Temporal effects on death by suicide: empirical evidence and possible molecular correlates.

Popular culture and medical lore have long postulated a connection between full moon and exacerbations of psychiatric disorders. We wanted to empirically analyze the hypothesis that suicides are increased during the period around full moons. We analyzed pre-COVID suicides from the Marion County Coroner's Office (n = 776), and show that deaths by suicide are significantly increased during the week of the full moon (p = 0.037), with older individuals (age ≥ 55) showing a stronger effect (p = 0.019). We also examined in our dataset which hour of the day (3-4 pm, p = 0.035), and which month of the year (September, p = 0.09) show the most deaths by suicide. We had blood samples on a subset of the subjects (n = 45), which enabled us to look at possible molecular mechanisms. We tested a list of top blood biomarkers for suicidality (n = 154) from previous studies of ours 7, to assess which of them are predictive. The biomarkers for suicidality that are predictive of death by suicide during full moon, peak hour of day, and peak month of year, respectively, compared to outside of those periods, appear to be enriched in circadian clock genes. For full moon it is AHCYL2, ACSM3, AK2, and RBM3. For peak hour it is GSK3B, AK2, and PRKCB. For peak month it is TBL1XR1 and PRKCI. Half of these genes are modulated in expression by lithium and by valproate in opposite direction to suicidality, and all of them are modulated by depression and alcohol in the same direction as suicidality. These data suggest that there are temporal effects on suicidality, possibly mediated by biological clocks, pointing to changes in ambient light (timing and intensity) as a therapeutically addressable target to decrease suicidality, that can be coupled with psychiatric pharmacological and addiction treatment preventive interventions.

Age related progression of clinical measures and gait in ambulant children and youth with bilateral cerebral palsy without a history of surgical intervention.

BACKGROUND: Age related progression needs to be considered when assessing current status and treatment outcomes in cerebral palsy (CP). RESEARCH QUESTION: What is the association between age, gait kinematics and clinical measures in children with bilateral CP? METHOD: A retrospective database review was conducted. Subjects with bilateral CP with baseline and follow-up 3D gait analyses, but no history of intervening surgery were identified. Clinical and summary kinematic measures were examined for age related change using repeat measures correlation. Interactions with GMFCS classification and whether surgery was recommended were examined using robust linear regression. Timeseries kinematic data for baseline and most recent follow-up analyses were analysed using statistical parametric mapping. RESULTS: 180 subjects were included. 75% of participants were classified as GMFCS I or II at baseline. Mean time to follow-up was 4.89 (2.8) years (range 1-15.9 years) with a mean age of 6.4 (2.4) at baseline and 11.3 (3.4) at final follow-up. 15.5% of subjects demonstrated an improvement in GMFCS classification while GDI remained stable. Age related progression was noted across many clinical measures with moderate correlations (r ≥ 0.5) noted for reduced popliteal angle, long lever hip abduction and internal hip rotation range. In gait, there was reduced hip extension in late stance (p < 0.001), increased knee flexion in mid-stance (p < 0.001), reduced peak knee flexion in swing (p < 0.001) and increased ankle dorsiflexion in stance (p < 0.001). In the coronal plane, there was reduced hip abduction in swing (p < 0.001). In the transverse plane, increased external rotation of the knee (p < 0.001) and reduced external ankle rotation were noted in early stance and through swing (p < 0.001). There were no changes in foot progression or hip rotation. SIGNIFICANCE: Individuals with CP show age related progression of clinical and kinematic variables. Treatment can only be deemed successful if outcomes exceed or match these age-related changes.

Persisting Symptomatic Severe Secondary Mitral Regurgitation in Heart Failure Patients.

