Collared Cementless Femoral Components Reduce the Revision Rates in Primary Total Hip Arthroplasty Using the Direct Anterior Approach: An Australian Orthopaedic Association National Joint Replacement Registry Study.

BACKGROUND: An increased risk of periprosthetic fracture and aseptic loosening is reported when the direct anterior approach (DAA) is used for total hip arthroplasty (THA), especially with cementless implants. We assessed the rate of revision comparing collared and collarless femoral stems when using the DAA for THA. METHODS: We used data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) for primary THA for osteoarthritis inserted with the DAA between January 2015 and December 2022. There were 48,567 THAs that used the DAA (26,690 collarless cementless, 10,161 collared cementless, and 11,716 cemented). Cumulative percent revision (CPR) was calculated for all-cause revision, revision for periprosthetic femoral fractures, and aseptic femoral stem loosening. Cox proportional hazard ratios were used to compare the revision of collared and collarless cementless stems. We also compared collared cementless stems and cemented stems. RESULTS: A higher rate of all-cause revision within three months of surgery was observed with collarless compared to collared cementless implants (HR [hazard ratio]: 1.99 [95% CI (confidence interval), 1.56 to 2.54]; P < 0.001). Similarly, collarless cementless implants were associated with a greater rate of revision for fracture in the first six months (HR: 2.90 [95% CI, 1.89 to 4.45]; P < 0.001) and after 6 months (HR 10.04 [95% CI 1.38 to 73.21]; P = 0.02), as well as an increased rate of revision for aseptic loosening after two years (HR: 5.76 [95% CI, 1.81 to 18.28], P = 0.003). Collared cementless and cemented stems performed similarly. CONCLUSION: Collared stems were associated with a reduced rate of all-cause revision for cementless THA performed via the DAA. The reduction in risk may be due to protection from periprosthetic femoral fracture and aseptic loosening.

Cardiopulmonary resuscitation and basic life support guidelines for people with disability: a scoping review.

PURPOSE: To explore literature, policies or procedures available to care providers on how to deliver CPR and BLS to people with a disability, for whom the current standard guidelines are not fit for purpose. MATERIAL AND METHODS: A scoping review was conducted using four databases, namely, CINHAL, PubMed, Scopus, Medline and Google Scholar. Keywords used included, disab*, wheelchairs, cardiopulmonary, resuscitation, "basic life support", life support care, and bystander CPR. 1119 papers were retrieved and 1043 were screened following removal of 76 for duplication. 18 full text articles were reviewed and 5 met the inclusion criteria. RESULTS: The five articles were from three counties and included one case study, three expert opinion papers and one intervention study. Four of the papers advocated in favour of improved CPR and BLS guidelines and three of the papers discussed techniques and ideas for supplementation of standard CPR and BLS. CONCLUSION: The scoping review has uncovered a paucity of evidence explaining delivery of CPR and BLS for people with disability and highlights the need for further research. In the absence of further evidence, it is reasonable for educators to provide ideas and discussion about supplementing CPR and BLS for people with disability to carers.

People with disability and wheelchair users are at a high risk for premature or preventable deaths.Improved first aid responses are proposed to be a mitigating factor for premature and preventable deaths.Improved first aid responses will afford people with disability and wheelchair users the same opportunities for care and rehabilitation as people without disability.Formal and informal carers do not currently have prescriptive guidelines to improve their knowledge on responding to emergency events for people with disabilities.Development of improved guidelines is recommended to reduce fear and anxiety for formal and informal carers whilst also increasing their confidence to respond to emergency situations.

Skeletal stability of inter-molar mandibular distraction osteogenesis in growing patients.

INTRODUCTION: The aim of this retrospective study was to firstly assess the stability of surgical advancement using inter-molar mandibular distraction osteogenesis (IMDO) and secondly to assess the impact of the surgical intervention on subsequent mandibular growth in patients with residual growth. METHODS: The sample consisted of 17 (13F and 4M) consecutively treated patients who underwent IMDO and orthodontic treatment. Cephalometric analysis was performed at three time points: T0 prior to distraction; T1 post-distraction immediately prior to surgical removal of the distractors; and T2 following completion of orthodontic treatment when the final lateral cephalogram was taken (0.86-4.37 years after T1). Statistical comparison of lower facial height, mandibular length, growth, condylar position and anterior mandibular rotation was performed. RESULTS: No association was found between changes in any of the cephalometric measurements and the length of the follow-up interval. The anterior mandibular segment underwent clockwise rotation during distraction and recovered to near its pre-distraction angulation during remodelling. An increase in the lower facial height of 1.88 ± 2.81mm also occurred during distraction (T0-T1) and was maintained during the follow-up period (T1-T2). Post-distraction (T1-T2) growth of lower facial height (p value 0.872) and mandibular length (p value 0.251) showed no association when compared to an untreated control group and an overall reduction in growth was reported. CONCLUSIONS: IMDO was highly stable within a follow-up period of 2.3 ± 0.9 years; however, growth appears to have been inhibited.

Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing.

The Human Silencing Hub (HuSH) complex is composed of TASOR, MPP8, and PPHLN1 subunits and serves as a conserved protein complex responsible for silencing transposable elements in vertebrate animals. Despite its importance, the regulatory mechanisms and recruitment dynamics governing this complex remain poorly understood. In this study, we have identified a second HuSH complex, termed HuSH2, centered around TASOR2, a paralog of the core TASOR protein in HuSH. Our findings indicate that every subunit in both HuSH and HuSH2 has an important role in achieving precise genomic localization to distinct, non-overlapping genomic loci. We utilized in silico protein structure prediction to simulate the interactions between MPP8 and both TASOR paralogs. Drawing on the insights gained from these predictions, we implemented amino acid substitutions that interfered with the binding of MPP8 to each HuSH complex. Leveraging these MPP8 transgenes and other constructs, we identified an important role played by the relative quantities of HuSH complexes in controlling the activity of LINE-1 elements. Furthermore, our results suggest that dynamic changes in TASOR and TASOR2 expression enable cells to finely tune the extent of HuSH-mediated silencing. Our study provides insights into the intricate interplay between HuSH complexes, illuminating their important role in the regulation of retrotransposon silencing.

Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.

Approximately 20% of head and neck squamous cell carcinomas (HNSCCs) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided into two groups: those that display aberrant accumulation of H3K27me3 and those that maintain steady levels of H3K27me3. The former group exhibits reduced proliferation, genome instability, and heightened sensitivity to genotoxic agents like PARP1/2 inhibitors. Conversely, H3K36M HNSCC models with constant H3K27me3 levels lack these characteristics unless H3K27me3 is elevated by DNA hypomethylating agents or inhibiting H3K27me3 demethylases KDM6A/B. Mechanistically, H3K36M reduces H3K36me by directly impeding the activities of the histone methyltransferase NSD3 and the histone demethylase LSD2. Notably, aberrant H3K27me3 levels induced by H3K36M expression are not a bona fide epigenetic mark because they require continuous expression of H3K36M to be inherited. Moreover, increased sensitivity to PARP1/2 inhibitors in H3K36M HNSCC models depends solely on elevated H3K27me3 levels and diminishing BRCA1- and FANCD2-dependent DNA repair. Finally, a PARP1/2 inhibitor alone reduces tumor burden in a H3K36M HNSCC xenograft model with elevated H3K27me3, whereas in a model with consistent H3K27me3, a combination of PARP1/2 inhibitors and agents that up-regulate H3K27me3 proves to be successful. These findings underscore the crucial balance between H3K36 and H3K27 methylation in maintaining genome instability, offering new therapeutic options for patients with H3K36me-deficient tumors.

Nurse experiences of partnership nursing when caring for children with long-term conditions and their families: A qualitative systematic review.

AIM: To explore the experiences of partnership nursing among nurses when caring for children and young people with long-term conditions, and their families. BACKGROUND: Partnership nursing is promoted as a positive model of care among paediatric nurses, where shared roles and decision-making, parental participation, mutual trust and respect, communication and negotiation are valued to create positive care experiences and enhance patient outcomes. Little is known about how nurses use partnership with both the patient and the parents in this triad to deliver partnership nursing. DESIGN: A qualitative systematic review followed Joanna Briggs Institute meta-aggregation approach and has been reported according to PRISMA guidelines. METHODS: A comprehensive systematic search was conducted in seven electronic databases. Studies were assessed according to a pre-determined inclusion criteria. Qualitative findings with illustrative participant quotes were extracted from included studies and grouped into categories to inform overall synthesised findings. Methodological quality assessment was conducted. FINDINGS: A total of 5837 publications were screened, and 41 qualitative studies were included. Three overarching synthesised findings were identified: (1) Using education to promote feelings of safety and support, (2) Partnering to develop a strong therapeutic relationship and (3) Optimising communication underpinned by shared decision-making principles to deliver individualised care. CONCLUSION: Nurses demonstrated successful partnership in their practice, but focused on developing dyadic nurse-parent and dyadic nurse-child partnerships. Future practice development that creates a three-way triadic partnership may aid therapeutic relationships and shared decision-making. IMPLICATIONS FOR CLINICAL PRACTICE: Clinicians can reflect on how dyadic partnerships (focusing on the child or the parent) may exclude opportunities for coherent care. Further exploration in practice, policy and research as to how nurses determine child competency and child and parent level of engagement in triadic partnership may improve the potential of meaningful shared decision-making.

Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.

Approximately 20% of head and neck squamous cell carcinomas (HNSCC) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided into two groups: those that display aberrant accumulation of H3K27me3 and those that maintain steady levels of H3K27me3. The first group shows decreased proliferation, genome instability, and increased sensitivity to genotoxic agents, such as PARP1/2 inhibitors. In contrast, the H3K36M HNSCC models with steady H3K27me3 levels do not exhibit these characteristics unless H3K27me3 levels are elevated, either by DNA hypomethylating agents or by inhibiting the H3K27me3 demethylases KDM6A/B. Mechanistically, we found that H3K36M reduces H3K36me by directly impeding the activities of the histone methyltransferase NSD3 and the histone demethylase LSD2. Notably, we found that aberrant H3K27me3 levels induced by H3K36M expression is not a bona fide epigenetic mark in HNSCC since it requires continuous expression of H3K36M to be inherited. Moreover, increased sensitivity of H3K36M HNSCC models to PARP1/2 inhibitors solely depends on the increased H3K27me3 levels. Indeed, aberrantly high H3K27me3 levels decrease BRCA1 and FANCD2-dependent DNA repair, resulting in higher sensitivity to DNA breaks and replication stress. Finally, in support of our in vitro findings, a PARP1/2 inhibitor alone reduce tumor burden in a H3K36M HNSCC xenograft model with elevated H3K27me3, whereas in a H3K36M HNSCC xenograft model with consistent H3K27me3 levels, a combination of PARP1/2 inhibitors and agents that upregulate H3K27me3 proves to be successful. In conclusion, our findings underscore a delicate balance between H3K36 and H3K27 methylation, essential for maintaining genome stability. This equilibrium presents promising therapeutic opportunities for patients with H3K36me-deficient tumors.

A systematic review and meta-analysis of short-stay programmes for total hip and knee replacement, focusing on safety and optimal patient selection.

BACKGROUND: Short-stay joint replacement programmes are used in many countries but there has been little scrutiny of safety outcomes in the literature. We aimed to systematically review evidence on the safety of short-stay programmes versus usual care for total hip (THR) and knee replacement (KR), and optimal patient selection. METHODS: A systematic review and meta-analysis. Randomised controlled trials (RCTs) and quasi-experimental studies including a comparator group reporting on 14 safety outcomes (hospital readmissions, reoperations, blood loss, emergency department visits, infection, mortality, neurovascular injury, other complications, periprosthetic fractures, postoperative falls, venous thromboembolism, wound complications, dislocation, stiffness) within 90 days postoperatively in adults ≥ 18 years undergoing primary THR or KR were included. Secondary outcomes were associations between patient demographics or clinical characteristics and patient outcomes. Four databases were searched between January 2000 and May 2023. Risk of bias and certainty of the evidence were assessed. RESULTS: Forty-nine studies were included. Based upon low certainty RCT evidence, short-stay programmes may not reduce readmission (OR 0.95, 95% CI 0.12-7.43); blood transfusion requirements (OR 1.75, 95% CI 0.27-11.36); neurovascular injury (OR 0.31, 95% CI 0.01-7.92); other complications (OR 0.63, 95% CI 0.26-1.53); or stiffness (OR 1.04, 95% CI 0.53-2.05). For registry studies, there was no difference in readmission, infection, neurovascular injury, other complications, venous thromboembolism, or wound complications but there were reductions in mortality and dislocations. For interrupted time series studies, there was no difference in readmissions, reoperations, blood loss volume, emergency department visits, infection, mortality, or neurovascular injury; reduced odds of blood transfusion and other complications, but increased odds of periprosthetic fracture. For other observational studies, there was an increased risk of readmission, no difference in blood loss volume, infection, other complications, or wound complications, reduced odds of requiring blood transfusion, reduced mortality, and reduced venous thromboembolism. One study examined an outcome relevant to optimal patient selection; it reported comparable blood loss for short-stay male and female participants (p = 0.814). CONCLUSIONS: There is low certainty evidence that short-stay programmes for THR and KR may have non-inferior 90-day safety outcomes. There is little evidence on factors informing optimal patient selection; this remains an important knowledge gap.

