Alpelisib for treatment of patients with PIK3CA-related overgrowth spectrum (PROS).

PURPOSE: PIK3CA-related overgrowth spectrum (PROS) encompasses several rare conditions resulting from activating variants in PIK3CA. Alpelisib, a PI3Kα-selective inhibitor, targets the underlying etiology of PROS, offering a novel therapeutic approach to current management strategies. This study evaluated the safety and efficacy of alpelisib in pediatric and adult patients with PROS. METHODS: EPIK-P1 (NCT04285723) was a non-interventional, retrospective chart review of 57 patients with PROS (≥2 years) treated with alpelisib through compassionate use. Patients had severe/life-threatening PROS-related conditions and confirmed PIK3CA pathogenic variant. The primary end point assessed patient response to treatment at Week 24 (6 months). RESULTS: Twenty-four weeks (6 months) after treatment initiation, 12 of 32 (37.5%) patients with complete case records included in the analysis of the primary end point experienced a ≥20% reduction in target lesion(s) volume. Additional clinical benefit independent from lesion volume reduction was observed across the full study population. Adverse events (AEs) and treatment-related AEs were experienced by 82.5% (47/57) and 38.6% (22/57) of patients, respectively; the most common treatment-related AEs were hyperglycemia (12.3%) and aphthous ulcer (10.5%). No deaths occurred. CONCLUSION: EPIK-P1 provides real-world evidence of alpelisib effectiveness and safety in patients with PROS and confirms PI3Kα as a valid therapeutic target for PROS symptom management.

Outcomes of COVID-19 in people with rheumatic and musculoskeletal disease in Ireland over the first 2 years of the pandemic.

BACKGROUND: Poor COVID-19 outcomes occur with higher frequency in people with rheumatic and musculoskeletal diseases (RMD). Better understanding of the factors involved is crucial to informing patients and clinicians regarding risk mitigation. AIM: To describe COVID-19 outcomes for people with RMD in Ireland over the first 2 years of the pandemic. METHODS: Data entered into the C19-GRA provider registry from Ireland between 24th March 2020 and 31st March 2022 were analysed. Differences in the likelihood of hospitalisation and mortality according to demographic and clinical variables were investigated. RESULTS: Of 237 cases included, 59.9% were female, 95 (41.3%) were hospitalised, and 22 (9.3%) died. Hospitalisation was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular and pulmonary disease, and cancer. Hospitalisation was less frequent in people with inflammatory arthritis and conventional synthetic or biologic disease-modifying antirheumatic drug use. Hospitalisation had a U-shaped relationship with disease activity, being more common in both high disease activity and remission. Mortality was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular disease, pulmonary disease, and obesity. Inflammatory arthritis was less frequent in those who died. CONCLUSION: Hospitalisation or death were more frequently experienced by RMD patients with increasing age, certain comorbidities including potentially modifiable ones, and certain medications and diagnoses amongst other factors. These are important 'indicators' that can help risk-stratify and inform the management of RMD patients.

Case study using RWD in the context of a pivotal trial for regulatory approval in a rare disease.

Rare disorders impact millions of children worldwide, and developing new medicines in this setting is associated with multiple challenges. In this paper, we share a successful story of how real-world data (RWD) were leveraged to accelerate evidence generation and patient access to a life-changing therapy in patients with severe manifestations of PIK3CA-related overgrowth spectrum who require systemic therapy. Despite all the existing regulatory guidelines considering real-world evidence (RWE), there is limited regulatory precedent of the use of this framework in support of a new indication. Thus, our case study illustrates design innovations based on the use of a compassionate use program, primarily in children, as a RWD source for approval of a new therapy in a rare disorder. We highlight the systematic considerations and mitigation of potential sources of bias in order to transform the data into actionable evidence. Our experience shows that RWE can be successfully used with appropriate study planning and mitigation in the context of a rare disorder with a high unmet medical need. Some lessons learned from this case study can benefit therapeutic development in rare disorders.

Long-term efficacy and safety of osilodrostat in Cushing's disease: final results from a Phase II study with an optional extension phase (LINC 2).

