Generation and characterization of monoclonal antibodies against pathologically phosphorylated TDP-43.

Inclusions containing TAR DNA binding protein 43 (TDP-43) are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). One of the disease-specific features of TDP-43 inclusions is the aberrant phosphorylation of TDP-43 at serines 409/410 (pS409/410). Here, we developed rabbit monoclonal antibodies (mAbs) that specifically detect pS409/410-TDP-43 in multiple model systems and FTD/ALS patient samples. Specifically, we identified three mAbs (26H10, 2E9 and 23A1) from spleen B cell clones that exhibit high specificity and sensitivity to pS409/410-TDP-43 peptides in an ELISA assay. Biochemical analyses revealed that pS409/410 of recombinant TDP-43 and of exogenous 25 kDa TDP-43 C-terminal fragments in cultured HEK293T cells are detected by all three mAbs. Moreover, the mAbs detect pS409/410-positive TDP-43 inclusions in the brains of FTD/ALS patients and mouse models of TDP-43 proteinopathy by immunohistochemistry. Our findings indicate that these mAbs are a valuable resource for investigating TDP-43 pathology both in vitro and in vivo.

Modified Senning procedure in a patient with dextrocardia with left atrial isomerism and anomalous systemic venous drainage: a rare case report.

The atrial switch procedure by Senning or Mustard technique primarily aims in correcting parallel systemic and pulmonary circulations at atrial level. This procedure may be used in late presenting D-transposition of great arteries with a deconditioned left ventricle, congenitally corrected transposition of great arteries and isolated ventricular inversion. We describe the case of a child with dextrocardia, left atrial isomerism with complex pulmonary and systemic venous drainage resulting in mixing at atrial level. She was successfully operated by modified Senning procedure performed through the left-sided atrium.

Simultaneous Focal Boost With Stereotactic Radiation Therapy for Localized Intermediate- to High-Risk Prostate Cancer: Primary Outcomes of the SPARC Phase 2 Trial.

PURPOSE: Dose-escalated radiation therapy is associated with better biochemical control at the expense of toxicity. Stereotactic body radiation therapy (SBRT) with dose escalation to the dominant intraprostatic lesion (DIL) provides a logical approach to improve outcomes in high-risk disease while limiting toxicity. This study evaluated the toxicity and quality of life (QoL) with CyberKnife-based SBRT and simultaneous integrated boost in localized prostate cancer. METHODS AND MATERIALS: Eligible participants included newly diagnosed, biopsy-proven unfavorable intermediate- to high-risk localized prostate cancer (at least 1 of the following: Gleason ≥4+3, magnetic resonance imaging(MRI)-defined T3a N0, prostate-specific antigen ≥20) with up to 2 MRI-identified DILs. Participants received 36.25 Gy in 5 fractions on alternative days with a simultaneous boost to DIL up to 47.5 Gy as allowed by organ-at-risk constraints delivered by CyberKnife. All participants received androgen deprivation therapy. The primary outcome measure was acute grade 2+ genitourinary toxicity. Acute and late genitourinary and gastrointestinal toxicity using Radiation Therapy Oncology Group scoring, biochemical parameters, International Prostate Symptom Score, International Index of Erectile Function 5, and EQ-5D QoL outcomes were assessed. RESULTS: Between 2013 and 2023, 20 participants were enrolled with a median follow-up of 30 months. The median D95 dose to DIL was 47.43 Gy. Cumulative acute grade 2+ genitourinary and gastrointestinal toxicity were 25% and 30%, respectively. One patient developed acute grade 3 genitourinary toxicity (5%). There is no late grade 3 genitourinary or gastrointestinal toxicity to date. International Prostate Symptom Score and urinary QoL scores recovered to baseline by 6 months. Patient-reported outcomes showed no significant change in EQ-5D QoL scores at 12 weeks and 1 year. There are no cases of biochemical relapse reported to date. CONCLUSIONS: CyberKnife SBRT-delivered dose of 36.25 Gy to the prostate with a simultaneous integrated boost up to 47.5 Gy is well tolerated. Acute and late genitourinary and gastrointestinal toxicity rates are comparable to other contemporary SBRT trials and series with focal boost.