Stakeholder perspectives on short-stay joint replacement programs: results from a national cross-sectional study.

BACKGROUND: The capacity to meet anticipated growth in joint replacement demand requires safe, efficient models of care. While short-stay joint replacement programs are being used internationally, they have not been widely implemented in many countries. Importantly, the critical challenges that need to be addressed ahead of large-scale program implementation remain unclear. This study aimed to investigate stakeholder perspectives on short-stay joint replacement programs, including perceived barriers and enablers to implementation and sustainability, and understand current practices in Australia. METHODS: Four key stakeholder groups were invited to participate in this national study: (1) health professionals who provide joint replacement care; (2) hospital administrators involved in joint replacement provision; (3) patients with recent joint replacement; and (4) carers of people with recent joint replacement. Data on perceived feasibility (0 (not at all feasible) - 10 (highly feasible), appeal (0 (not at all appealing) - 10 (highly appealing), current practices, and barriers and enablers were collected using visual analogue scales, multiple response option and open-ended questions, via an online platform. Descriptive analysis and free-text content analysis was undertaken. RESULTS: Data were available from 1,445 participants including 360 health professionals, 20 hospital administrators, 1,034 patients, and 31 carers. Short-stay program implementation was considered moderately feasible by health professionals (median 6, interquartile range (IQR) 3-8) and hospital administrators (median 5, IQR 5-6). Short-stay programs were moderately appealing to patients (median 7, IQR 2-9) but of little appeal to carers (median 3, IQR 1-7). Prominent implementation barriers included perceived limited appropriateness of short-stay programs, inadequate home supports, and issues around reimbursement models or program funding. Not having daily physiotherapy access and concerns about pain and mobility at home were common barriers for patients. Concern about patients' ability to manage daily activities was the most common barrier for carers. Access to post-discharge services, better funding models, improved staffing, and consistent protocols and national care standards were prominent enablers. CONCLUSIONS: This national study has uniquely captured multiple stakeholder perspectives on short-stay joint replacement programs. The findings can guide future quality improvement and implementation initiatives and the development of resources to best support patients, carers, clinicians, and hospitals.

Developing a model of neonatal nurse-controlled analgesia: A Delphi study.

AIM: To develop a nurse-led model of analgesia to manage post-operative pain in the surgical neonate. DESIGN: A four-round e-Delphi study was conducted from March to December 2022. METHODS: An e-Delphi method was used seeking a consensus of 70% or greater. Fifty-one experts were invited to join the panel. Members consisted of multi-disciplinary healthcare professionals who work in areas associated with neonatal care. In round 1, 49 statements relative to neonatal pain assessment and management were distributed to the panel. Panel members were asked to rate their level of agreeance on a Likert scale from 1 to 5 (1 = strongly disagree to 5 = strongly agree). Ratings equal to or greater than 4 represented agreement, 3 indicated uncertainty and 2 or less disagreement with the proposed statement. An opportunity for free-text responses after each statement was provided. This iterative process continued for three rounds. In the fourth and final round, the completed model of neonatal nurse-controlled analgesia was presented along with a further opportunity to provide feedback on the final version. RESULTS: Four rounds of statements and voting were required to reach consensus on a model of neonatal nurse-controlled analgesia. The model consists of criteria for use, over-arching guidelines and three separate pathways based on an individual baby's pain assessment scores, need for pain relieving interventions and time-lapsed post-surgical procedure. CONCLUSION: A comprehensive model of neonatal nurse-controlled analgesia, applicable to the Australasian context, was developed in collaboration with a group of neonatal experts. IMPACT: This study provides a multi-modal family-integrated model to manage neonatal post-operative pain. By providing nurses with increased autonomy to assess and manage acute pain, this model has the potential to not only provide a more responsive and individualized approach to alleviate discomfort, but highlights the integral role of parent partnerships in the neonatal intensive care. REPORTING METHOD: This study was reported in line with the Conducting and REporting of DElphi studies (CREDE) guidance on Delphi studies. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution was utilized for this study.

