Pan-European study of genotypes and phenotypes in the Arabidopsis relative Cardamine hirsuta reveals how adaptation, demography, and development shape diversity patterns.

We study natural DNA polymorphisms and associated phenotypes in the Arabidopsis relative Cardamine hirsuta. We observed strong genetic differentiation among several ancestry groups and broader distribution of Iberian relict strains in European C. hirsuta compared to Arabidopsis. We found synchronization between vegetative and reproductive development and a pervasive role for heterochronic pathways in shaping C. hirsuta natural variation. A single, fast-cycling ChFRIGIDA allele evolved adaptively allowing range expansion from glacial refugia, unlike Arabidopsis where multiple FRIGIDA haplotypes were involved. The Azores islands, where Arabidopsis is scarce, are a hotspot for C. hirsuta diversity. We identified a quantitative trait locus (QTL) in the heterochronic SPL9 transcription factor as a determinant of an Azorean morphotype. This QTL shows evidence for positive selection, and its distribution mirrors a climate gradient that broadly shaped the Azorean flora. Overall, we establish a framework to explore how the interplay of adaptation, demography, and development shaped diversity patterns of 2 related plant species.

Proteomics Defines Plasma Biomarkers for the Early Diagnosis of Biliary Atresia.

Early diagnosis of biliary atresia (BA) is crucial for improving the chances of survival and preserving the liver function of pediatric patients with BA. Herein, we performed proteomics analysis using data-independent acquisition (DIA) and parallel reaction monitoring (PRM) to explore potential biomarkers for the early diagnosis of BA compared to other non-BA jaundice cases. Consequently, we detected and validated differential protein expression in the plasma of patients with BA compared to the plasma of patients with intrahepatic cholestasis. Bioinformatics analysis revealed the enriched biological processes characteristic of BA by identifying the differential expression of specific proteins. Signaling pathway analysis revealed changes in the expression levels of proteins associated with an alteration in immunoglobulin levels, which is indicative of immune dysfunction in BA. The combination of polymeric immunoglobulin receptor expression and immunoglobulin lambda variable chain (IGL c2225_light_IGLV1-47_IGLJ2), as revealed via machine learning, provided a useful early diagnostic model for BA, with a sensitivity of 0.8, specificity of 1, accuracy of 0.89, and area under the curve value of 0.944. Thus, our study identified a possible effective plasma biomarker for the early diagnosis of BA and could help elucidate the underlying mechanisms of BA.

The incidence of postoperative periprosthetic femoral fracture following total hip replacement: An analysis of UK National Joint Registry and Hospital Episodes statistics data.

BACKGROUND: Postoperative periprosthetic femoral fracture (POPFF) after total hip replacement (THR) requires complex surgery and is associated with a high morbidity, mortality, and cost. Although the United Kingdom based National Joint Registry (NJR) captures over 95% of THRs treated with revision, before June 2023 it did not capture POPFF treated with fixation. We aimed to estimate the incidence and epidemiology of POPFF treated with either surgery in England. METHODS AND FINDINGS: We performed a retrospective analysis of a mandatory, prospective database (NJR) linked to Hospital Episode Statistics (HES). All linkable primary THRs between 01/01/2004 and 31/12/2020 were included. Revision or fixation of POPFF were identified using a combination of procedural and diagnosis codes. We identified 809,832 THRs representing 5,542,332 prosthesis years at risk. A total of 5,100 POPFF were identified that had been surgically treated by revision, fixation, or both, and 2,831 of these fractures were treated with fixation alone, meaning 56% were not represented with revision data alone. The incidence of POPFF needing surgery was 0.92 (95% CI 0.90, 0.95) per 1,000 prostheses years. This incidence was higher in patients over the age of 70 at the time of primary THR (1.31 [95% CI 1.26, 1.35] per 1,000 prostheses years) and for patients who underwent THR for hip fracture (2.19 [95% CI 1.97, 2.42] per 1,000 prostheses years). This incidence appears to be increasing year on year. The cumulative probability of sustaining a POPFF within 10 years of THR was 1% and over 15% of patients died within 1 year of surgery for a POPFF. CONCLUSIONS: To date, the incidence of POPFF may have been underestimated with over 50% of cases missed if the case identification in this study is correct. After including these cases, we observed that POPFF is the largest reason for major reoperation following THR and patients sustaining these injuries have a high risk of death. The prevention and treatment of POPFF and requires further resource allocation and research.