Working the Edge: The Emotional Experiences of Commissioning and Funding Arrangements for Service Leaders in the Sexual Violence Voluntary Sector.

The specialist voluntary sector plays a crucial role in supporting survivors of sexual violence. However, in England, short-term funding underpins the sector's financial stability. This article examines sector leaders' ways of coping, resisting and being affected by funding practices. Using the concept of edgework, we show how funding and commissioning dynamics push individuals to the edge of service sustainability, job satisfaction, and emotional well-being. We examine how these edges are "worked," for example, by circumventing and remolding the edge. We offer an original way to theorize participants, make visible the emotional toll of service precarity and offer suggestions for support.

In Vitro Pharmacological Modulation of PIEZO1 Channels in Frontal Cortex Neuronal Networks.

PIEZO1 is a mechanosensitive ion channel expressed in various organs, including but not limited to the brain, heart, lungs, kidneys, bone, and skin. PIEZO1 has been implicated in astrocyte, microglia, capillary, and oligodendrocyte signaling in the mammalian cortex. Using murine embryonic frontal cortex tissue, we examined the protein expression and functionality of PIEZO1 channels in cultured networks leveraging substrate-integrated microelectrode arrays (MEAs) with additional quantitative results from calcium imaging and whole-cell patch-clamp electrophysiology. MEA data show that the PIEZO1 agonist Yoda1 transiently enhances the mean firing rate (MFR) of single units, while the PIEZO1 antagonist GsMTx4 inhibits both spontaneous activity and Yoda1-induced increase in MFR in cortical networks. Furthermore, calcium imaging experiments revealed that Yoda1 significantly increased the frequency of calcium transients in cortical cells. Additionally, in voltage clamp experiments, Yoda1 exposure shifted the cellular reversal potential towards depolarized potentials consistent with the behavior of PIEZO1 as a non-specific cation-permeable channel. Our work demonstrates that murine frontal cortical neurons express functional PIEZO1 channels and quantifies the electrophysiological effects of channel activation in vitro. By quantifying the electrophysiological effects of PIEZO1 activation in vitro, our study establishes a foundation for future investigations into the role of PIEZO1 in neurological processes and potential therapeutic applications targeting mechanosensitive channels in various physiological contexts.

Effectiveness of a novel consultant nurse-led breast pain clinic in secondary care.

BACKGROUND: Patients with breast pain are usually seen in 'one-stop clinic' (OSC) with breast imaging. In the absence of associated red flag features, the incidence of breast cancer is extremely low. With increase in referrals the OSC capacity is over-stretched. We developed a consultant nurse-led dedicated 'breast pain clinic' in September 2021 without routine breast imaging. After meticulous history and examination, patients obtained detailed counselling and advice regarding breast pain management. If any abnormality was noted then appointment was given for OSC. AIM: To assess the effectiveness of a consultant nurse-led dedicated 'breast pain clinic'. METHODS: A prospective study of all consecutive patients seen in 'breast pain clinic' from September 2021 until September 2022. Feedback was sought from all patients. RESULTS: Altogether 429 patients were seen. The mean age was 48.7 years (range 18-86). 87.6% (n = 376) patients required no breast imaging. Only 12.4% (n = 53) patients needed referral to OSC and subsequently 2 patients (0.46%) were diagnosed with breast cancer. Ninety-eight percent of patients felt reassured and 99.2% patients were extremely likely/likely to recommend this service to family and friends. Out of 376 patients who were discharged from breast pain clinic, 12 patients were referred again over a median follow-up period of 15 months, and 2 out of them were diagnosed with breast cancer. CONCLUSION: A consultant nurse-led 'breast pain clinic' provides service improvement as it eases the pressure on the OSC. Most patients were managed without breast imaging with high level of patient satisfaction and low rereferral rate.

Natural history and outcomes in paediatric RASopathy-associated hypertrophic cardiomyopathy.