BACKGROUND: Many patients with Cushing's disease (CD) require long-term medical therapy to control their hypercortisolism. In the core phase of a Phase II study (LINC 2; NCT01331239), osilodrostat normalized mean urinary free cortisol (mUFC) in 78.9% of patients with CD. Here, we report long-term efficacy and safety data for osilodrostat following completion of an optional extension to LINC 2. METHODS: Adult patients with CD were enrolled in a 22-week prospective Phase II study. Patients with mUFC ≤ upper limit of normal (ULN) or receiving clinical benefit at week 22 could enter the optional extension. The proportion of complete (mUFC ≤ ULN) or partial (mUFC > ULN but ≥ 50% decrease from baseline) mUFC responders was assessed over time. RESULTS: Sixteen of 19 enrolled patients entered the extension. Median (range) osilodrostat exposure from baseline to study end was 5.4 years (0.04-6.7); median (range) average dose was 10.6 mg/day (1.1-47.9). Overall response rate (complete and partial mUFC responders) was consistently ≥ 50%. Sustained control of most cardiovascular-related parameters was observed during the extension. The long-term safety profile was consistent with that reported during the core phase. Testosterone levels (females) decreased towards baseline levels during long-term follow-up, with no new or worsening cases of hirsutism during the extension. CONCLUSIONS: In the longest prospective study of a steroidogenesis inhibitor to date, osilodrostat provided sustained reductions in mUFC for up to 6.7 years of treatment, with no new safety signals emerging during the extension. These findings support osilodrostat as an effective long-term treatment for patients with CD.

Temporal trends in COVID-19 outcomes in people with rheumatic diseases in Ireland: data from the COVID-19 Global Rheumatology Alliance registry.

OBJECTIVES: Although evidence is accumulating globally, data on outcomes in rheumatic disease and COVID-19 in Ireland are limited. We used data from the COVID-19 Global Rheumatology Alliance (C19-GRA) to describe time-varying COVID-19 outcomes for people with rheumatic disease in Ireland. METHODS: Data entered into the C19-GRA provider registry from Ireland between 24 March 2020 and 9 July 2021 were analysed. Differences in the likelihood of hospitalization and mortality according to demographic and clinical variables were investigated using Chi-squared test or Fisher's exact test, as appropriate. Trends in odds of hospitalization and mortality over time were investigated using logistic regression with the time period as a categorical variable. RESULTS: Of 212 cases included, 59.4% were female and median age was 58.0 years (range 13-96). Of the 212 cases, 92 (43%) were hospitalized and 22 (10.4%) died. Increasing age, a diagnosis of gout, ever smoking, glucocorticoid use, having comorbidities and specific comorbidities of cancer, cardiovascular and pulmonary disease were more common in those hospitalized. A diagnosis of inflammatory arthritis, csDMARD and/or b/tsDMARD use were less frequent in those hospitalized. Increasing age, a diagnosis of gout, ever smoking, having comorbidities and specific comorbidities of obesity, cardiovascular and pulmonary disease were more common in those who died. Odds of hospitalization or mortality did not change over time. CONCLUSION: No temporal trend was observed in either COVID-19-related hospitalization or mortality outcomes for people with rheumatic disease in Ireland.

Predictors of hospitalization in patients with rheumatic disease and COVID-19 in Ireland: data from the COVID-19 global rheumatology alliance registry.

OBJECTIVES: Given the limited data regarding the risk of hospitalization in patients with rheumatic disease and coronavirus disease 2019 (COVID-19) in Ireland, we used the COVID-19 Global Rheumatology Alliance (GRA) registry data to study outcomes and their predictors. The primary objective was to explore potential predictors of hospitalization. METHODS: We examined data on patients and their disease-related characteristics entered in the COVID-19 GRA provider registry from Ireland (from 24 March 2020 to 31 August 2020). Multivariable logistic regression was used to assess the association of demographic and clinical characteristics with hospitalization. RESULTS: Of 105 patients, 47 (45.6%) were hospitalized and 10 (9.5%) died. Multivariable logistic regression analysis showed that age [odds ratio (OR) = 1.06, 95% CI 1.01, 1.10], number of co-morbidities (OR = 1.93, 95% CI 1.11, 3.35) and glucocorticoid use (OR = 15.01, 95% CI 1.77, 127.16) were significantly associated with hospitalization. A diagnosis of inflammatory arthritis was associated with lower odds of hospitalization (OR = 0.09, 95% CI 0.02, 0.32). CONCLUSION: Increasing age, co-morbidity burden and glucocorticoid use were associated with hospitalization, whereas a diagnosis of inflammatory arthritis was associated with lower odds of hospitalization.