Aims We aimed to assess the rate of persisting severe symptomatic secondary mitral regurgitation (MR) in a newly diagnosed heart failure (HF) population following optimisation of guideline directed medical therapy (GDMT), cardiac resynchronisation therapy (CRT) and revascularisation. Methods We assessed all new patients referred to our hospital group's HF clinics. We retrospectively reviewed these patients at HF clinic enrolment, HF programme completion, as well as most recent follow up. Results Of the 242 new patients referred to our HF clinics, there were 10 patients (4.1%) who had either persisting symptomatic severe secondary MR at HF programme completion, or had undergone mitral valve surgery. There were no percutaneous mitral valve repairs at the time of these patients' referrals. The rates of ACE/ARB/ARNI, BB and MRA use were 87.8%, 94.1%, and 49.8% in those with mid ranged, or reduced ejection fraction. The rates of ICD and CRT therapy were 15.1% and 4.4% at follow up. Patients with severe MR had higher time adjusted rates of death or hospitalization for heart failure. Conclusion In a well-treated newly diagnosed HF population, repeat assessment at HF programme completion suggests 4.1% of patients have a persisting indication for percutaneous mitral valve repair based on persisting severe symptomatic secondary MR.

Recent Advances in T1 and T2 Mapping in the Assessment of Fulminant Myocarditis by Cardiac Magnetic Resonance.

PURPOSE OF REVIEW: This review was undertaken to summarise recent data relating to T1 and T2 relaxation times in the assessment of myocarditis using cardiac MRI, and the effect new studies have had on the established diagnostic criteria, leading to recently proposed revised criteria for the cardiac MRI assessment of myocarditis. RECENT FINDINGS: In 2018, updates to the 2009 Lake Louise Criteria (LLC) were proposed, based on studies showing improved accuracy of T1 mapping techniques over T1 signal intensity ratio-based imaging, although for the detection of myocardial oedema either T2-weighted images or increased T2 relaxation times can be used. Non-ischaemic distribution of scar on late gadolinium-enhanced (LGE) T1-weighted imaging remains in the newly revised criteria, which, although can have low sensitivity due to fibrosis presenting diffusely or due to CMR being performed early in the disease process before scar formation, remains in the LLC due to its high specificity. Early gadolinium enhancement has been removed from the LLC, as T1 quantification has higher diagnostic accuracy for the detection of myocardial injury. In the CMR assessment of myocarditis, T1 and T2 quantifications are now recommended over T1- and T2-weighted imaging. Late gadolinium enhancement in a non-ischaemic pattern remains in the updated criteria, whereas early gadolinium enhancement has been superseded by T1 quantification.

Primary surgical management of anterior pelvic organ prolapse: a systematic review, network meta-analysis and cost-effectiveness analysis.

BACKGROUND: Anterior compartment prolapse is the most common pelvic organ prolapse (POP) with a range of surgical treatment options available. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of surgical treatments for the repair of anterior POP. METHODS: We conducted a systematic review of randomised controlled trials comparing surgical treatments for women with POP. Network meta-analysis was possible for anterior POP, same-site recurrence outcome. A Markov model was used to compare the cost-utility of surgical treatments for the primary repair of anterior POP from a UK National Health Service perspective. MAIN RESULTS: We identified 27 eligible trials for the network meta-analysis involving eight surgical treatments tested on 3194 women. Synthetic mesh was the most effective in preventing recurrence at the same site. There was no evidence to suggest a difference between synthetic non-absorbable mesh, synthetic partially absorbable mesh, and biological mesh. The cost-utility analysis, which incorporated effectiveness, complications and cost data, found non-mesh repair to have the highest probability of being cost-effective. The conclusions were robust to model inputs including effectiveness, costs and utility values. CONCLUSIONS: Anterior colporrhaphy augmented with mesh appeared to be cost-ineffective in women requiring primary repair of anterior POP. There is a need for further research on long-term effectiveness and the safety of mesh products to establish their relative cost-effectiveness with a greater certainty. TWEETABLE ABSTRACT: New study finds mesh cost-ineffective in women with anterior pelvic organ prolapse.

Short Periods of Hypoxia Upregulate Sphingosine Kinase 1 and Increase Vasodilation of Arteries to Sphingosine 1-Phosphate (S1P) via S1P3.