Sequence of the supernumerary B chromosome of maize provides insight into its drive mechanism and evolution.

B chromosomes are enigmatic elements in thousands of plant and animal genomes that persist in populations despite being nonessential. They circumvent the laws of Mendelian inheritance but the molecular mechanisms underlying this behavior remain unknown. Here we present the sequence, annotation, and analysis of the maize B chromosome providing insight into its drive mechanism. The sequence assembly reveals detailed locations of the elements involved with the cis and trans functions of its drive mechanism, consisting of nondisjunction at the second pollen mitosis and preferential fertilization of the egg by the B-containing sperm. We identified 758 protein-coding genes in 125.9 Mb of B chromosome sequence, of which at least 88 are expressed. Our results demonstrate that transposable elements in the B chromosome are shared with the standard A chromosome set but multiple lines of evidence fail to detect a syntenic genic region in the A chromosomes, suggesting a distant origin. The current gene content is a result of continuous transfer from the A chromosomal complement over an extended evolutionary time with subsequent degradation but with selection for maintenance of this nonvital chromosome.

Systematic Review and Meta-Analysis of Studies Comparing the Rate of Post-operative Periprosthetic Fracture Following Hip Arthroplasty With a Polished Taper Slip versus Composite Beam Stem.

BACKGROUND: We compared the incidence of postoperative periprosthetic femoral fractures (POPFF) following hip arthroplasty with either a cemented polished taper slip (PTS) stem or a cemented composite beam (CB) stem in comparative studies. METHODS: A systematic review of comparative studies, written in English and published in peer-reviewed journals since the year 2000, was conducted. Study quality was assessed using the Newcastle-Ottawa scale.The overall study qualities were good. There were 913,021 patients from 18 cohorts included in the meta-analysis. There were 294,540 patients who received a CB stem and 618,481 received a PTS stem. Cohorts were classified as high- or low-risk for POPFF based on patient risk factors. A metanalysis was performed using a random effects model, and the relative incidence with 95% confidence intervals (CIs) was reported. RESULTS: The patients at low risk of POPFF had an incidence rate ratio of 3.14 (CI: 2.48, 3.98) for the PTS group versus the CB group. Whereas, the patients at high risk of POPFF had an incidence rate ratio of 9.87 (CI: 3.63, 26.80) for the PTS group versus the CB group. CONCLUSIONS: The risk of POPFF is lower when hip arthroplasty was performed using a CB stem versus a PTS stem. This protective effect was greatest in patients who had a higher risk of POPFF. Surgeons should consider the effect of cemented stem choice on the risk of subsequent periprosthetic femur fracture, particularly in frail or elderly patients who are at a higher risk of postoperative periprosthetic femoral fracture.

CD177+ cells produce neutrophil extracellular traps that promote biliary atresia.