Becoming a non-resident father: Marginalised through distress, disadvantage and disempowerment.

ISSUE ADDRESSED: Becoming a non-resident father through divorce is stressful and this often results in compromised mental health and well-being. Non-resident fathers' mental well-being has been measured at very low levels which may require clinical treatment, especially when correlated with child access and family court issues. A United Nations report highlighted how non-resident fathers may be marginalised, but to date, limited literature considers the lives of non-resident fathers from their own perspective and reflecting their own voice and it has been claimed that as fathers are often absent from parenting research, this absence, they are not heard. The aim of this paper was to identify how non-resident fathers' interactions with legal and welfare services and ex-partners may result in their marginalisation and affect their mental health. METHODS: In-depth interviews with open-ended questions were conducted with 19 non-resident fathers, both long term, newly divorced or in the divorce process, so as to capture a long range view of their experiences. Thematic Analysis was used for data analysis and the generation of the themes. RESULTS: Three themes emerged from the data: (1) Becoming a non-resident father with two sub themes; (2) Being in a state of distress, with three sub-themes and (3) Managing distress and seeking help, with two sub-themes. Participants reported a lack of agency, lack of power in decision making and a lack of social and financial resources all contributing to the deterioration in their self-reported experiences of mental health. This impact was highlighted by the number of participants who undertook counselling or psychological assistance to deal with their perceived marginalisation, feeling of invisibility and disempowerment. CONCLUSIONS: The implications of marginalisation for non-resident fathers' mental health, as outlined by the participants, are discussed regarding the impact of becoming a non-resident father, legal aspects, welfare service experiences and relationship with ex-partner. The chronic stress experienced by non-resident fathers who often find themselves in a situation which is difficult to resolve without major compromises to their desired outcomes must be recognised. SO WHAT: One means of achieving better mental health for non-resident fathers is to address the impact of marginalisation and lack of agency and that court processes are resolved swiftly with a view to increasing non-resident father's agency in post-divorce decision making.

Development and Replication of Objective Measurements of Social Visual Engagement to Aid in Early Diagnosis and Assessment of Autism.

Importance: Autism spectrum disorder is a common and early-emerging neurodevelopmental condition. While 80% of parents report having had concerns for their child's development before age 2 years, many children are not diagnosed until ages 4 to 5 years or later. Objective: To develop an objective performance-based tool to aid in early diagnosis and assessment of autism in children younger than 3 years. Design, Setting, and Participants: In 2 prospective, consecutively enrolled, broad-spectrum, double-blind studies, we developed an objective eye-tracking-based index test for children aged 16 to 30 months, compared its performance with best-practice reference standard diagnosis of autism (discovery study), and then replicated findings in an independent sample (replication study). Discovery and replication studies were conducted in specialty centers for autism diagnosis and treatment. Reference standard diagnoses were made using best-practice standardized protocols by specialists blind to eye-tracking results. Eye-tracking tests were administered by staff blind to clinical results. Children were enrolled from April 27, 2013, until September 26, 2017. Data were analyzed from March 28, 2018, to January 3, 2019. Main Outcomes and Measures: Prespecified primary end points were the sensitivity and specificity of the eye-tracking-based index test compared with the reference standard. Prespecified secondary end points measured convergent validity between eye-tracking-based indices and reference standard assessments of social disability, verbal ability, and nonverbal ability. Results: Data were collected from 1089 children: 719 children (mean [SD] age, 22.4 [3.6] months) in the discovery study, and 370 children (mean [SD] age, 25.4 [6.0] months) in the replication study. In discovery, 224 (31.2%) were female and 495 (68.8%) male; in replication, 120 (32.4%) were female and 250 (67.6%) male. Based on reference standard expert clinical diagnosis, there were 386 participants (53.7%) with nonautism diagnoses and 333 (46.3%) with autism diagnoses in discovery, and 184 participants (49.7%) with nonautism diagnoses and 186 (50.3%) with autism diagnoses in replication. In the discovery study, the area under the receiver operating characteristic curve was 0.90 (95% CI, 0.88-0.92), sensitivity was 81.9% (95% CI, 77.3%-85.7%), and specificity was 89.9% (95% CI, 86.4%-92.5%). In the replication study, the area under the receiver operating characteristic curve was 0.89 (95% CI, 0.86-0.93), sensitivity was 80.6% (95% CI, 74.1%-85.7%), and specificity was 82.3% (95% CI, 76.1%-87.2%). Eye-tracking test results correlated with expert clinical assessments of children's individual levels of ability, explaining 68.6% (95% CI, 58.3%-78.6%), 63.4% (95% CI, 47.9%-79.2%), and 49.0% (95% CI, 33.8%-65.4%) of variance in reference standard assessments of social disability, verbal ability, and nonverbal cognitive ability, respectively. Conclusions and Relevance: In two diagnostic studies of children younger than 3 years, objective eye-tracking-based measurements of social visual engagement quantified diagnostic status as well as individual levels of social disability, verbal ability, and nonverbal ability in autism. These findings suggest that objective measurements of social visual engagement can be used to aid in autism diagnosis and assessment.