Sphingosine kinase [(SK), isoforms SK1 and SK2] catalyzes the formation of the bioactive lipid, sphingosine 1-phosphate (S1P). This can be exported from cells and bind to S1P receptors to modulate vascular function. We investigated the effect of short-term hypoxia on SK1 expression and the response of arteries to S1P. SK1 expression in rat aortic and coronary artery endothelial cells was studied using immunofluorescence and confocal microscopy. Responses of rat aortic rings were studied using wire myography and reversible hypoxia induced by bubbling myography chambers with 95% N2:5% CO2 Inhibitors were added 30 minutes before induction of hypoxia. S1P induced endothelium-dependent vasodilation via activation of S1P3 receptors and generation of nitric oxide. Hypoxia significantly increased relaxation to S1P and this was attenuated by (2R)-1-[[(4-[[3-methyl-5-[(phenylsulfonyl)methyl] phenoxy]methyl]phenyl]methyl]-2-pyrrolidinemethanol [(PF-543), SK1 inhibitor] but not (R)-FTY720 methyl ether [(ROMe), SK2 inhibitor]. Hypoxia also increased vessel contractility to the thromboxane mimetic, 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F2α, which was further increased by PF-543 and ROMe. Hypoxia upregulated SK1 expression in aortic and coronary artery endothelial cells and this was blocked by PF-543 and 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole [(SKi), SK1/2 inhibitor]. The effects of PF-543 and SKi were associated with increased proteasomal/lysosomal degradation of SK1. A short period of hypoxia increases the expression of SK1, which may generate S1P to oppose vessel contraction. Under hypoxic conditions, upregulation of SK1 is likely to lead to increased export of S1P from the cell and vasodilation via activation of endothelial S1P3 receptors. These data have significance for perfusion of tissue during episodes of ischemia.

Infective endocarditis: a retrospective cohort study.

BACKGROUND: Infective endocarditis (IE) is a potentially life-threatening infection of the heart's endocardial surface. Despite advances in the diagnosis and management of IE, morbidity and mortality remain high. AIM: To characterize the demographics, bacteriology and outcomes of IE cases presenting to an Irish tertiary referral centre. DESIGN: Retrospective cohort study. METHODS: Patients were identified using Hospital Inpatient Enquiry and Clinical Microbiology inpatient consult data, from January 2005 to January 2014. Patients were diagnosed with IE using Modified Duke Criteria. Standard Bayesian statistics were employed for analysis and cases were compared to contemporary international registries. RESULTS: Two hundred and two patients were diagnosed with IE during this period. Mean age 54 years. Of these, 136 (67%) were native valve endocarditis (NVE), 50 (25%) were prosthetic valve endocarditis (PVE) and 22 (11%) were cardiovascular implantable electronic device-associated endocarditis. Culprit organism was identified in 176 (87.1%) cases and Staphylococcal species were the most common (57.5%). Fifty-nine per cent of NVE required surgery compared to 66% of PVE. Mean mortality rate was 17.3%, with NVE being the lowest (12.5%) and PVE the highest (32%). Increasing age was also associated with increased mortality. Fifty-three (26.2%) patients had embolic complications. CONCLUSIONS: This Irish cohort exhibited first-world demographic patterns comparable to those published in contemporary international literature. PVE required surgery more often and was associated with higher rates of mortality than NVE. Embolic complications were relatively common and represent important sequelae, especially in the intravenous drug user population. It is also pertinent to aggressively treat older cohorts as they were associated with increased mortality.

Is Helmet and Faceguard Modification Common in Hurling and Camogie and Why Is It Done?