BACKGROUND & AIMS: We have previously reported on the potential pathogenic role of neutrophils in biliary atresia (BA). Herein, we aimed to delineate the role of CD177+ neutrophils in the pathogenesis of BA. METHODS: Immune cells from the livers of mice with rhesus rotavirus-induced BA were analysed. Single-cell RNA-sequencing was performed to specifically analyse Gr-1+ (Ly6C/Ly6G+) cells in the liver. Gene expression profiles of CD177+ cells were analysed using the Smart-Seq RNA-sequencing method, and the pathogenesis of BA was examined in Cd177-/- mice. Neutrophil extracellular trap (NET) inhibitors were used to determine the role of CD177+ cell-derived NETs in BA-associated bile duct damage, and a pilot clinical study evaluated the potential effects of N-acetylcysteine on NET release in BA. RESULTS: Increased levels of Gr-1+ cells were observed in the livers of mice with rhesus rotavirus-induced BA. RNA-sequencing analysis revealed that CD177+ cells were the main population of Gr-1+ cells and expressed elevated levels of both interferon-stimulated and neutrophil degranulation genes. Cd177-/- BALB/c mice exhibited delayed disease onset and reduced morbidity and mortality. High numbers of mitochondria were detected in CD177+ cells derived from mice with BA; these cells were associated with increased levels of reactive oxygen species and increased NET formation, which induced the apoptosis of biliary epithelial cells in cocultures. In a pilot clinical study, the administration of N-acetylcysteine to patients with BA reduced CD177+ cell numbers and reactive oxygen species levels, indicating a potential beneficial effect. CONCLUSIONS: Our data indicate that CD177+ cells play an important role in the initiation of BA pathogenesis via NET formation. CLINICAL TRIAL REGISTRATION: The pilot study of N-acetylcysteine treatment in patients with BA was registered on the Chinese Clinical Trial Registry (ChiCTR2000040505). LAY SUMMARY: Neutrophils (a type of innate immune cell, i.e. an immune cell that doesn't target a specific antigen) are thought to play a role in the development of biliary atresia (a rare but potentially lethal condition of the bile ducts that occurs in infants). Herein, we found that neutrophils expressing a particular protein (CD177) played an important role in bile duct damage by releasing a special structure (NET) that can trap and kill pathogens but that can also cause severe tissue damage. A pilot study in patients with biliary atresia showed that inhibiting NETs could have a beneficial effect.

Mortality After Postoperative Periprosthetic Fracture of the Femur After Hip Arthroplasty in the Last Decade: Meta-Analysis of 35 Cohort Studies Including 4841 Patients.

BACKGROUND: Postoperative periprosthetic fracture of the femur (POPFF) is associated with increased mortality. There is a lack of general estimates of mortality after POPFF and a need for higher-level evidence in this area. The aim of this study was to estimate mortality after POPFF using data reported in cohort studies from the last decade. METHODS: Literature search was conducted using Medline and Embase. The primary outcome was all-cause mortality during time as an inpatient, within 30 days, within 90 days, and within one year of POPFF. Mortality (95% confidence interval [CI]) was estimated using metaregression. RESULTS: A total of 4841 patients from 35 cohort studies were included. Study quality was generally low. The weighted mean follow-up was 2.3 years, and the most common POPFF was Vancouver B. The pooled mortality as an inpatient was 2.4% (95% CI 1.6% to 3.4%). The pooled mortality within 30 days was 3.3% (95% CI 2.0% to 5.0%). The pooled mortality within 90 days was 4.8% (95% CI 3.6% to 6.1%). The pooled mortality within one year was 13.4% (95% CI 11.9% to 14.8%). Mortality after POPFF was like that of neck of femur fracture up to 30 days, but better at one year. CONCLUSION: Mortality is like that experienced by patients after neck of femur fracture up to 30 days, but better at one year, which may represent the lower underlying risk of death in the POPFF cohort. These results may form the basis for evaluation of services treating POPFF in the future.

Down-regulation of STAT3 enhanced chemokine expression and neutrophil recruitment in biliary atresia.

Biliary atresia (BA) is an immune-related disorder and signal transducer and activator of transcription 3 (STAT3) is a key signalling molecule in inflammation. The present study was designed to clarify the function of STAT3 in BA. STAT3 expression was examined in patients and a mouse BA model in which STAT3 levels were further altered with a specific inhibitor or activator. Neutrophil accumulation and the levels of the neutrophil chemoattractants (C-X-C motif) ligand 1 (CXCL1) and IL-8 were determined. The effects of STAT3 inhibition on IL-8 expression were examined in human biliary epithelial cell (BEC) cultures. Functional changes in liver STAT3+ neutrophils in the mouse model were analysed with 10× single cell RNA-seq methods. Results showed STAT3 and p-STAT3 expression was reduced in BA liver tissue compared with control samples. Administration of a STAT3 inhibitor increased jaundice and mortality and reduced body weight in BA mice. In contrast, the STAT3 activator ameliorated BA symptoms. Extensive neutrophil accumulation together with CXCL1 up-regulation, both of which were suppressed by an anti-CXCL1 antibody, were observed in the STAT3 inhibitor-treated group. Recombinant IL-8 administration increased disease severity in BA mice, and the STAT3 activator had the reverse effect. Inhibiting STAT3 increased apoptosis of human BECs together with up-regulated IL-8 expression. RNA-seq analysis revealed reduced the numbers of STAT3 expressing neutrophil in BA which was accompanied by marked enhanced interferon-related antiviral activities. In conclusion, STAT3 reduction, enhanced IL-8 and CXCL1 expression and promoted the accumulation of interferon-responsive neutrophils resulting in BEC damage in BA.