AIMS: This study aimed to describe the natural history and predictors of all-cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18 years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS-LAH)]. One hundred forty-nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan-like syndrome, and 3 (2%) NS-LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36-80) mmHg, P = 0.004]. Over a median follow-up of 197.5 [inter-quartile range (IQR) 93.58-370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6-175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69-98.51], 90.42% (95% CI 84.04-94.33), and 84.12% (95% CI 75.42-89.94) at 1, 5, and 10 years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non-sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all-cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event. CONCLUSIONS: These findings highlight a distinct category of patients with Noonan-like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy-related HCM.

Quantifying neutrophil extracellular trap release in a combined infection-inflammation NET-array device.

Excessive release of neutrophil extracellular traps (NETs) has been reported in various human pathologies, including COVID-19 patients. Elevated NET levels serve as a biomarker, indicating increased coagulopathy and immunothrombosis risks in these patients. Traditional immunoassays employed to quantify NET release focus on bulk measurements of released chromatin in simplified microenvironments. In this study, we fabricated a novel NET-array device to quantify NET release from primary human neutrophils with single-cell resolution in the presence of the motile bacteria Pseudomonas aeruginosa PAO1 and inflammatory mediators. The device was engineered to have wide chambers and constricted loops to measure NET release in variably confined spaces. Our open NET-array device enabled immunofluorescent labeling of citrullinated histone H3, a NET release marker. We took time-lapse images of primary healthy human neutrophils releasing NETs in clinically relevant infection and inflammation-rich microenvironments. We then developed a computer-vision-based image processing method to automate the quantification of individual NETs. We showed a significant increase in NET release to Pseudomonas aeruginosa PAO1 when challenged with inflammatory mediators tumor necrosis factor-α [20 ng mL-1] and interleukin-6 [50 ng mL-1], but not leukotriene B4 [20 nM], compared to the infection alone. We also quantified the temporal dynamics of NET release and differences in the relative areas of NETs, showing a high percentage of variable size NET release with combined PAO1 - inflammatory mediator treatment, in the device chambers. Importantly, we demonstrated reduced NET release in the confined loops of our combined infection-inflammation microsystem. Ultimately, our NET-array device stands as a valuable tool, facilitating experiments that enhance our comprehension of the spatiotemporal dynamics of NET release in response to infection within a defined microenvironment. In the future, our system can be used for high throughput and cost-effective screening of novel immunotherapies on human neutrophils in view of the importance of fine-tuning NET release in controlling pathological neutrophil-driven inflammation.

Improving Immunization Health Care Data Quality using Two-Dimensional Barcoding and Barcode Scanning Practices.

BACKGROUND: Manual data entry is time-consuming, inefficient, and error prone. In contrast, leveraging two-dimensional (2D) barcodes and barcode scanning tools is a rapid and effective practice for automatically entering vaccine data accurately and completely. CDC pilots documented clinical and public health impacts of 2D barcode scanning practices on data quality and completeness, time savings, workflow efficiencies, and staff experience. OBJECTIVES: Data entry practices and entered records from routine and mass vaccination settings were analyzed. Data quality improvement opportunities were identified. METHODS: A sample of 50 million emergency use authorization (EUA) coronavirus disease 2019 (COVID-19) vaccine records were analyzed for accuracy and completeness across three data fields: lot number, expiration date, and National Drug Code (NDC). The EUA COVID-19 vaccines lacked a 2D barcode containing these data fields, which necessitated manual data entry at administration. A CDC pilot at clinic compared scanned and manually entered data for routine vaccines across these same data fields. RESULTS: Analysis of 50 million manually entered EUA COVID-19 vaccine administration records indicated significant gaps in data accuracy and completeness across three data fields. Over half of the analyzed EUA vaccine NDCs (53%) and one-third of the expiration dates (35%) had missing or inaccurate data recorded. Pilot data also showed many errors when manually entered. However, when the pilot's routine vaccines were scanned (out of 71,969 records), nearly all entries were complete and accurate across all three data fields (ranging from 99.7% to 99.999% accurate). CONCLUSION: Vaccine 2D barcode scanning practices increased data accuracy and completeness (up to 99.999% accurate) across data fields assessed. When used consistently, vaccine 2D barcode scanning can resolve issues demonstrated in manually entered data. To realize these benefits, the immunization community should widely use scanning practices. To increase use, CDC developed a Vaccine 2D Barcode National Adoption Strategy and implementation resources.