Aims Despite no previous research, it is anecdotally reported that hurling and camogie players modify their helmet and faceguard, which is against GAA regulations and can potentially increase injury risk. This study aimed to establish the prevalence and rationale behind modifications in hurling and camogie. Methods An online questionnaire was completed by 304 players aged over 18 (62% hurlers, 38% camogie players) which consisted of 27 questions. Results Appearance (43%) was the primary reasons for helmet brand choice, with just 1.6% citing safety as a main reason for choice. Surprisingly, 8% of helmets were already modified when purchased and 31% of participants made further modifications, primarily switching faceguards and removal of bars. Restricted vision, comfort and perceived poor quality of the helmet/faceguard were the most common reasons for modification. Players predominantly (75.8%) agreed that further education on modifications is required. Conclusion Future research on the relationship between helmet/faceguard modification and injury risk is required.

Genetic epidemiology of malignant hyperthermia in the UK.

BACKGROUND: Gaps in our understanding of genetic susceptibility to malignant hyperthermia (MH) limit the application and interpretation of genetic diagnosis of the condition. Our aim was to define the prevalence and role of variants in the three genes implicated in MH susceptibility in the largest comprehensively phenotyped MH cohort worldwide. METHODS: We initially included one individual from each positive family tested in the UK MH Unit since 1971 to detect variants in RYR1, CACNA1S, or STAC3. Screening for genetic variants has been ongoing since 1991 and has involved a range of techniques, most recently next generation sequencing. We assessed the pathogenicity of variants using standard guidelines, including family segregation studies. The prevalence of recurrent variants of unknown significance was compared with the prevalence reported in a large database of sequence variants in low-risk populations. RESULTS: We have confirmed MH susceptibility in 795 independent families, for 722 of which we have a DNA sample. Potentially pathogenic variants were found in 555 families, with 25 RYR1 and one CACNA1S variants previously unclassified recurrent variants significantly over-represented (P<1×10-7) in our cohort compared with the Exome Aggregation Consortium database. There was genotype-phenotype discordance in 86 of 328 families suitable for segregation analysis. We estimate non-RYR1/CACNA1S/STAC3 susceptibility occurs in 14-23% of MH families. CONCLUSIONS: Our data provide current estimates of the role of variants in RYR1, CACNA1S, and STAC3 in susceptibility to MH in a predominantly white European population.

Early and mid-term outcomes after transcatheter aortic valve implantation (TAVI) in Ireland.

BACKGROUND: TAVI is a percutaneous approach to aortic valve replacement in high surgical risk patients deemed inoperable. AIM: To evaluate the early and mid-term outcomes for an Irish TAVI cohort over a six-year period at St James's Hospital and Blackrock Clinic, Dublin, Ireland. RESULTS: In total 147 patients, 56% male with an average age of 82 underwent TAVI between December 2008 and December 2014. Thirty day, one year and two year survival was 90.5%, 83% and 71% respectively. Major vascular complications and renal failure were the biggest predictors of mortality at 30 days (p = 0.02). We observed a pacing rate of 13.5%, the majority in patients who had Medtronic Corevalve implants (p < 0.05). With increasing procedural experience there was a reduction in length of stay from 10 days to 7.5 days. CONCLUSION: This review, the first of its kind in Ireland showed favorable rates of 30 day and one year and two year survival post TAVI with procedural success and complication rates similar to international registry data.

Uptake of Cancer Screening Tests Among Recipients of Solid Organ Transplantation.

Population-based cancer screening recommendations are also suggested for solid organ transplant recipients (SOTR); however, recommendation adherence is unknown. In a population-based cohort of SOTR in Ontario between 1997 and 2010, we determined the uptake of breast, cervical, and colorectal cancer screening tests and identified factors associated with up-to-date screening using recurrent event analysis. We identified 4436 SOTR eligible for colorectal, 2252 for cervical, and 1551 for breast cancer screening. Of those, 3437 (77.5%), 1572 (69.8%), and 1417 (91.4%), respectively, were not up-to-date for cancer screening tests during the observation period. However, these rates are likely an overestimate due to the inability to differentiate between tests done for screening or for diagnosis. SOTR with fewer comorbidities had higher rates of becoming screen up-to-date. Assessment by a primary care provider (PCP) was associated with becoming up-to-date with cancer screening (breast relative risk [RR] = 1.40, 95% confidence interval [CI]: 1.12-1.76, cervical RR = 1.29, 95% CI: 1.06-1.57, colorectal RR = 1.30, 95% CI: 1.15-1.48). Similar results were observed for continuity of care by transplant specialist at a transplant center. In conclusion, cancer screening for most SOTR does not adhere to standard recommendations. Involvement of PCPs in posttransplant care and continuity of care at a transplant center may improve the uptake of screening.

