Elevated lipoprotein(a) as a predictor for coronary events in older men

Elevated circulating lipoprotein (a) [Lp(a)] is associated with an increased risk of first and recurrent cardiovascular events; however, the effect of baseline Lp(a) levels on long-term outcomes in an elderly population is not well understood. The current single-center prospective study evaluated the association of Lp(a) levels with incident acute coronary syndrome to identify populations at risk of future events. Lp(a) concentration was assessed in 755 individuals (mean age of 71.9 years) within the community and followed for up to 8 years (median time to event, 4.5 years; interquartile range, 2.5–6.5 years). Participants with clinically relevant high levels of Lp(a) (>50 mg/dl) had an increased absolute incidence rate of ASC of 2.00 (95% CI, 1.0041) over 8 years (P = 0.04). Moreover, Kaplan-Meier cumulative event analyses demonstrated the risk of ASC increased when compared with patients with low (<30 mg/dl) and elevated (30–50 mg/dl) levels of Lp(a) over 8 years (Gray’s test; P = 0.16). Within analyses adjusted for age and BMI, the hazard ratio was 2.04 (95% CI, 1.0–4.2; P = 0.05) in the high versus low Lp(a) groups. Overall, this study adds support for recent guidelines recommending a one-time measurement of Lp(a) levels in cardiovascular risk assessment to identify subpopulations at risk and underscores the potential utility of this marker even among older individuals at a time when potent Lp(a)-lowering agents are undergoing evaluation for clinical use

Evaluation of a manualised speech and language therapy programme for children with social communication disorder: the SCIP feasibility study

Background: Children with Social (Pragmatic) Communication Disorder (SPCD) have long-3 term needs in using and processing social language and have a high risk of later mental health difficulties. A manualised speech and language therapy programme, the Social Communication Intervention Programme (SCIP) provides therapy content for SPCD. A feasibility study is required to derive more precise estimates of key parameters for a future trial of SCIP. Aims: To assess the feasibility of conducting a substantive randomized controlled trial of SCIP for children with SPCD. Methods: A questionnaire was distributed to paediatric speech and language therapists in England. Survey questions addressed number of eligible children, routine intervention provision and trial recruitment factors. In the second phase, a single-arm intervention feasibility study was completed. 15 speech and language practitioners identified 24 children aged 5-11 years with SPCD. Practitioners received training/supervision to deliver 20 SCIP therapy sessions to each child. At Time 1 parents of participating children provided three communication goals; expected steps in each goal were defined. After intervention, parents and practitioners independently rated each goal compared to baseline ability. Two research practitioners compared parent post-intervention commentaries with outcome scores to derive guidance about clinical significance. All practitioners recorded audio commentaries on therapy experiences. Post-intervention interviews were conducted with 6 practitioners and 6 parents. An expert panel completed a Delphi consultation on trial design. Results: Routine practice for SPCD varies widely. Children tend to be embedded in autism provision. Participation in a future trial was well-supported, provided resources are available to services. Outcomes analysis indicated all children except one made some progress on parent ratings; all children made progress on practitioner ratings. A power analysis for a future trial was carried out using current outcome measure as putative primary endpoint. Practitioners’ audio-diaries provided suggestions for training and adaption in a future trial. Outcomes and therapy methods were acceptable to practitioners and parents. Conclusions: The feasibility study evaluated a novel outcome measure of social communication skills in SPCD. A power calculation indicated a feasible framework for a trial within a realistic period of time. Recommendations for recruitment methods, adaptation of manual and training were 6 supported by practitioners and an expert panel

Molecular excitation in the Interstellar Medium: recent advances in collisional, radiative and chemical processes

We review the different excitation processes in the interstellar mediumComment: Accepted in Chem. Re

Intracellular proteomics and extracellular vesiculomics as a metric of disease recapitulation in 3D-bioprinted aortic valve arrays

In calcific aortic valve disease (CAVD), mechanosensitive valvular cells respond to fibrosis- and calcification-induced tissue stiffening, further driving pathophysiology. No pharmacotherapeutics are available to treat CAVD because of the paucity of (i) appropriate experimental models that recapitulate this complex environment and (ii) benchmarking novel engineered aortic valve (AV)–model performance. We established a biomaterial-based CAVD model mimicking the biomechanics of the human AV disease-prone fibrosa layer, three-dimensional (3D)–bioprinted into 96-well arrays. Liquid chromatography–tandem mass spectrometry analyses probed the cellular proteome and vesiculome to compare the 3D-bioprinted model versus traditional 2D monoculture, against human CAVD tissue. The 3D-bioprinted model highly recapitulated the CAVD cellular proteome (94% versus 70% of 2D proteins). Integration of cellular and vesicular datasets identified known and unknown proteins ubiquitous to AV calcification. This study explores how 2D versus 3D-bioengineered systems recapitulate unique aspects of human disease, positions multiomics as a technique for the evaluation of high throughput–based bioengineered model systems, and potentiates future drug discovery

The pathophysiology of restricted repetitive behavior

Restricted, repetitive behaviors (RRBs) are heterogeneous ranging from stereotypic body movements to rituals to restricted interests. RRBs are most strongly associated with autism but occur in a number of other clinical disorders as well as in typical development. There does not seem to be a category of RRB that is unique or specific to autism and RRB does not seem to be robustly correlated with specific cognitive, sensory or motor abnormalities in autism. Despite its clinical significance, little is known about the pathophysiology of RRB. Both clinical and animal models studies link repetitive behaviors to genetic mutations and a number of specific genetic syndromes have RRBs as part of the clinical phenotype. Genetic risk factors may interact with experiential factors resulting in the extremes in repetitive behavior phenotypic expression that characterize autism. Few studies of individuals with autism have correlated MRI findings and RRBs and no attempt has been made to associate RRB and post-mortem tissue findings. Available clinical and animal models data indicate functional and structural alterations in cortical-basal ganglia circuitry in the expression of RRB, however. Our own studies point to reduced activity of the indirect basal ganglia pathway being associated with high levels of repetitive behavior in an animal model. These findings, if generalizable, suggest specific therapeutic targets. These, and perhaps other, perturbations to cortical basal ganglia circuitry are mediated by specific molecular mechanisms (e.g., altered gene expression) that result in long-term, experience-dependent neuroadaptations that initiate and maintain repetitive behavior. A great deal more research is needed to uncover such mechanisms. Work in areas such as substance abuse, OCD, Tourette syndrome, Parkinson’s disease, and dementias promise to provide findings critical for identifying neurobiological mechanisms relevant to RRB in autism. Moreover, basic research in areas such as birdsong, habit formation, and procedural learning may provide additional, much needed clues. Understanding the pathophysioloy of repetitive behavior will be critical to identifying novel therapeutic targets and strategies for individuals with autism

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707