Blinatumomab in Practice.

PURPOSE OF REVIEW: Acute lymphoblastic leukemia (ALL) is a rare hematologic neoplasm in adults, with most cases defined by pathology related to abnormal B cell proliferation known as B-cell ALL. The course is challenging, with less-than-optimal survival outcomes, even with aggressive multiagent chemotherapy and consideration for stem cell transplantation. Novel therapies focused on targetable pathways are being investigated to improve outcomes while simultaneously decreasing toxicity. In our review, we aim to evaluate the utilization of blinatumomab in B-cell ALL and provide insight on how this guides our management. RECENT FINDINGS: Blinatumomab is a bispecific T-cell engager (BiTE) immunotherapy that neutralizes malignant cells by instigating CD3-positive T cells to target CD19-positive B cells. However, this therapy targets both malignant and non-malignant lymphocytes with potentially severe side effects such as cytokine release syndrome or neurotoxicity. Evidence evaluating utilization in the relapsed or refractory setting has been most supported; however, newer trials have also indicated improved survival in the frontline treatment of B-cell ALL. As this therapy is relatively new, the treatment team may include members who are less experienced with the typical treatment course and drug mechanics. This review synthesized available data investigating the effectiveness of blinatumomab effectiveness and its adverse events in addition to providing guidance on safe administration methods utilizing a multidisciplinary healthcare team. When care is coordinated in these settings, serious side effects can be recognized early, allowing for necessary intervention leading to improved quality of life and overall survival. Future research will continue to evaluate blinatumomab in different lines of therapy and expand its way into community settings.

Sex and heredity are determinants of oral oxycodone self-administration in 36 Inbred Rat Strains: correlations with behavioral tests of anxiety and novelty-seeking.

Most individuals affected in the national epidemic of oxycodone abuse began taking oral oxycodone by prescription. We studied vulnerability to oxycodone intake in a rat model of oral drug self-administration (SA), since pharmacokinetics affect abuse potential. Females (33 inbred strains) and males (26) obtained oxycodone at increasing concentrations in operant sessions (FR5; 1-16-h) followed by extinction and reinstatement. Active spout licks were greater in females than males during 4-h and 16-h sessions (p< 0.001 for all). Across all stages of oxycodone SA, intake/session was greater in females (p<0.001). Both sexes escalated intake during 16-h extended access vs 4-h sessions (p<2e-16). Intake and active licks varied greatly by strain. The heritability (h2) of active licks/4-h at increasing oxycodone dose was larger in males (h2 females: 0.30-0.39 vs. males: 0.41-0.53). Under a progressive ratio schedule, breakpoints differed by strain (p<2e-16) and by sex in some strains (p=0.018). For cue-induced reinstatement, active licks were greater in females than males (p<0.001). Behavior in naive rats was assessed using elevated plus maze (EPM), open field (OF) and novel object interaction. (NOI) tests. We correlated these behaviors with 28 parameters of oxycodone SA. EPM-defining traits were most commonly associated with SA in both sexes, whereas more OF and NOI traits were SA-associated in males. Overall, sex and heredity are major determinants of the motivation to take and seek oxycodone, which escalates during extended access. The correlation of EPM, a measure of anxiety, with multiple SA parameters indicates the influence of pleiotropic genes.

Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques.