Short-stem hip arthroplasty in Australia and the Netherlands: a comparison of 12,680 cases between the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) and the Dutch Arthroplasty Register (LROI).

BACKGROUND AND PURPOSE: We compared the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) and the Dutch Arthroplasty Register (LROI) regarding patient, prosthesis, and procedure characteristics as well as revision rates for uncemented short-stem total hip arthroplasties (THAs). PATIENTS AND METHODS: All THAs with an uncemented short-stemmed femoral component performed between 2009 and 2021 were included from the AOANJRR (n = 9,328) and the LROI (n = 3,352). Kaplan-Meier survival analyses and multivariable Schemper's weighted Cox regression analyses with data from 2009-2021 and 2015-2021 were performed with overall revision as endpoint. RESULTS: In Australia, the proportion of male patients (51% vs. 40%), patients with ASA III-IV score (30% vs. 3.7%), BMI ≥ 30.0 (39% vs. 19%), and femoral heads of 36 mm (58% vs. 20%) were higher than in the Netherlands. Short-stem THAs in Australia and the Netherlands had comparable 10-year revision rates (3.4%, 95% confidence interval [CI] 2.9-4.0 vs. 4.8%, CI 3.7-6.3). Multivariable Cox regression analyses with data from 2009-2021 showed a higher risk for revision of short-stem THAs performed in the Netherlands (HR 1.8, CI 1.1-2.8), whereas the risk for revision was comparable (HR 0.9, CI 0.5-1.7) when adjusted for more potential confounders using data from 2015-2021. CONCLUSION: Short-stem THAs in Australia and the Netherlands have similar crude and adjusted revision rates, which are acceptable at 10 years of follow-up.

Development of a multiplex assay to assess activated p300/CBP in circulating prostate tumor cells.

Reduced SIRT2 deacetylation and increased p300 acetylation activity leads to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18) in castration-resistant prostate cancer (CRPC). We examined whether circulating tumor cells (CTCs) identify patients with altered p300/CBP acetylation. CTCs were isolated from 13 advanced PC patients using Exclusion-based Sample Preparation (ESP) technology. Bound cells underwent immunofluorescent staining for histone modifying enzymes (HMEs) of interest and image capture with NIS-Elements software. Using the cBioPortal PCF/SU2C dataset, the response of CRPC to androgen receptor signaling inhibitors (ARSI) was analyzed in 50 subjects. Staining optimization and specificity revealed clear expression of acetyl-p300, acetyl-H3K18, and SIRT2 on CTCs (CK positive, CD45 negative cells). Exposure to A-485, a selective p300/CBP catalytic inhibitor, reduced p300 and H3K18 acetylation. In CRPC patients, a-p300 strongly correlated with its target acetylated H3k18 (Pearson's R = 0.61), and SIRT2 expression showed robust negative correlation with a-H3k18 (R = -0.60). A subgroup of CRPC patients (6/11; 55%) demonstrated consistent upregulation of acetylation based on these markers. To examine the clinical impact of upregulation of the CBP/p300 axis, CRPC patients with reduced deacetylase SIRT2 expression demonstrate shorter response times to ARSI therapy (5.9 vs. 12 mo; p = 0.03). A subset of CRPC patients demonstrate increased p300/CBP activity based on a novel CTC biomarker assay. With further development, this biomarker suite may be used to identify candidates for CBP/p300 acetylation inhibitors in clinical development.

Cardiopulmonary resuscitation and basic life support for people with atypical chest shapes and wheelchair users: Toward supplemented education and emergency management plans.