Correlation of magnetic resonance and arthroscopy in the diagnosis of shoulder injury.

BACKGROUND: Advances in shoulder magnetic resonance imaging (MRI) and arthrography (MRA) have revolutionised musculoskeletal diagnosis and surgical planning. Despite this, the overall accuracy of MRI, with or without intra-articular contrast, can be variable. METHODS: In this prospective non-randomised analysis, 200 participants (74.5% males) with suspected shoulder injuries underwent MRI (41.0%) or MRA followed by arthroscopy. A study specific proforma was developed to ensure consistency of reporting by radiologists and surgeons. The reports were compared to assess the predictive power of MRI/MRA. Specific assessment of rotator cuff tendon appearance, long head of biceps (LHB) tendon appearance, position and anchor, subacromial space, glenoid labrum and humeral cartilage grade were included. RESULTS: Shoulder MRA demonstrated a higher agreement with arthroscopy than MRI for supraspinatus, infraspinatus and subscapularis tendon appearance (κ = 0.77 vs. κ = 0.61, κ = 0.55 vs. κ = 0.53 and κ = 0.58 vs. κ = 0.46 respectively). There were also superior agreement rates with MRA compared to MRI for LHB tendon appearance (κ = 0.70 vs. κ =0.54) and position (κ = 0.89 vs. κ = 0.72). As an overall assessor of shoulder pathology we found significantly higher total agreement scores when MRA was used (p = 0.002). DISCUSSION: Whilst magnetic resonance imaging with arthrography is an extremely useful tool to assess underlying pathological shoulder states it does not confer 100% accuracy. In cases whereby this modality is inconclusive, an examination under anaesthesia and diagnostic arthroscopic assessment for the detection of intra-articular shoulder pathology may be considered.

A tool to evaluate proportionality and necessity in the use of restrictive practices in forensic mental health settings: the DRILL tool (Dundrum restriction, intrusion and liberty ladders).

BACKGROUND: Prevention of violence due to severe mental disorders in psychiatric hospitals may require intrusive, restrictive and coercive therapeutic practices. Research concerning appropriate use of such interventions is limited by lack of a system for description and measurement. We set out to devise and validate a tool for clinicians and secure hospitals to assess necessity and proportionality between imminent violence and restrictive practices including de-escalation, seclusion, restraint, forced medication and others. METHODS: In this retrospective observational cohort study, 28 patients on a 12 bed male admissions unit in a secure psychiatric hospital were assessed daily for six months. Data on adverse incidents were collected from case notes, incident registers and legal registers. Using the functional assessment sequence of antecedents, behaviours and consequences (A, B, C) we devised and applied a multivariate framework of structured professional assessment tools, common adverse incidents and preventive clinical interventions to develop a tool to analyse clinical practice. We validated by testing assumptions regarding the use of restrictive and intrusive practices in the prevention of violence in hospital. We aimed to provide a system for measuring contextual and individual factors contributing to adverse events and to assess whether the measured seriousness of threating and violent behaviours is proportionate to the degree of restrictive interventions used. General Estimating Equations tested preliminary models of contexts, decisions and pathways to interventions. RESULTS: A system for measuring adverse behaviours and restrictive, intrusive interventions for prevention had good internal consistency. Interventions were proportionate to seriousness of harmful behaviours. A 'Pareto' group of patients (5/28) were responsible for the majority (80%) of adverse events, outcomes and interventions. The seriousness of the precipitating events correlated with the degree of restrictions utilised to safely manage or treat such behaviours. CONCLUSION: Observational scales can be used for restrictive, intrusive or coercive practices in psychiatry even though these involve interrelated complex sequences of interactions. The DRILL tool has been validated to assess the necessity and demonstrate proportionality of restrictive practices. This tool will be of benefit to services when reviewing practices internally, for mandatory external reviewing bodies and for future clinical research paradigms.

Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase.

BACKGROUND: Cushing's disease is a rare endocrine disorder characterised by cortisol overproduction with severe complications. Therapies for cortisol reduction are often necessary. Here we report the outcomes from the pivotal phase III study of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, mitochondrial [11ß-hydroxylase]; Novartis Pharma AG, Basel, Switzerland) in patients with Cushing's disease. METHODS: LINC 3 was a prospective, multicentre, open-label, phase III study with a double-blind randomised withdrawal period, that comprised four periods. Patients aged 18-75 years, with confirmed persistent or recurrent Cushing's disease (defined as mean 24-h urinary free cortisol [UFC] concentration >1·5 times the upper limit of normal [ULN] and morning plasma adrenocorticotropic hormone above the lower limit of normal) who had previously had pituitary surgery or irradiation, or were newly diagnosed and who refused surgery or were not surgical candidates, were recruited from 66 hospital sites and private clinical practices in 19 countries. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks (1-30 mg twice daily; film-coated tablets for oral administration) on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, weeks 13-24, osilodrostat was continued at the therapeutic dose determined during period 1. In period 3, beginning at week 26, participants who had a mean 24-h UFC concentration of less than or equal to the ULN at week 24, without up-titration after week 12, were randomly assigned (1:1), via an interactive-response technology, stratified by osilodrostat dose at week 24 and history of pituitary irradiation, to continue osilodrostat or switch to placebo for 8 weeks. Participants and investigators were masked to treatment assignment. Ineligible participants continued open-label osilodrostat. In period 4, weeks 35-48, all participants were given open-label osilodrostat until core-study end. The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3. The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (ie, mean 24-h UFC concentration of ≤ULN) at the end of the randomised withdrawal period (week 34), without up-titration during this period. The key secondary endpoint was the proportion of participants with a complete response at the end of the single-arm, open-label period (ie, period 2, week 24) without up-titration during weeks 13-24. Analysis was by intention-to-treat for all patients who received at least one dose of osilodrostat (full analysis set; key secondary endpoint) or randomised treatment (randomised analysis set; primary endpoint) and safety was assessed in all enrolled patients who received at least one dose of osilodrostat and had at least one post-baseline safety assessment. LINC 3 is registered with ClinicalTrials.gov, NCT02180217, and is now complete. FINDINGS: Between Nov 12, 2014, and March 22, 2017, 202 patients were screened and 137 were enrolled. The median age was 40·0 years (31·0-49·0) and 106 (77%) participants were female. 72 (53%) participants were eligible for randomisation during the withdrawal phase, of whom 36 were assigned to continue osilodrostat and 35 were assigned to placebo; one patient was not randomly assigned due to investigator decision and continued open-label osilodrostat. More patients maintained a complete response with osilodrostat versus with placebo at week 34 (31 [86%] vs ten [29%]; odds ratio 13·7 [95% CI 3·7-53·4]; p<0·0001). At week 24, 72 (53%; 95% CI 43·9-61·1) of 137 patients maintained a complete response without up-titration after week 12. Most common adverse events (ie, occurred in >25% of participants) were nausea (57 [42%]), headache (46 [34%]), fatigue (39 [28%]), and adrenal insufficiency (38 [28%]). Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase. INTERPRETATION: Twice-daily osilodrostat rapidly reduced mean 24-h UFC and sustained this reduction alongside improvements in clinical signs of hypercortisolism; it was also generally well tolerated. Osilodrostat is an effective new treatment option that is approved in Europe for the treatment of endogenous Cushing's syndrome and in the USA for Cushing's disease. FUNDING: Novartis Pharma AG.

Moral cognition, the missing link between psychotic symptoms and acts of violence: a cross-sectional national forensic cohort study.