The Role of Neonatal Gr-1+ Myeloid Cells in a Murine Model of Rhesus-Rotavirus-Induced Biliary Atresia.

Activation of innate immunity together with cholangiocyte damage occurs in biliary atresia (BA). However, detailed information on the inflammatory cells involved is lacking. This study investigates both the pathophysiology of CD11b+Gr-1+ cells in a mouse model of BA and their presence in BA patients. CD11b+Gr-1+ cells were targeted by an anti-Ly6G antibody in murine BA induced by inoculation with rhesus rotavirus. Expression of the Ly6G homolog CD177+ was examined in biopsies from BA patients. The symptoms of BA were ameliorated, and survival was prolonged in those mice receiving 5 to 10 µg of antibody per mouse every 3 days for four times compared with the mice treated with virus alone. However, the mice later developed chronic BA with persistent low body weight and jaundice. Hepatic inflammatory cells were reduced compared with acute BA. Blockade of extrahepatic bile ducts occurred, whereas intrahepatic ductules were partially preserved, and a progressive increase in liver fibrosis was observed. High levels of CD11b+Gr-1+ cells were present in these mice. The administration of an anti-Ly6G antibody again in those chronic BA mice reduced jaundice and restored body weight. In BA patients CD177+ cells were highly expressed in the liver. Our data suggest that the chronic mouse BA model shares key characteristics with clinical BA and indicates the importance of CD11b+Gr-1+ cells in the initiation and progression of BA.

Risk Factors for Intraoperative Periprosthetic Femoral Fractures During Primary Total Hip Arthroplasty. An Analysis From the National Joint Registry for England and Wales and the Isle of Man.

BACKGROUND: The aim of this study is to estimate risk factors for intraoperative periprosthetic femoral fractures (IOPFF) and each anatomic subtype (calcar crack, trochanteric fracture, femoral shaft fracture) during primary total hip arthroplasty. METHODS: This retrospective cohort study included 793,823 primary total hip arthroplasties between 2004 and 2016. Multivariable regression modeling was used to estimate relative risk of patient, surgical, and implant factors for any IOPFF and for all anatomic subtypes of IOPFF. Clinically important interactions were assessed using multivariable regression. RESULTS: Patient factors significantly increasing the risk of fracture were female gender, American Society of Anesthesiologists grade 3 to 5, and preoperative diagnosis including avascular necrosis of the hip, previous trauma, inflammatory disease, pediatric disease, and previous infection. Overall risk of IOPFF associated with age was greatest in patients below 50 years and above 80 years. Risk of any fracture reduced with computer-guided surgery and in non-National Health Service hospitals. Nonposterior approaches increased the risk of shaft and trochanteric fracture only. Cementless implants significantly increased the risk of only calcar cracks and shaft fractures and not trochanteric fractures. CONCLUSION: Fracture risk increases in patients younger than 50 and older than 80 years, females, American Society of Anesthesiologists grade 3 to 5, and indications other than primary osteoarthritis. Large cumulative reduction in IOPFF risk may occur with use of cemented implants, posterior approach, and computer-guided surgery. LEVEL OF EVIDENCE: Level 3b (cohort study).

Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes.

Orthologs of the yeast telomere protein Stn1 are present in plants, but other components of the Cdc13/Stn1/Ten1 (CST) complex have only been found in fungi. Here we report the identification of conserved telomere maintenance component 1 (CTC1) in plants and vertebrates. CTC1 encodes an approximately 140 kDa telomere-associated protein predicted to contain multiple OB-fold domains. Arabidopsis mutants null for CTC1 display a severe telomere deprotection phenotype accompanied by a rapid onset of developmental defects and sterility. Telomeric and subtelomeric tracts are dramatically eroded, and chromosome ends exhibit increased G overhangs, recombination, and end-to-end fusions. AtCTC1 both physically and genetically interacts with AtSTN1. Depletion of human CTC1 by RNAi triggers a DNA damage response, chromatin bridges, increased G overhangs, and sporadic telomere loss. These data indicate that CTC1 participates in telomere maintenance in diverse species and that a CST-like complex is required for telomere integrity in multicellular organisms.

Silver nanoparticle treatment ameliorates biliary atresia syndrome in rhesus rotavirus inoculated mice.

Biliary atresia (BA) is a neonatal biliary system disease closely associated with viral infection and bile duct inflammation. Silver nanoparticles (AgNps) have previously revealed antiviral and anti-inflammatory properties. In this study, we have investigated the effects of AgNps in the treatment of the Rhesus rotavirus inoculation induced BA in mice. The morphology, liver histopathology, clinical biochemistry examination, and inflammatory cells were analyzed in BA mice. Results indicated that AgNps could significantly increase the survival rate of BA mice, and reduce jaundice and weight lost and the liver enzymes and bilirubin metabolism clinical parameters were close to the normal levels. Diminished numbers of NK cells were observed by flow cytometry analysis and immunohistochemical staining. Furthermore, the viral load was reduced and transcripts for TGF-ß mRNA were augmented after AgNps treatment. Collectively, our results suggest that AgNps treatment has beneficial effects on the BA mouse model partially through upregulation of TGF-ß.

Alternative Ac/Ds transposition induces major chromosomal rearrangements in maize.

Barbara McClintock reported that the Ac/Ds transposable element system can generate major chromosomal rearrangements (MCRs), but the underlying mechanism has not been determined. Here, we identified a series of chromosome rearrangements derived from maize lines containing pairs of closely linked Ac transposable element termini. Molecular and cytogenetic analyses showed that the MCRs in these lines comprised 17 reciprocal translocations and two large inversions. The breakpoints of all 19 MCRs are delineated by Ac termini and characteristic 8-base-pair target site duplications, indicating that the MCRs were generated by precise transposition reactions involving the Ac termini of two closely linked elements. This alternative transposition mechanism may have contributed to chromosome evolution and may also occur during V(D)J recombination resulting in oncogenic translocations.

Mucosal inflammation at the respiratory interface: a zebrafish model.

Inflammatory diseases of the respiratory system such as asthma and chronic obstructive pulmonary disease are increasing globally and remain poorly understood conditions. Although attention has long focused on the activation of type 1 and type 2 helper T cells of the adaptive immune system in these diseases, it is becoming increasingly apparent that there is also a need to understand the contributions and interactions between innate immune cells and the epithelial lining of the respiratory system. Cigarette smoke predisposes the respiratory tissue to a higher incidence of inflammatory disease, and here we have used zebrafish gills as a model to study the effect of cigarette smoke on the respiratory epithelium. Zebrafish gills fulfill the same gas-exchange function as the mammalian airways and have a similar structure. Exposure to cigarette smoke extracts resulted in an increase in transcripts of the proinflammatory cytokines TNF-α, IL-1ß, and MMP9 in the gill tissue, which was at least in part mediated via NF-κB activation. Longer term exposure of fish for 6 wk to cigarette smoke extract resulted in marked structural changes to the gills with lamellar fusion and mucus cell formation, while signs of inflammation or fibrosis were absent. This shows, for the first time, that zebrafish gills are a relevant model for studying the effect of inflammatory stimuli on a respiratory epithelium, since they mimic the immunopathology involved in respiratory inflammatory diseases of humans.

Evaluating a complex model designed to increase access to high quality primary mental health care for under-served groups: a multi-method study.

BACKGROUND: Many people with mental distress are disadvantaged because care is not available or does not address their needs. In order to increase access to high quality primary mental health care for under-served groups, we created a model of care with three discrete elements: community engagement, primary care training and tailored wellbeing interventions. We have previously demonstrated the individual impact of each element of the model. Here we assess the effectiveness of the combined model in increasing access to and improving the quality of primary mental health care. We test the assumptions that access to the wellbeing interventions is increased by the presence of community engagement and primary care training; and that quality of primary mental health care is increased by the presence of community engagement and the wellbeing interventions. METHODS: We implemented the model in four under-served localities in North-West England, focusing on older people and minority ethnic populations. Using a quasi-experimental design with no-intervention comparators, we gathered a combination of quantitative and qualitative information. Quantitative information, including referral and recruitment rates for the wellbeing interventions, and practice referrals to mental health services, was analysed descriptively. Qualitative information derived from interview and focus group responses to topic guides from more than 110 participants. Framework analysis was used to generate findings from the qualitative data. RESULTS: Access to the wellbeing interventions was associated with the presence of the community engagement and the primary care training elements. Referrals to the wellbeing interventions were associated with community engagement, while recruitment was associated with primary care training. Qualitative data suggested that the mechanisms underlying these associations were increased awareness and sense of agency. The quality of primary mental health care was enhanced by information gained from our community mapping activities, and by the offer of access to the wellbeing interventions. There were variable benefits from health practitioner participation in community consultative groups. We also found that participation in the wellbeing interventions led to increased community engagement. CONCLUSIONS: We explored the interactions between elements of a multilevel intervention and identified important associations and underlying mechanisms. Further research is needed to test the generalisability of the model. TRIAL REGISTRATION: Current Controlled Trials, reference ISRCTN68572159 . Registered 25 February 2013.

Modulatory effects of adiponectin on the polarization of tumor-associated macrophages.

The plasticity of macrophages with selective functional phenotypes partially arises in respective to their microenvironment. Tumor-associated macrophages (TAMs) may promote disease progression with tumor specific manner. Here we report that in pediatric malignant soft-tissue tumors, the presence of TAMs and expression of adiponectin (APN) are heterogeneous. Both APN and TAMs had high expression in rhabdomyosarcoma, especially in the malignant subtype, alveolar rhabdomyosarcoma. To investigate the mode of action of APN on TAM activation, a murine MN/MCA1 sarcoma model was used. The Results revealed that exogenous APN had no effect on MN/MCA1 proliferation but tumor size was markedly reduced in apn(-/-) mice versus WT controls. The accumulation of TAMs in apn(-/-) mice was also reduced which correlated to downregulated serum levels of MCP-1. Likewise, TAMs in apn(-/-) mice exhibited a M1-like phenotype, characterized by increase in MHC II(high) population and M1 phenotypic markers, such as iNOS gene and serum TNF-α accompanied by a decrease in M2 markers, namely YM1 gene and serum IL-10. In addition, APN deficiency increased the number of CD4(+) T cells, CD8(+) T cells and NK cells in tumors and reduced tumor metastasis. The altered phenotype of TAMs in apn(-/-) mice was associated with a marked decrease in phospho-p38 and treatment with a p38 MAPK inhibitor significantly reduced tumor size and increased MHC II expression on TAMs in WT mice, implying p38 MAPK signaling pathway may contribute to APN-mediated TAM polarization. Collectively, our findings suggest that APN may have a potential role in regulating soft tissue sarcoma growth.

Community Engagement in a complex intervention to improve access to primary mental health care for hard-to-reach groups.

BACKGROUND: Despite the availability of effective evidence-based treatments for depression and anxiety, many 'harder-to-reach' social and patient groups experience difficulties accessing treatment. We developed a complex intervention, the AMP (Improving Access to Mental Health in Primary Care) programme, which combined community engagement (CE), tailored (individual and group) psychosocial interventions and primary care involvement. OBJECTIVES: To develop and evaluate a model for community engagement component of the complex intervention. This paper focuses on the development of relationships between stakeholders, their engagement with the issue of access to mental health and with the programme through the CE model. DESIGN: Our evaluation draws on process data, qualitative interviews and focus groups, brought together through framework analysis to evaluate the issues and challenges encountered. SETTING & PARTICIPANTS: A case study of the South Asian community project carried out in Longsight in Greater Manchester, United Kingdom. KEY FINDINGS: Complex problems require multiple local stakeholders to work in concert. Assets based approaches implicitly make demands on scarce time and resources. Community development approaches have many benefits, but perceptions of open-ended investment are a barrier. The time-limited nature of a CE intervention provides an impetus to 'do it now', allowing stakeholders to negotiate their investment over time and accommodating their wider commitments. Both tangible outcomes and recognition of process benefits were vital in maintaining involvement. CONCLUSIONS: CE interventions can play a key role in improving accessibility and acceptability by engaging patients, the public and practitioners in research and in the local service ecology.