This article explores current practice issues in basic life support (BLS) and cardiopulmonary resuscitation (CPR) delivery for people with disability and poses recommendations for development of education and training where specialist nurses and other health professionals can facilitate BLS and CPR techniques catering for people with atypical chest shapes wheelchair users and people at high risk of choking. People with a disability are at higher risk of premature and unexpected death. At present there is a significant gap in knowledge about how to deliver optimal BLS or CPR to people with atypical chest shapes wheelchair users and people at high risk of choking. This leave carers to augment guidelines during emergency situations. Introduction of supplemented BLS and CPR together with development of emergency care plans for people with disability could reduce the number of people with disability dying premature or preventable deaths.

Effect of Aspirin vs Enoxaparin on 90-Day Mortality in Patients Undergoing Hip or Knee Arthroplasty: A Secondary Analysis of the CRISTAL Cluster Randomized Trial.

Importance: Ischemic heart disease remains the leading cause of mortality following hip and knee arthroplasty. Due to its antiplatelet and cardioprotective properties, aspirin has been proposed as an agent that could reduce mortality when used as venous thromboembolism (VTE) prophylaxis following these procedures. Objective: To compare aspirin with enoxaparin in reducing 90-day mortality for patients undergoing hip or knee arthroplasty procedures. Design, Setting, and Participants: This study was a planned secondary analysis of the CRISTAL cluster randomized, crossover, registry-nested trial performed across 31 participating hospitals in Australia between April 20, 2019, and December 18, 2020. The aim of the CRISTAL trial was to determine whether aspirin was noninferior to enoxaparin in preventing symptomatic VTE following hip or knee arthroplasty. The primary study restricted the analysis to patients undergoing total hip or knee arthroplasty for a diagnosis of osteoarthritis only. This study includes all adult patients (aged ≥18 years) undergoing any hip or knee arthroplasty procedure at participating sites during the course of the trial. Data were analyzed from June 1 to September 6, 2021. Interventions: Hospitals were randomized to administer all patients oral aspirin (100 mg daily) or subcutaneous enoxaparin (40 mg daily) for 35 days after hip arthroplasty and 14 days after knee arthroplasty procedures. Main Outcomes and Measures: The primary outcome was mortality within 90 days. The between-group difference in mortality was estimated using cluster summary methods. Results: A total of 23 458 patients from 31 hospitals were included, with 14 156 patients allocated to aspirin (median [IQR] age, 69 [62-77] years; 7984 [56.4%] female) and 9302 patients allocated to enoxaparin (median [IQR] age, 70 [62-77] years; 5277 [56.7%] female). The mortality rate within 90 days of surgery was 1.67% in the aspirin group and 1.53% in the enoxaparin group (estimated difference, 0.04%; 95% CI, -0.05%-0.42%). For the subgroup of 21 148 patients with a nonfracture diagnosis, the mortality rate was 0.49% in the aspirin group and 0.41% in the enoxaparin group (estimated difference, 0.05%; 95% CI, -0.67% to 0.76%). Conclusions and Relevance: In this secondary analysis of a cluster randomized trial comparing aspirin with enoxaparin following hip or knee arthroplasty, there was no significant between-group difference in mortality within 90 days when either drug was used for VTE prophylaxis. Trial Registration: http://anzctr.org.au Identifier: ACTRN12618001879257.

Mining Migrant Worker Recruitment Policy and the Production of a Silicosis Epidemic in Late 20th-Century Southern Africa.

Objectives: Between the 1980s and 2000s, an epidemic of silicosis was identified in migrant black gold miners, many from neighbouring countries, who had worked in the South African gold mines. This study uses the newly available employment database of a large gold mining company to demonstrate how a sustained rise in employment duration in a new cohort of black migrant workers resulted from changes in recruitment policy, and it examines the implications for current surveillance and redress. Methods: Contract data of 300,774 workers from the employment database of a multi-mine gold mining company were analysed for 1973-2018. Piecewise linear regression was applied to determine trends in cumulative employment, including South African versus cross-border miners. The proportions with cumulative employment of at least 10, 15, or 20 years, typical thresholds for chronic silicosis, were also calculated. Results: Five calendar phases were identified between 1973 and 2018. During the second phase, 1985-2013, mean cumulative duration of employment rose fivefold, from 4 to 20 years. Cumulative employment continued to rise, although more slowly, before peaking in 2014 at 23.5 years and falling thereafter to 20.1 years in 2018. Over most of the 1973-2018 period, miners from neighbouring countries had greater cumulative employment than South African miners. Overall, the proportion of miners exiting with at least 15 years of cumulative employment rose from 5% in 1988 to 75% in 2018. This report identifies a number of fundamental changes in labour recruitment policy in the gold mining industry in the 1970s which provide an explanation for the subsequent rise in cumulative exposure and associated silicosis risk. Conclusions: These new data support the hypothesis of a silicosis epidemic driven by increasing cumulative silica dust exposure in a new cohort of circular migrant workers from the 1970s. They inform current programmes to improve surveillance of this neglected population for silicosis and related disease and to provide medical examinations and compensation to a large number of former gold mines. The analysis highlights the lack of information on cumulative employment and silicosis risk among migrant miners in previous decades. The findings have global relevance to the plight of such migrant workers in hazardous occupations.