BACKGROUND: People with schizophrenia are ten times more likely to commit homicide than a member of the general population. The relationship between symptoms of schizophrenia and acts of violence is unclear. There has also been limited research on what determines the seriousness and form of violence, such as reactive or instrumental violence. Moral cognition may play a paradoxical role in acts of violence for people with schizophrenia. Thoughts which have moral content arising from psychotic symptoms may be a cause of serious violence. METHOD: We investigated if psychotic symptoms and moral cognitions at the time of a violent act were associated with acts of violence using a cross-sectional national forensic cohort (n = 55). We examined whether moral cognitions were associated with violence when controlling for neurocognition and violence proneness. We explored the association between all psychotic symptoms present at the time of the violent act, psychotic symptoms judged relevant to the violent act and moral cognitions present at that time. Using mediation analysis, we examined whether moral cognitions were the missing link between symptoms and the relevance of symptoms for violence. We also investigated if specific moral cognitions mediated the relationship between specific psychotic symptoms, the seriousness of violence (including homicide), and the form of violence. RESULTS: Psychotic symptoms generally were not associated with the seriousness or form of violence. However, specific moral cognitions were associated with the seriousness and form of violence even when controlling for neurocognition and violence proneness. Specific moral cognitions were associated with specific psychotic symptoms present and relevant to violence. Moral cognitions mediated the relationship between the presence of specific psychotic symptoms and their relevance for violence, homicide, seriousness of violence, and the form of violence. CONCLUSIONS: Moral cognitions including the need to reduce suffering, responding to an act of injustice or betrayal, the desire to comply with authority, or the wish to punish impure or disgusting behaviour, may be a key mediator explaining the relationship between psychotic symptoms and acts of violence. Our findings may have important implications for risk assessment, treatment and violence prevention.

The psychiatric management of prisoners on hunger strike: developing a management algorithm using the Delphi technique.

PURPOSE: The assessment and management of prisoners on hunger strikes in a custodial setting is complex. There is limited clinical guidance available for psychiatrists to draw upon in such cases. The purpose of this paper is to develop a management algorithm through expert elicitation to inform the psychiatric care of prisoners on a hunger strike. DESIGN/METHODOLOGY/APPROACH: A Delphi method was used to elicit views from Irish forensic psychiatrists, a legal expert and an expert in ethics using a structured questionnaire. Themes were extracted from the results of the questionnaire to propose a management algorithm. A consensus was reached on management considerations. FINDINGS: Five consultant forensic psychiatrists, a legal expert and an expert on psychiatric ethics ( n=7) consented to participation, with a subsequent response rate of 71.4 per cent. Consensus was achieved on a proposed management algorithm. Assessment for mental disorder, capacity to refuse food and motivation for food refusal are seen as key psychiatric tasks. The need to work closely with the prison general practitioner and the value of multidisciplinary working and legal advice are described. Relevant aspects of law included mental health, criminal law (insanity) and capacity legislation. ORIGINALITY/VALUE: This study outlines a management algorithm for the psychiatric assessment and management of prisoners on a hunger strike, a subject about which there is limited guidance to date. Although written from an Irish perspective, this study outlines key considerations for psychiatrists in keeping with international guidance and therefore may be generalisable to other jurisdictions.

A randomized controlled trial of cognitive remediation for a national cohort of forensic patients with schizophrenia or schizoaffective disorder.

BACKGROUND: Evidence is accumulating that Cognitive Remediation Training (CRT) is effective for ameliorating cognitive deficits experienced by patients with schizophrenia and accompanying functional impairment. There has been no randomized controlled trial of CRT using a nationally representative population of forensic patients, despite the significant cognitive deficits frequently present within this group. METHODS: Sixty-five patients with schizophrenia or schizoaffective disorder were enrolled in a single blind randomized controlled trial of CRT versus treatment as usual (TAU); representing 94% of those eligible within a national forensic cohort. The primary outcome measure was the composite score of the MATRICS Consensus Cognitive Battery (MCCB). Secondary outcome measures included neurocognitive and social cognitive domains, symptoms, and 'real world' functioning. Patient satisfaction was examined using an exit interview. Participants were reassessed at 8 months follow up. All data were analyzed using an intention to treat design (ITT). RESULTS: For the primary outcome measure, the MCCB composite score, there were significant differences between those who participated in CRT and those receiving TAU at both end of treatment and 8 months follow up (Cohen's d = 0.34. Significant improvements were observed in visual and working memory. Mediation analysis found that those who cognitively benefited from CRT had corresponding improved functioning, and more net positive therapeutic moves i.e. moves to units with lower security within the hospital. Ninety-six percent believed their cognitive gains positively affected their daily lives. CONCLUSIONS: CRT may be an acceptable and efficacious intervention for forensic patients with schizophrenia or schizoaffective disorder. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02360813 . Trial registered Feb 4th 2015, last updated May 1st 2015.