Rhesus macaques (RMs) are a common pre-clinical model used to test HIV vaccine efficacy and passive immunization strategies. Yet, it remains unclear to what extent the Fc-Fc receptor (FcR) interactions impacting antiviral activities of antibodies in RMs recapitulate those in humans. Here, we evaluated the FcR-related functionality of natural killer cells (NKs) from peripheral blood of uninfected humans and RMs to identify intra- and inter-species variation. NKs were screened for FcγRIIIa (human) and FcγRIII (RM) genotypes (FcγRIII(a)), receptor signaling, and antibody-dependent cellular cytotoxicity (ADCC), the latter mediated by a cocktail of monoclonal IgG1 antibodies with human or RM Fc. FcγRIII(a) genetic polymorphisms alone did not explain differences in NK effector functionality in either species cohort. Using the same parameters, hierarchical clustering separated each species into two clusters. Importantly, in principal components analyses, ADCC magnitude, NK contribution to ADCC, FcγRIII(a) cell-surface expression, and frequency of phosphorylated CD3ζ NK cells all contributed similarly to the first principal component within each species, demonstrating the importance of measuring multiple facets of NK cell function. Although ADCC potency was similar between species, we detected significant differences in frequencies of NK cells and pCD3ζ+ cells, level of cell-surface FcγRIII(a) expression, and NK-mediated ADCC (P<0.001), indicating that a combination of Fc-FcR parameters contribute to overall inter-species functional differences. These data strongly support the importance of multi-parameter analyses of Fc-FcR NK-mediated functions when evaluating efficacy of passive and active immunizations in pre- and clinical trials and identifying correlates of protection. The results also suggest that pre-screening animals for multiple FcR-mediated NK function would ensure even distribution of animals among treatment groups in future preclinical trials.

Successful implementation of a quality improvement bundle to reduce opioid overprescribing following total hip and knee arthroplasty.

BACKGROUND: Opioid overprescribing is commonplace after total hip (THA) and total knee arthroplasty (TKA). Preliminary data demonstrated that approximately 32% of the opioids prescribed at discharge from our hospital following THA and TKA remain unused. This is a concern given that unused prescribed opioids are available for diversion and may result in misuse and abuse. METHODS: Pre-intervention data were collected between 1 November 2018 and 10 December 2018. An intervention bundle was then introduced, including education of patients and providers, a standardised pain management algorithm and an autopopulated discharge prescription. The aim of this quality improvement initiative was to reduce the amount of opioid (average oral morphine equivalents (OME)) dispensed (based on the discharge prescription provided) following THA and TKA at our institution by 15% by 1 April 2019. DESIGN: Using an interrupted time series design, the outcome measure was the amount of opioid (OME) dispensed from the discharge prescription provided. Process measures included the percentage of autopopulated discharge prescriptions, the percentage of patients receiving education at discharge and the percentage of nurses and residents receiving standardised education. Balancing measures included patient satisfaction with postoperative pain management, and the percentage of patients filling the second half of the part-fill or requiring a subsequent opioid prescription. RESULTS: With 600 patients identified, mean OME dispensed at discharge was reduced by 26.3% (from 522.2 to 384.9 mg) after our interventions started. Utilisation of autopopulated part-fill prescriptions was 95.8%. There was no change in patient satisfaction nor in the proportion of patients requiring an additional opioid prescription post-intervention. Only 39% of patients filled the second half of the part-fill prescription post-intervention. CONCLUSIONS: Mean OME dispensed at discharge per patient was reduced with no change in patient satisfaction after introduction of the intervention bundle.

Service evaluation of an independent domestic violence advocate post in a children's hospital.

Domestic violence and abuse (DVA) has detrimental effects on the health and well-being of children and young people exposed to it, whether they witness or experience it. The introduction of independent domestic violence advocates in UK hospitals has enhanced the safety of victims of DVA. In 2020-2021 an independent domestic violence advocate post was piloted at a children's hospital for one year, the advocate's role being to train hospital staff and support women who had experienced DVA. A service evaluation showed that the training and support provided by the independent domestic violence advocate had benefits for women, children and staff. It also confirmed that the commissioning of services for children exposed to DVA is often underfunded and overshadowed by the provision of support to adults.

Conjugation of HIV-1 envelope to hepatitis B surface antigen alters vaccine responses in rhesus macaques.