Novel Husbandry Practices Result in Rapid Rates of Growth and Sexual Maturation Without Impacting Adult Behavior in the Blind Mexican Cavefish.

Animal model systems are dependent on the standardization of husbandry protocols that maximize growth and reduce generation time. The Mexican tetra, Astyanax mexicanus, exists as eyed surface and blind cave dwelling populations. The opportunity for comparative approaches between independently evolved populations has led to the rapid growth of A. mexicanus as a model for evolution and biomedical research. However, a slow and inconsistent growth rate remains a major limitation to the expanded application of A. mexicanus. Fortunately, this temporal limitation can be addressed through husbandry changes that accelerate growth rates while maintaining optimal health outcomes. Here, we describe a husbandry protocol that produces rapid growth rates through changes in diet, feeding frequency, growth sorting and progressive changes in tank size. This protocol produced robust growth rates and decreased the age of sexual maturity in comparison to our previous protocol. To determine whether changes in feeding impacted behavior, we tested fish in exploration and schooling assays. We found no difference in behavior between the two groups, suggesting that increased feeding and rapid growth will not impact the natural variation in behavioral traits. Taken together, this standardized husbandry protocol will accelerate the development of A. mexicanus as a genetic model.

Predictive value of post-void residual volume as an adjunctive tool in the clinical evaluation of cauda equina syndrome.

The early diagnosis of cauda equina syndrome (CES) is crucial for a favourable outcome. Several studies have reported the use of an ultrasound scan of the bladder as an adjunct to assess the minimum post-void residual volume of urine (mPVR). However, variable mPVR values have been proposed as a threshold without consensus on a value for predicting CES among patients with relevant symptoms and signs. The aim of this study was to perform a meta-analysis and systematic review of the published evidence to identify a threshold mPVR value which would provide the highest diagnostic accuracy in patients in whom the diagnosis of CES is suspected. The search strategy used electronic databases (PubMed, Medline, EMBASE, and AMED) for publications between January 1996 and November 2021. All studies that reported mPVR in patients in whom the diagnosis of CES was suspected, followed by MRI, were included. A total of 2,115 studies were retrieved from the search. Seven fulfilled the inclusion criteria. These included 1,083 patients, with data available from 734 being available for meta-analysis. In 125 patients, CES was confirmed by MRI. The threshold value of mPVR reported in each study varied and could be categorized into 100 ml, 200 ml, 300 ml, and 500 ml. From the meta-analysis, 200 ml had the highest diagnostic accuracy, with 82% sensitivity (95% confidence interval (CI) 0.72 to 0.90) and 65% specificity (95% CI 0.70 to 0.90). When compared using summative receiver operating characteristic curves, mPVR of 200 ml was superior to other values in predicting the radiological confirmation of CES. mPVR is a useful tool when assessing patients in whom the diagnosis of CES is suspected. Compared with other values a mPVR of 200 ml had superior sensitivity, specificity, and positive and negative predictive values. In a patient with a suggestive history and clinical findings, a mPVR of > 200 ml should further raise the suspicion of CES. Caution is recommended when considering the mPVR in isolation and using it as an 'exclusion tool', and it should only be used as an adjunct to a full clinical assessment.

An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets.

Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function, and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin, but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated by probucol treatment in addition to increased contact between lipid droplets (LDs) and mitochondria. Conversely, LD expansion, which occurs following mitochondrial damage, was suppressed by probucol and probucol-mediated mitophagy enhancement required LDs. Probucol-mediated LD dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage.