. Our findings in this retrospective study do not justify their routine use. Selective scanning will reduce cost and exposure to radioisotopes without compromising diagnostic accuracy or treatment outcomes.

Nine-hundred-and-one women presenting in an antenatal clinic at the 60th week of pregnancy were tested for antithyroid antibodies. A group of 113 antibody-positive women and 108 antibody-negative age-matched controls were HLA typed and followed prospectively at 6-weekly intervals through pregnancy and for 12 months postpartum. Forty-five of the women developed biochemical evidence of postpartum thyroid dysfunction (PPTD) of whom 36 were antibody positive. Compared with a local control population (n = 600), and using multiplex analysis, there was a significant increase in the combinations HLA B8, DR3 and HLA A1, B8, DR3 from 22.5% to 40.0% (P less than 0.02) and from 18.6% to 35.6% (P less than 0.01) respectively in the women who developed PPTD. The well-recognized association of these haplotypes with other organ-specific autoimmune diseases provides further support for autoimmune events being implicated in the development of PPTD.

In view of the rising trend in caesarean section rates all over the world and women requesting caesarean section without any medical indication, we conducted a questionnaire survey to assess the opinion of clinicians in the field of obstetrics to assess their views regarding this issue. We found that clinicians agree that the caesarean section rates are increasing and most of them hold the media and women responsible for this rising trend. However, in situations where no definite medical indication was evident, most of the clinicians favoured caesarean section. The findings of this study suggest that there is a need for change in the attitude of clinicians before attempting to educate women regarding the caesarean section for non-medical reasons.

BACKGROUND: Falls in hospital account for almost two-fifths of the patient safety incidents reported to the National Reporting and Learning System in U.K. Studies have suggested an increased incidence of falls in single-bedded hospitals. OBJECTIVE: To compare the outcome of in-patient falls occurring in units with 100% single rooms (SRs) and multi-bedded wards (M-BWs). SAMPLING DESIGN AND METHODS: An observational study. Retrospective standard incident reporting data (DATIX) on in-patient falls and associated injury were obtained from both sites over 18 months each. There was no change in demographics, size and characteristics of population except change in the geography of new hospitals. RESULTS: The total number of in-patient fall incidents reported over the 3 years was 1,749. The mean age of patients on M-BW and SR sites was 81.0 ± 2.4 (51.3% females) and 80.3 ± 10.3 (50.7% females), respectively. The mean incidence of falls/1,000 patient-bed days on M-BW and SR sites was 5.44 ± 4.76 and 15.82 ± 19.56, respectively (P < 0.01). Overall fracture incidence/1,000 patient-bed days on M-BW and SR sites was 0.07 ± 0.48 and 0.36 ± 1.52 (P < 0.01), respectively. The hip fracture incidence/1,000 patient-bed days on M-BW and SR sites was 0.04 ± 0.38 and 0.15 ± 1.00 (P < 0.01), respectively. One-year mortality from the date of first incident fall was lower in M-BWs (41.1%) compared with SRs (47.1%), but this is not significant (P = 0.12). CONCLUSION: This observational study shows a significantly increased incidence of falls and fracture in a hospital design with SRs compared with a multi-bedded facility. Consideration should be given to increased incidence of falls and falls-related injury in SRs when deciding on the percentage of single-room provision in new hospitals to admit frail older adults.

Autoimmune thyroid disease is the predominant form of thyroid dysfunction in the developed world. Although its precise cause is currently unclear, principles of management have been established. There is a vigorous debate about the management of the increasingly commonly recognised subclinical forms of thyroid dysfunction despite recent recommendations. Nodular thyroid disease and thyroid carcinoma have received wide attention. The effects of drugs and pregnancy on thyroid function have also been investigated widely. This short review attempts to give an overview and clarify the current management of common thyroid disorders.

Amyloid-related imaging abnormalities (ARIA), thought to reflect immune responses to vascular amyloid, have been detected in several amyloid-modifying therapy trials for Alzheimer's disease (AD). We report a case of ARIA developing spontaneously during the course of Presenilin 1 (PSEN1)-associated familial AD (FAD), in an APOE4 homozygous patient. Severe cerebral amyloid angiopathy with associated inflammation was subsequently found at autopsy. Recognition that ARIA may arise spontaneously during FAD and of the potential risk factors for its development are important observations given the recent launch of amyloid-modifying therapy trials for FAD.

OBJECTIVE: During the COVID-19 pandemic the continuation or cessation of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) has been contentious. Mechanisms have been proposed for both beneficial and detrimental effects. Recent studies have focused on mortality with no literature having examined length of hospital stay. The aim of this study was to determine the influence of ACEi and ARBs on COVID-19 mortality and length of hospital stay. METHODS: COPE (COVID-19 in Older People) is a multicenter observational study including adults of all ages admitted with either laboratory or clinically confirmed COVID-19. Routinely generated hospital data were collected. Primary outcome: mortality; secondary outcomes: Day-7 mortality and length of hospital stay. A mixed-effects multivariable Cox's proportional baseline hazards model and logistic equivalent were used. RESULTS: 1371 patients were included from eleven centres between 27th February to 25th April 2020. Median age was 74 years [IQR 61-83]. 28.6% of patients were taking an ACEi or ARB. There was no effect of ACEi or ARB on inpatient mortality (aHR = 0.85, 95%CI 0.65-1.11). For those prescribed an ACEi or ARB, hospital stay was significantly reduced (aHR = 1.25, 95%CI 1.02-1.54, p = 0.03) and in those with hypertension the effect was stronger (aHR = 1.39, 95%CI 1.09-1.77, p = 0.007). CONCLUSIONS: Patients and clinicians can be reassured that prescription of an ACEi or ARB at the time of COVID-19 diagnosis is not harmful. The benefit of prescription of an ACEi or ARB in reducing hospital stay is a new finding.