An effective HIV-1 vaccine remains a critical unmet need for ending the AIDS epidemic. Vaccine trials conducted to date have suggested the need to increase the durability and functionality of vaccine-elicited antibodies to improve efficacy. We hypothesized that a conjugate vaccine based on the learned response to immunization with hepatitis B virus could be utilized to expand T cell help and improve antibody production against HIV-1. To test this, we developed an innovative conjugate vaccine regimen that used a modified vaccinia virus Ankara (MVA) co-expressing HIV-1 envelope (Env) and the hepatitis B virus surface antigen (HBsAg) as a prime, followed by two Env-HBsAg conjugate protein boosts. We compared the immunogenicity of this conjugate regimen to matched HIV-1 Env-only vaccines in two groups of 5 juvenile rhesus macaques previously immunized with hepatitis B vaccines in infancy. We found expansion of both HIV-1 and HBsAg-specific circulating T follicular helper cells and elevated serum levels of CXCL13, a marker for germinal center activity, after boosting with HBsAg-Env conjugate antigens in comparison to Env alone. The conjugate vaccine elicited higher levels of antibodies binding to select HIV Env antigens, but we did not observe significant improvement in antibody functionality, durability, maturation, or B cell clonal expansion. These data suggests that conjugate vaccination can engage both HIV-1 Env and HBsAg specific T cell help and modify antibody responses at early time points, but more research is needed to understand how to leverage this strategy to improve the durability and efficacy of next-generation HIV vaccines.

Which computable biomedical knowledge objects will be regulated? Results of a UK workshop discussing the regulation of knowledge libraries and software as a medical device.

Introduction: To understand when knowledge objects in a computable biomedical knowledge library are likely to be subject to regulation as a medical device in the United Kingdom. Methods: A briefing paper was circulated to a multi-disciplinary group of 25 including regulators, lawyers and others with insights into device regulation. A 1-day workshop was convened to discuss questions relating to our aim. A discussion paper was drafted by lead authors and circulated to other authors for their comments and contributions. Results: This article reports on those deliberations and describes how UK device regulators are likely to treat the different kinds of knowledge objects that may be stored in computable biomedical knowledge libraries. While our focus is the likely approach of UK regulators, our analogies and analysis will also be relevant to the approaches taken by regulators elsewhere. We include a table examining the implications for each of the four knowledge levels described by Boxwala in 2011 and propose an additional level. Conclusions: If a knowledge object is described as directly executable for a medical purpose to provide decision support, it will generally be in scope of UK regulation as "software as a medical device." However, if the knowledge object consists of an algorithm, a ruleset, pseudocode or some other representation that is not directly executable and whose developers make no claim that it can be used for a medical purpose, it is not likely to be subject to regulation. We expect similar reasoning to be applied by regulators in other countries.

Neutrophil attachment via Mac-1 (αMß2; CD11b/CD18; CR3) integrins induces PAD4 deimination of profilin and histone H3.

Neutrophil adhesion to endothelia, entry into tissues and chemotaxis constitute essential steps in the immune response to infections that drive inflammation. Neutrophils bind to other cells and migrate via adhesion receptors, notably the αMß2 integrin dimer (also called Mac-1, CR3 or CD11b/CD18). Here, the response of neutrophils to integrin engagement was examined by monitoring the activity of peptidylarginine deiminase 4 (PAD4). Histone H3 deimination was strongly stimulated by manganese, an integrin-activating divalent cation, even in the absence of additional inflammatory stimuli. Manganese-induced cell attachment resulted in neutrophil swarm formation that paralleled histone deimination, whereas antibodies that impair integrin binding prevented both cell adhesion and histone deimination. Manganese treatment led to putative deimination of profilin, a protein that functions as an actin-organizing hub, as detected by two-dimensional gel electrophoresis and citrulline immunoblotting. Cl-amidine, a covalent inhibitor of PAD4, and GSK484, a specific PAD4 inhibitor, blocked profilin deimination. Neutrophil migration toward leukotriene B4 and toward synovial fluid from a rheumatoid arthritis patient were inhibited by chloramidine, thus supporting the contribution of deimination to chemotaxis. The data, based on a simplified system for integrin activation, imply a mechanism whereby integrin attachment coordinates neutrophil responses to inflammation and orchestrates deimination of nuclear and cytoskeletal proteins. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.

Patient Perspectives on Transitions from Acute to Community-Based Physiotherapy Care Following Total Knee Replacement Surgery Within the Context of a Bundled Care Model.

Purpose: Research on fiscal implications of the bundled care (BC) model exist; however, patient-perceived experiences are less well known. As BC expands in Ontario, this study aims to examine these experiences with physiotherapy care within the total knee replacement (TKR) BC programme. Methods: Qualitative cross-sectional study design. Semi-structured one-on-one telephone interviews were conducted with eight patients four to six weeks post-TKR. Thematic analysis was used. Results: This exploratory study identified three themes across the care journey that patients perceived as influencing their physiotherapy experiences: timely access to physiotherapy care, quality of physiotherapy care, and patient outcomes. Communication, clinical support, and social support were sub-themes. Conclusions: Patients' overall experiences with BC physiotherapy were positive. Areas for improvement included coordination of postoperative physiotherapy and return-to-work support. Patients valued group settings and were interested in meeting previous TKR patients. Health system planners are advised to consider incorporating patient experiences when evaluating and developing BC programmes to achieve patient-centred outcomes.

Objectif : il existe des recherches sur les conséquences budgétaires du modèle des faisceaux de soins (FS), mais les expériences perçues par les patients sont moins connues. Puisque le FS se généralise en Ontario, la présente étude vise à examiner ces expériences dans le contexte des soins physiothérapiques au sein du programme de FS de l'arthroplastie totale du genou (ATG). Méthodologie : étude transversale qualitative. Les chercheurs ont effectué des entrevues téléphoniques individuelles semi-structurées auprès de huit patients, de quatre à six semaines après une ATG. Ils ont utilisé une analyse thématique. Résultats : cette étude exploratoire a permis de faire ressortir trois thèmes dans le parcours des soins que les patients perçoivent comme influents sur leurs expériences de la physiothérapie : l'accès rapide aux soins de physiothérapie, la qualité de ces soins et l'issue des patients. Les sous-thèmes de la communication, du soutien clinique et du soutien social ont également été dégagés. Conclusions : les expériences globales des patients à l'égard de la physiothérapie des FS étaient positives. Les secteurs à améliorer incluaient la coordination de la physiothérapie postopératoire et le soutien au retour au travail. Les patients aimaient les contextes de groupe et s'intéressaient à rencontrer des patients qui avaient déjà subi une ATG. Les planificateurs du système de santé sont invités à envisager d'intégrer les expériences des patients lorsqu'ils évaluent et développent des programmes de FS pour obtenir des résultats axés sur les patients.

Where do those experiencing sexual violence seek help and is routine enquiry acceptable within a sexual healthcare setting? Findings from a population-based survey.

OBJECTIVES: Most sexual violence (SV) remains undisclosed to healthcare professionals. The aims of this study were to identify where support would be sought after SV and whether routine enquiry about SV was acceptable in a sexual healthcare setting. DESIGN: An online population-based survey collected data on a history of SV and preferences on support after SV, in addition to sociodemographic data. Respondents' views on being routinely asked about SV were sought. SETTING AND PARTICIPANTS: This online survey was based in England, UK. There were 2007 respondents. RESULTS: The police were the most frequent first choice for support after experiencing SV (n=520; 25.9%); however, this was less common in individuals in younger age groups (p<0.001) and in those with a history of SV (17.2% vs 29.9%, p<0.001). For the 27.1% (532 of 1960) of respondents who reported a history of SV, the first choice of place for support was Rape Crisis or similar third-sector organisation. The majority of respondents supported routine enquiry about SV during Sexual and Reproductive Health Service (SRHS) consultations (84.4%), although acceptability was significantly lower in older age groups. CONCLUSIONS AND STUDY IMPLICATIONS: A greater awareness of the influence of sociodemographic factors, including ethnicity, age, gender, disability and a history of SV, when planning and delivering services for those who have experienced SV is needed. A history of SV is common in the general population, and a 'one-size-fits-all' approach to encourage disclosure and access to support is unlikely to be optimal. Routine enquiry about SV is highly acceptable in an SRHS setting and likely to improve disclosure when appropriately implemented.