Prospective observational cohort study of 'treatment as usual' over four years for patients with schizophrenia in a national forensic hospital.

BACKGROUND: We evaluated change in response to multi-modal psychosocial 'treatment as usual' programs offered within a forensic hospital. METHODS: Sixty nine patients with a diagnosis of schizophrenia or schizoaffective disorder were followed for up to four years. Patient progress was evaluated using the DUNDRUM-3, a measure of patient ability to participate and benefit from multi-modal psychosocial programs and the HCR-20 dynamic items, a measure of violence proneness. We report reliable change index (RCI) and reliable and clinically meaningful change (RMC). We assessed patients' cognition using the MCCB, psychopathology using the PANSS. The effect of cognition and psychopathology on change in DUNDRUM-3 was examined using hierarchical multiple regression with age, gender, and baseline DUNDRUM-3 scores. RESULTS: The DUNDRUM-3 changed significantly (p < 0.004, d = 0.367, RCI 32% of 69 cases, RMC 23%) and HCR-20-C (p < 0.003, d = 0.377, RCI 10%). Both cognition and psychopathology accounted for significant variance in DUNDRUM-3 at follow up. Those hospitalized for less than five years at baseline changed more than longer stay patients. Mediation analysis demonstrated that the relationship between cognition and change in violence proneness (HCR-20-C) was both directly affected and indirectly mediated by change in DUNDRUM-3. CONCLUSIONS: Change in response to multi-modal psychosocial programs (DUNDRUM-3) reduced a measure of violence proneness over four years. Forensic in-patients' ability to benefit from psychosocial treatment appears to be a function of the outcome measure used, unit of measurement employed, degree of cognitive impairment, psychopathology, and length of stay. Lower risk of re-offending may be partially attributable to participation and engagement in psychosocial interventions.

Moral cognition and homicide amongst forensic patients with schizophrenia and schizoaffective disorder: A cross-sectional cohort study.

Forensic patients with schizophrenia who had carried out a homicide scored higher on a measure of moral cognition (MFQ-30) than other violent patients. Neurocognitive impairment was associated with homicide by mediation via higher scores for in-group loyalty.

Brief Report: Genetic Variation of the α1 -Antitrypsin Gene Is Associated With Increased Autoantibody Production in Rheumatoid Arthritis.

OBJECTIVE: To examine the prevalence of α1 -antitrypsin deficiency (AATD) in rheumatoid arthritis (RA), and to determine whether AATD is associated with higher levels of rheumatoid factor (RF), antinuclear antibodies (ANAs), and anti-citrullinated peptide autoantibodies (ACPAs). METHODS: RF, ANAs, and ACPAs were measured by standard immunoturbidimetry, immunofluorescence assay, and enzyme-linked immunosorbent assay, respectively. Characterization of AAT phenotypes was performed by isoelectric focusing and immunofixation. The chi-square test with Yates' correction and the Mann-Whitney U test were used to assess the prevalence of alleles associated with AATD in RA and to compare mean antibody titers, respectively. RESULTS: Of 246 patients with RA, 24 who were heterozygous for AATD were identified, with no statistically significant difference in the prevalence of AATD between RA patients and the general population (P = 0.39). A positive association between heterozygosity for AATD and the production of ACPAs was observed (P < 0.0001), with increased ACPA titers recorded in the AATD RA cohort compared with the general population (P = 0.01). CONCLUSION: AAT heterozygous status in RA is strongly associated with positive ACPAs and may define a distinct subset of patients with increased disease severity.