Assessing the pathogenicity of RYR1 variants in malignant hyperthermia.

BACKGROUND: . Missense variants in the ryanodine receptor 1 gene ( RYR1 ) are associated with malignant hyperthermia but only a minority of these have met the criteria for use in predictive DNA diagnosis. We examined the utility of a simplified method of segregation analysis and a functional assay for determining the pathogenicity of recurrent RYR1 variants associated with malignant hyperthermia. METHODS: . We identified previously uncharacterised RYR1 variants found in four or more malignant hyperthermia families and conducted simplified segregation analyses. An efficient cloning and mutagenesis strategy was used to express ryanodine receptor protein containing one of six RYR1 variants in HEK293 cells. Caffeine-induced calcium release, measured using a fluorescent calcium indicator, was compared in cells expressing each variant to that in cells expressing wild type ryanodine receptor protein. RESULTS.: We identified 43 malignant hyperthermia families carrying one of the six RYR1 variants. There was segregation of genotype with the malignant hyperthermia susceptibility phenotype in families carrying the p.E3104K and p.D3986E variants, but the number of informative meioses limited the statistical significance of the associations. HEK293 functional assays demonstrated an increased sensitivity of RyR1 channels containing the p.R2336H, p.R2355W, p.E3104K, p.G3990V and p.V4849I compared with wild type, but cells expressing p.D3986E had a similar caffeine sensitivity to cells expressing wild type RyR1. CONCLUSIONS: . Segregation analysis is of limited value in assessing pathogenicity of RYR1 variants in malignant hyperthermia. Functional analyses in HEK293 cells provided evidence to support the use of p.R2336H, p.R2355W, p.E3104K, p.G3990V and p.V4849I for diagnostic purposes but not p.D3986E.

Investigation of outbreaks of Pneumocystis jirovecii pneumonia in two Scottish renal units.

Pneumocystis jirovecii is recognized as an opportunistic pathogen. In recent years, human-to-human transmission of P. jirovecii has been demonstrated. However, outbreaks of P. jirovecii infections are not well defined because the epidemiological setting that facilitates transmission is not fully understood. This article describes two outbreaks of P. jirovecii pneumonia (PCP) in renal transplant patients in the West of Scotland. In total, 25 patients in two geographically contiguous locations were affected. Allele B was identified as the dominant type, along with allele A3. It was not possible to determine the exact reason for clustering of cases, although the outpatient clinic setting featured in one of the outbreaks. The outbreaks ceased with the use of trimethoprim-sulphamethoxazole prophylaxis; the target populations that received prophylaxis were different in the two outbreaks. Infection control teams should be alert to the possibility of outbreaks of PCP.

FGFR3-TACC3 fusion proteins act as naturally occurring drivers of tumor resistance by functionally substituting for EGFR/ERK signaling.

The epidermal growth factor receptor (EGFR) is a clinically validated target in head and neck squamous cell carcinoma (HNSCC), where EGFR-blocking antibodies are approved for first-line treatment. However, as with other targeted therapies, intrinsic/acquired resistance mechanisms limit efficacy. In the FaDu HNSCC xenograft model, we show that combined blockade of EGFR and ERBB3 promotes rapid tumor regression, followed by the eventual outgrowth of resistant cells. RNA sequencing revealed that resistant cells express FGFR3-TACC3 fusion proteins, which were validated as drivers of the resistant phenotype by several approaches, including CRISPR-mediated inactivation of FGFR3-TACC3 fusion genes. Interestingly, analysis of signaling in resistant cell lines demonstrated that FGFR3-TACC3 fusion proteins promote resistance by preferentially substituting for EGFR/RAS/ERK signaling rather than ERBB3/PI3K/AKT signaling. Furthermore, although FGFR3-TACC3 fusion proteins promote resistance of additional EGFR-dependent HNSCC and lung cancer cell lines to EGFR blockade, they are unable to compensate for inhibition of PI3K signaling in PIK3CA-mutant HNSCC cell lines. Validation of FGFR3-TACC3 fusion proteins as endogenous drivers of resistance in our screen provides strong evidence that these fusions are capable of substituting for EGFR signaling. Thus, FGFR3-TACC3 fusion proteins may represent a novel mechanism of acquired resistance in EGFR-dependent cancers of multiple cell lineages.

Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium.

Aberrant Wnt signaling within breast cancer is associated with poor prognosis, but regulation of this pathway in breast tissue remains poorly understood and the consequences of immediate or long-term dysregulation remain elusive. The exact contribution of the Wnt-regulating proteins adenomatous polyposis coli (APC) and APC2 in the pathogenesis of human breast cancer are ill-defined, but our analysis of publically available array data sets indicates that tumors with concomitant low expression of both proteins occurs more frequently in the 'triple negative' phenotype, which is a subtype of breast cancer with particularly poor prognosis. We have used mouse transgenics to delete Apc and/or Apc2 from mouse mammary epithelium to elucidate the significance of these proteins in mammary homeostasis and delineate their influences on Wnt signaling and tumorigenesis. Loss of either protein alone failed to affect Wnt signaling levels or tissue homeostasis. Strikingly, concomitant loss led to local disruption of ß-catenin status, disruption in epithelial integrity, cohesion and polarity, increased cell division and a distinctive form of ductal hyperplasia with 'squamoid' ghost cell nodules in young animals. Upon aging, the development of Wnt activated mammary carcinomas with squamous differentiation was accompanied by a significantly reduced survival. This novel Wnt-driven mammary tumor model highlights the importance of functional redundancies existing between the Apc proteins both in normal homeostasis and in tumorigenesis.

The cost of inpatient management of heart failure patients: a microcosting study in the Irish healthcare setting.

AIMS: To formally assess the resource use and cost of the inpatient treatment of heart failure (HF) from the health-payer's perspective. In addition, to compare costs in our cohort to (a) locally derived patient-level costs (PLC) and (b) national costs as per disease-related group (DRG). METHODS AND RESULTS: Study population Demographics and resource utilisation data were obtained from a cohort of 30 patients (57% male, mean age 70 years) admitted into a single tertiary centre with heart failure. Patients were identified retrospectively. Costing A microcosting approach was used to examine admission costs that were compared to PLC costs and DRG costs. Main outcome measure The bootstrap estimation was used to determine mean inpatient length of stay (LOS) with standard deviation (±SD) and mean costs ±SD. RESULTS: The bootstrapped mean cost per HF episode was €10,474 ± 2478. The major cost drivers were ward stay (mean cost €6068 ± €1681): laboratory costs (€1373 ± 79) and cath lab costs (€1415 ± 729). HF was more expensive to manage in patients ≤65 years (€18,930 ± 5546) compared to those aged over 65 years (€6209 ± 1732); p = 0.001. No significant difference was found in managing heart failure in males (€11,035 ± 3564) versus females (€9629 ± 3294), p = 0.69. DRG costing frequently over or underestimated the admission cost. PLC costs were similar to microcosting derived costs. The bootstrapped mean LOS per HF episode was 15.7 days ± 3.4. CONCLUSIONS: This study confirms that heart failure is a costly condition and that inpatient stay is the major cost driver. HF was significantly more expensive to manage in patients ≤65 years compared to those aged over 65 years. DRG costing frequently over or underestimated the admission cost. Patient-level costs and microcosting are more accurate methods of costing inpatient HF admissions. To our knowledge, this is the first study of the cost of the inpatient treatment of HF within the context of the Irish healthcare setting.