Parameters affecting telomere-mediated chromosomal truncation in Arabidopsis.

Conversion of a double-strand break into a telomere is a dangerous, potentially lethal event. However, little is known about the mechanism and control of de novo telomere formation (DNTF). DNTF can be instigated by the insertion of a telomere repeat array (TRA) into the host genome, which seeds the formation of a new telomere, resulting in chromosome truncation. Such events are rare and concentrated at chromosome ends. Here, we introduce tetraploid Arabidopsis thaliana as a robust genetic model for DNTF. Transformation of a 2.6-kb TRA into tetraploid plants resulted in a DNTF efficiency of 56%, fivefold higher than in diploid plants and 50-fold higher than in human cells. DNTF events were recovered across the entire genome, indicating that genetic redundancy facilitates recovery of DNTF events. Although TRAs as short as 100 bp seeded new telomeres, these tracts were unstable unless they were extended above a 1-kb size threshold. Unexpectedly, DNTF efficiency increased in plants lacking telomerase, and DNTF rates were lower in plants null for Ku70 or Lig4, components of the nonhomologous end-joining repair pathway. We conclude that multiple competing pathways modulate DNTF, and that tetraploid Arabidopsis will be a powerful model for elucidating the molecular details of these processes.

Development and evaluation of culturally sensitive psychosocial interventions for under-served people in primary care.

BACKGROUND: Psychological therapy is effective for symptoms of mental distress, but many groups with high levels of mental distress face significant barriers in terms of access to care, as current interventions may not be sensitive to their needs or their understanding of mental health. There is a need to develop forms of psychological therapy that are acceptable to these groups, feasible to deliver in routine settings, and clinically and cost effective. METHODS: We developed a culturally sensitive wellbeing intervention with individual, group and sign-posting elements, and tested its feasibility and acceptability for patients from ethnic minorities and older people in an exploratory randomised trial. RESULTS: We recruited 57 patients (57% of our target) from 4 disadvantaged localities in the NW of England. The results of the exploratory trial suggest that the group receiving the wellbeing interventions improved compared to the group receiving usual care. For elders, the largest effects were on CORE-OM and PHQ-9. For ethnic minority patients, the largest effect was on PHQ-9. Qualitative data suggested that patients found the intervention acceptable, both in terms of content and delivery. CONCLUSIONS: This exploratory trial provides some evidence of the efficacy and acceptability of a wellbeing intervention for older and ethnic minority groups experiencing anxiety and depression, although challenges in recruitment and engagement remain. Evidence from our exploratory study of wellbeing interventions should inform new substantive trial designs. TRIAL REGISTRATION: Current controlled trials ISRCTN68572159.

Cemented femoral stem design and postoperative periprosthetic fracture risk following total hip arthroplasty.

Polished taper-slip (PTS) cemented stems have an excellent clinical track record and are the most common stem type used in primary total hip arthroplasty (THA) in the UK. Due to low rates of aseptic loosening, they have largely replaced more traditional composite beam (CB) cemented stems. However, there is now emerging evidence from multiple joint registries that PTS stems are associated with higher rates of postoperative periprosthetic femoral fracture (PFF) compared to their CB stem counterparts. The risk of both intraoperative and postoperative PFF remains greater with uncemented stems compared to either of these cemented stem subtypes. PFF continues to be a devastating complication following primary THA and is associated with high complication and mortality rates. Recent efforts have focused on identifying implant-related risk factors for PFF in order to guide preventative strategies, and therefore the purpose of this article is to present the current evidence on the effect of cemented femoral stem design on the risk of PFF.