MicroRNA-302d targets IRF9 to regulate the IFN-induced gene expression in SLE.

Systemic lupus erythematosus (SLE) is a complex disease targeting multiple organs as a result of overactivation of the type I interferon (IFN) system, a feature currently being targeted by multiple biologic therapies against IFN-α. We have identified an estrogen-regulated microRNA, miR-302d, whose expression is decreased in SLE patient monocytes and identify its target as interferon regulatory factor (IRF)-9, a critical component of the transcriptional complex that regulates expression of interferon-stimulated genes (ISGs). In keeping with the reduced expression of miR-302d in SLE patient monocytes, IRF9 levels were increased, as was expression of a number of ISGs including MX1 and OAS1. In vivo evaluation revealed that miR-302d protects against pristane-induced inflammation in mice by targeting IRF9 and hence ISG expression. Importantly, patients with enhanced disease activity have markedly reduced expression of miR-302d and enhanced IRF9 and ISG expression, with miR-302d negatively correlating with IFN score. Together these findings identify miR-302d as a key regulator of type I IFN driven gene expression via its ability to target IRF9 and regulate ISG expression, underscoring the importance of non-coding RNA in regulating the IFN pathway in SLE.

Leadership and management in UK medical school curricula.

Purpose Although medical leadership and management (MLM) is increasingly being recognised as important to improving healthcare outcomes, little is understood about current training of medical students in MLM skills and behaviours in the UK. The paper aims to discuss these issues. Design/methodology/approach This qualitative study used validated structured interviews with expert faculty members from medical schools across the UK to ascertain MLM framework integration, teaching methods employed, evaluation methods and barriers to improvement. Findings Data were collected from 25 of the 33 UK medical schools (76 per cent response rate), with 23/25 reporting that MLM content is included in their curriculum. More medical schools assessed MLM competencies on admission than at any other time of the curriculum. Only 12 schools had evaluated MLM teaching at the time of data collection. The majority of medical schools reported barriers, including overfilled curricula and reluctance of staff to teach. Whilst 88 per cent of schools planned to increase MLM content over the next two years, there was a lack of consensus on proposed teaching content and methods. Research limitations/implications There is widespread inclusion of MLM in UK medical schools' curricula, despite the existence of barriers. This study identified substantial heterogeneity in MLM teaching and assessment methods which does not meet students' desired modes of delivery. Examples of national undergraduate MLM teaching exist worldwide, and lessons can be taken from these. Originality/value This is the first national evaluation of MLM in undergraduate medical school curricula in the UK, highlighting continuing challenges with executing MLM content despite numerous frameworks and international examples of successful execution.

Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10.

The link between oncogenic RAS expression and the acquisition of the invasive phenotype has been attributed to alterations in cellular activities that control degradation of the extracellular matrix. Oncogenic RAS-mediated upregulation of matrix metalloproteinase 2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (uPA) is critical for invasion through the basement membrane and extracellular matrix. The uPA converts cell surface-bound plasminogen to plasmin, a process that is regulated by the binding of plasminogen to specific receptors on the cell surface, however, the identity of the plasminogen receptors that function in this capacity is unclear. We have observed that transformation of cancer cells with oncogenic forms of RAS increases plasmin proteolytic activity by 2- to 4-fold concomitant with a 3-fold increase in cell invasion. Plasminogen receptor profiling revealed RAS-dependent increases in both S100A10 and cytokeratin 8. Oncogenic RAS expression increased S100A10 gene expression which resulted in an increase in S100A10 protein levels. Analysis with the RAS effector-loop mutants that interact specifically with Raf, Ral GDS pathways highlighted the importance of the RalGDS pathways in the regulation of S100A10 gene expression. Depletion of S100A10 from RAS-transformed cells resulted in a loss of both cellular plasmin generation and invasiveness. These results strongly suggest that increases in cell surface levels of S100A10, by oncogenic RAS, plays a critical role in RAS-stimulated plasmin generation, and subsequently, in the invasiveness of oncogenic RAS expressing cancer cells.