Pregnancy outcomes for women with pre-existing renal disease and the role of a dedicated joint maternal medicine and renal clinic: A retrospective cohort study.

OBJECTIVE: To reaffirm the value of a joint obstetric and renal clinic on obstetric outcomes in patients with high-risk pregnancies due to chronic kidney disease (CKD). METHODS: This was a retrospective cohort study of patients who attended the clinic between 2005 and December 2021. The hospital is a regional tertiary unit for renal medicine and a maternal medicine hub. The data included all women with pre-existing renal conditions who were cared for in a dedicated renal and obstetric clinic. Datasets were extracted from hospital notes, the renal database, clinical data and maternity electronic health records. The data analyzed included pre-existing renal conditions, biochemical parameters related to the renal condition, pregnancy outcomes included miscarriages, gestation, mode of delivery, postpartum hemorrhage (PPH), loss, birth weight and neonatal admission. RESULTS: The results were as follows: Lupus nephritis: four term deliveries; three had pre-eclampsia; two PPH and two miscarriages. Four estimated glomerular filtration rates (eGFRs) returned to baseline levels within 12 months. With regard to IgA nephropathy there were five live births, four term deliveries, two pre-eclampsia (PE) and five cesarean sections (CS). All eGFRs returned to baseline within 12 months. With regard to patients with adult polycystic kidney disease (APKD), there were six live births, two had pre-eclampsia and there were five term vaginal deliveries. CONCLUSION: Patients with lupus nephritis, APKD, and IgA demonstrated a higher incidence of adverse pregnancy outcomes as compared with our local pregnant population. Our findings reflect those of larger studies and support the role of combined renal/obstetric clinics. More research and larger scale studies are needed into specific CKD conditions and their outcomes.

Hypothalamic subunit volumes and relations to violence and psychopathy in male offenders with or without a psychotic disorder.

The hypothalamus is key to body homeostasis, including regulating cortisol, testosterone, vasopressin, and oxytocin hormones, modulating aggressive behavior. Animal studies have linked the morphology and function of the hypothalamus to aggression and affiliation, with a subregional pattern reflecting the functional division between the hypothalamic nuclei. We explored the relationship between hypothalamic subunit volumes in violent offenders with (PSY-V) and without (NPV) a psychotic disorder, and the association with psychopathy traits. 3T MRI scans (n = 628, all male 18-70 years) were obtained from PSY-V, n = 38, NPV, n = 20, non-violent psychosis patients (PSY-NV), n = 134, and healthy controls (HC), n = 436. The total hypothalamus volume and its eleven nuclei were delineated into five subunits using Freesurfer v7.3. Psychopathy traits were assessed with Psychopathy Checklist-revised (PCL-R). ANCOVAs and linear regressions were used to analyze associations with subunit volumes. Both groups with a history of violence exhibited smaller anterior-superior subunit volumes than HC (NPV Cohen's d = 0.56, p = 0.01 and PSY-V d = 0.38, p = 0.01). There were no significant differences between HC and PSY-NV. PCL-R scores were positively associated with the inferior tubular subunit on a trend level (uncorrected p = 0.045, Cohen's d = 0.04). We found distinct hypothalamic subunit volume reductions in persons with a history of violence independent of concomitant psychotic disorder but not in persons with psychosis alone. The results provide further information about the involvement of the hypothalamus in aggression, which ultimately may lead to the development of targeted treatment for the clinical and societal challenge of aggression and violent behavior.

Adaptive Care Planning: A paradigm shift.

A key challenge of implementing advance care planning lies in the fact that decisions made in advance require patients and their family members to imagine what their clinical picture will look like rather than knowing or experiencing the clinical circumstances as they unfold. Even more important is the acknowledgment of the unpredictability of a given clinical course. This type of situation requires adaptiveness and flexibility in decision-making that frequently occurs in the moment(s) triggered by changes in health state(s). We describe an alternative frameshifting approach called "Adaptive Care Planning (AdaptCP)," which features an evolving communication between physicians and patients/families with ongoing incorporation of the patient's/family's perspective. This process continues iteratively until each decision can be reached in a way that is both harmonious with the patient's/family's perspective and is consistent with medical treatment options that are actionable for the healthcare team. We include a table of tools drawn from the literature that can help clinicians when implementing AdaptCP.

Violent Offending in Males With or Without Schizophrenia: A Role for Social Cognition?

BACKGROUND AND HYPOTHESIS: Reduced social cognition has been reported in individuals who have committed interpersonal violence. It is unclear if individuals with schizophrenia and a history of violence have larger impairments than violent individuals without psychosis and non-violent individuals with schizophrenia. We examined social cognition in two groups with violent offenses, comparing their performance to non-violent individuals with schizophrenia and healthy controls. STUDY DESIGN: Two social cognitive domains were assessed in four groups: men with a schizophrenia spectrum disorder with (SSD-V, n = 27) or without (SSD-NV, n = 42) a history of violence, incarcerated men serving preventive detention sentences (V, n = 22), and healthy male controls (HC, n = 76). Theory of mind (ToM) was measured with the Movie for the Assessment of Social Cognition (MASC), body emotion perception with Emotion in Biological Motion (EmoBio) test. STUDY RESULTS: Kruskal-Wallis H-tests revealed overall group differences for social cognition. SSD-V had a global and clinically significant social cognitive impairment. V had a specific impairment, for ToM. Binary logistic regressions predicting violence category membership from social cognition and psychosis (SSD status) were conducted. The model with best fit, explaining 18%-25% of the variance, had ToM as the only predictor. CONCLUSIONS: Social cognitive impairment was present in individuals with a history of violence, with larger and more widespread impairment seen in schizophrenia. ToM predicted violence category membership, psychosis did not. The results suggest a role for social cognition in understanding interpersonal violence.

Impulsivity across severe mental disorders: a cross-sectional study of immune markers and psychopharmacotherapy.

BACKGROUND: Impulsivity is a transdiagnostic feature linked to severe clinical expression and a potential target for psychopharmacological strategies. Biological underpinnings are largely unknown, but involvement of immune dysregulation has been indicated, and the effects of psychopharmacological agents vary. We investigated if impulsivity was associated with circulating immune marker levels and with a range of psychopharmacological treatment regimens in severe mental disorders. METHODS: Impulsivity was assessed in a sample (N = 657) of patients with schizophrenia or schizophreniform disorder (SCZ) (N = 116) or bipolar disorder (BD) (N = 159) and healthy participants (N = 382) using the Barratt Impulsiveness Scale (BIS-11) questionnaire. Plasma levels of systemic immune markers (RANTES, IL-1RA, IL-18, IL-18BP, sTNFR-1) were measured by enzyme immunoassays. Patients underwent thorough clinical assessment, including evaluation of psychotropic medication. Associations were assessed using linear regressions. RESULTS: Impulsivity  was positively associated with SCZ (p < 0.001) and BD (p < 0.001) diagnosis and negatively associated with age (p < 0.05), but not significantly associated with any of the circulating immune markers independently of diagnostic status. Among patients, impulsivity was negatively associated with lithium treatment (p = 0.003) and positively associated with antidepressant treatment (p = 0.011) after controlling for diagnosis, psychotropic co-medications, manic symptoms, and depressive symptoms. CONCLUSIONS: We report elevated impulsivity across SCZ and BD but no associations to systemic immune dysregulation based on the current immune marker selection. The present study reveals associations between impulsivity in severe mental disorders and treatment with lithium and antidepressants, with opposite directions. Future studies are warranted to determine the causal directionality of the observed associations with psychopharmacotherapy.

Quantifying KRAS G12C Covalent Drug Inhibitor Activity in Mouse Tumors Using Mass Spectrometry.

The growing opportunities recognized for covalent drug inhibitors, like KRAS G12C inhibitors, are driving the need for mass spectrometry methods that can quickly and robustly measure therapeutic drug activity in vivo for drug discovery research and development. Effective front-end sample preparation is critical for proteins extracted from tumors but is generally labor intensive and impractical for large sample numbers typical in pharmacodynamic (PD) studies. Herein, we describe an automated and integrated sample preparation method for the measurement of activity levels of KRAS G12C drug inhibitor alkylation from complex tumor samples involving high throughput detergent removal and preconcentration followed by quantitation using mass spectrometry. We introduce a robust assay with an average intra-assay coefficient of variation (CV) of 4% and an interassay CV of 6% obtained from seven studies, enabling us to understand the relationship between KRAS G12C target occupancy and the therapeutic PD effect from mouse tumor samples. Further, the data demonstrated that the drug candidate GDC-6036, a KRAS G12C covalent inhibitor, shows dose-dependent target inhibition (KRAS G12C alkylation) and MAPK pathway inhibition, which correlate with high antitumor potency in the MIA PaCa-2 pancreatic xenograft model.

Psychopathy subdomains in violent offenders with and without a psychotic disorder.

BACKGROUND: Violence in psychosis has been linked to antisocial behavior and psychopathy traits. Psychopathy comprises aspects of interpersonal, affective, lifestyle, and antisocial traits which may be differently involved in violent offending by persons with psychotic disorders. We explored psychopathy subdomains among violent offenders with and without a psychotic disorder. METHODS: 46 males, with a history of severe violence, with (n = 26; age 35.85 ± 10.34 years) or without (n = 20; age 39.10 ± 11.63 years) a diagnosis of a psychotic disorder, were assessed with the Psychopathy Checklist-Revised (PCL-R). PCL-R was split into subdomains following the four-facet model. Group differences in total and subdomain scores were analyzed with a general linear model with covariates. RESULTS: Total PCL-R scores did not differ between the groups (p = 0.61, Cohen's d = 0.17). The violent offenders without psychotic disorders had higher facet 2 scores than the patient group with psychotic disorders (p = 0.029, Cohen's d = 0.77). Facet 1, 3, or 4 scores did not differ between the groups. Controlling for age did not alter the results. CONCLUSION: Patients with a psychotic disorder and a history of severe violence have lower affective psychopathy scores than violent offenders without psychotic disorders. This observation may point toward distinct underlying mechanisms for violence and may provide a target for focused treatment and prevention.

The age of violence: Mapping brain age in psychosis and psychopathy.

Young chronological age is one of the strongest predictors for antisocial behaviour in the general population and for violent offending in individuals with psychotic disorders. An individual's age can be predicted with high accuracy using neuroimaging and machine-learning. The deviation between predicted and chronological age, i.e., brain age gap (BAG) has been suggested to reflect brain health, likely relating partly to neurodevelopmental and aging-related processes and specific disease mechanisms. Higher BAG has been demonstrated in patients with psychotic disorders. However, little is known about the brain-age in violent offenders with psychosis and the possible associations with psychopathy traits. We estimated brain-age in 782 male individuals using T1-weighted MRI scans. Three machine learning models (random forest, extreme gradient boosting with and without hyper parameter tuning) were first trained and tested on healthy controls (HC, n = 586). The obtained BAGs were compared between HC and age matched violent offenders with psychosis (PSY-V, n = 38), violent offenders without psychosis (NPV, n = 20) and non-violent psychosis patients (PSY-NV, n = 138). We ran additional comparisons between BAG of PSY-V and PSY-NV and associations with Positive and Negative Syndrome Scale (PANSS) total score as a measure of psychosis symptoms. Psychopathy traits in the violence groups were assessed with Psychopathy Checklist-revised (PCL-R) and investigated for associations with BAG. We found significantly higher BAG in PSY-V compared with HC (4.9 years, Cohen'sd = 0.87) and in PSY-NV compared with HC (2.7 years, d = 0.41). Total PCL-R scores were negatively associated with BAG in the violence groups (d = 1.17, p < 0.05). Additionally, there was a positive association between psychosis symptoms and BAG in the psychosis groups (d = 1.12, p < 0.05). While the significant BAG differences related to psychosis and not violence suggest larger BAG for psychosis, the negative associations between BAG and psychopathy suggest a complex interplay with psychopathy traits. This proof-of-concept application of brain age prediction in severe mental disorders with a history of violence and psychopathy traits should be tested and replicated in larger samples.

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia.

It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.

Interleukin-18 signaling system links to agitation in severe mental disorders.

OBJECTIVE: Agitation is a challenging clinical feature in severe mental disorders, but its biological correlates are largely unknown. Inflammasome-related abnormalities have been linked to severe mental disorders and implicated in animal models of agitation. We investigated if levels of circulating inflammasome-related immune markers were associated with agitation in severe mental disorders. METHODS: Individuals with a psychotic or affective disorder (N = 660) underwent blood sampling and clinical characterization. Plasma levels of interleukin (IL)-18, IL-18 binding protein (IL-18BP), IL-18 receptor 1 (IL-18R1), IL-18 receptor accessory protein (IL-18RAP), and IL-1 receptor antagonist (IL-1RA) were measured. Agitation levels were estimated with the Positive and Negative Syndrome Scale Excited Component. Multiple linear- and logistic regression were used to investigate the associations between agitation and the immune markers, while controlling for confounders. The influence of psychotic and affective symptoms was assessed in follow-up analyses. RESULTS: Agitation was positively associated with IL-18BP (ß = 0.13, t = 3.41, p = 0.0007) after controlling for multiple confounders, including BMI, smoking, medication, and substance use. Adjustment for psychotic, manic, and depressive symptoms did not affect the results. There were no significant associations between agitation and the other investigated immune markers (IL-1RA (ß = 0.06, t = 1.27, p = 0.20), IL-18 (ß = 0.05, t = 1.25, p = 0.21), IL-18R1 (ß = 0.04, t = 1.01, p = 0.31), IL-18RAP (odds ratio = 0.96, p = 0.30)). In a subsample (N = 463), we also adjusted for cortisol levels, which yielded unaltered results. CONCLUSION: Our findings add to the accumulating evidence of immune system disturbances in severe mental disorders and suggest the IL-18 system as a part of the biological correlate of agitation independent of affective and psychotic symptoms.

Associations between amygdala nuclei volumes, psychosis, psychopathy, and violent offending.

The amygdala is involved in fear perception and aggression regulation, and smaller volumes have been associated with psychotic and non-psychotic violence. We explored the relationship between amygdala nuclei volumes in violent offenders with and without psychosis, and the association to psychopathy traits. 3T MRI scans (n = 204, males, 18-66 years) were obtained from psychotic violent offenders (PSY-V, n = 29), non-psychotic violent offenders (NPV, n = 19), non-violent psychosis patients (PSY-NV, n = 67), and healthy controls (HC, n = 89). Total amygdala and 9 amygdala nuclei volumes were obtained with FreeSurfer. Psychopathy traits were measured with the Psychopathy Checklist-revised (PCL-R). Multivariate analyses explored diagnostic differences in amygdala nuclei volumes and associations to psychosis, violence, and psychopathy traits. PSY-V had a smaller basal nucleus, anterior amygdaloid area, and cortical amygdalar transition area (CATA), whereas PSY-NV had a smaller CATA than HC. Volumes in NPV did not differ from HC, and there were no associations between PCL-R total or factor scores and any of the nuclei or whole amygdala volumes. The lower volumes of amygdala nuclei involved in fear modulation, stress responses, and social interpretation may point towards some mechanisms of relevance to violence in psychosis, but the results warrant replication in larger subject samples.

Promises and pitfalls of digital knowledge exchange resulting from the COVID-19 pandemic.

In this article, we integrate our authorship experiences with insights from nine interviews of knowledge exchange practitioners at the Canadian Forest Service about challenges and opportunities of digital knowledge exchange (KE) brought on by the COVID-19 pandemic. We aim to inform how best to maintain effective KE practices and processes in a digital-first world. Interpersonal trust and relationships are pivotal to effective knowledge exchange; thus, removing these dimensions risks losing aspects of social learning, informal and meaningful discussions, and personal connections that affect how we interpret and respond to subtle affective and social cues. For KE practitioners, lack of in-person interactions risks internal KE coordination and relevance of KE work, and diminished ability to predict and respond to user needs. However, the accelerated digital adoption has increased reach and accessibility for diverse people to exchange knowledge, and enables more frequent and rapid response to issues and events by virtually gathering diverse people almost instantly. The acceleration in digital innovation and culture has thus resulted in new tools and diversified approaches for the KE toolbox to inform decisions and practices. The long-term sustainability and effectiveness of digital KE depend on two interconnected factors: addressing the persistence of the digital divide and people's abilities to make and maintain meaningful social connections in the absence of regular face-to-face contact. We thus offer three considerations to guide KE efforts and initiative in a digital-first world: (1) consider both digital divide and equity; (2) revisit user needs and preferences for KE to address the diversity of users, and (3) leverage the diversification of KE approaches and innovations.

Disentangling the relationship between cholesterol, aggression, and impulsivity in severe mental disorders.

OBJECTIVE: Low total cholesterol has been linked with adverse mental symptoms such as aggression and impulsivity in severe mental disorders (SMDs). This putative association may affect the clinician's decision making about cholesterol lowering in this patient group. Here, we investigated the associations between cholesterol levels, aggression, and impulsivity in a large representative sample of in- and outpatients with SMD. METHODS: Patients with schizophrenia- or bipolar spectrum disorders (N = 1 001) underwent thorough clinical characterization and blood sampling (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol). Aggression was characterized by the Positive and Negative Syndrome Scale Excited Component. Impulsivity was measured with the Barratt Impulsiveness Scale in a subsample of patients (N = 288). We used a multinomial logistic regression model to analyze the association between cholesterol and aggression and a multiple linear regression model to analyze the association between cholesterol and impulsivity, while controlling for confounders. RESULTS: We found no significant associations between cholesterol levels and aggression or impulsivity. There were no significant interactions between cholesterol and diagnostic group or inpatient versus outpatient status. Controlling for medication use, body mass index, alcohol or illicit substance use did not affect the results. CONCLUSION: In this large sample of patients with schizophrenia- and bipolar spectrum disorders, we found no associations between cholesterol levels and aggression or impulsivity. This has clinical implications as patients with SMD are at increased CVD risk and currently undertreated with statins.

Evolving Palliative Care Practices among Marshall Islanders in Hawai'i: Generational Comparisons.

Little is known about Marshallese palliative care practices. We explored traditional and contemporary Marshallese palliative care practices and examined generational differences. We performed three focus groups in 2011-2012 among Marshall Islanders in Hawai'i. A native speaking interpreter assisted group facilitators. Data were analyzed using classical thematic triangulation methods to identify specific Marshallese palliative care practices, the effect of economic and social challenges in Hawai'i, and generational differences comparing young and old. Nineteen persons (10 men and 9 women, youth aged 17-27 years, and elders as defined in Marshallese culture, aged 46-79) participated. A "good death" was defined as "peaceful and pain free," occurring from natural causes. Factors associated with a "good death" included gathering of family to absolve conflicts, and proper and timely cultural practices. Factors associated with "bad deaths" included young age, active suffering, accidents, suicides, "black magic/curses," or lack of timely or proper burial. Comparing generational differences, older Marshallese had differing opinions regarding preferred place of death, burial site, cultural practice preservation, artificial prolongation of life, and cremation. Barriers included mortuary fees, cost of transporting bodies, United States (US) government policies, and wait times for death certificates. Many cultural factors contribute to "good" or "bad" deaths. Attitudes toward palliative care practices differ by generation. Having previously documented different approaches by Yapese, a generalized "one size fits all" approach to Micronesians is inappropriate. Overcoming identified barriers may facilitate practices necessary for a good death in Micronesian populations in their home nations and as they migrate to communities throughout the US.

Hippocampal subfield and amygdala nuclei volumes in schizophrenia patients with a history of violence.

Schizophrenia (SCZ) is associated with an increased risk of violence compared to the general population. Previous studies have indicated smaller hippocampal and amygdala volumes in violent than non-violent psychotic patients. However, little is known about volumetric differences at the subdivision level of these structures. In the present study, hippocampal subfields and amygdala nuclei volumes were estimated with FreeSurfer from 3 T MRI of SCZ patients with (SCZ-V, n = 24) and without (SCZ-NV, n = 51) a history of severe violence and 90 healthy controls (HC). Volumetric differences between groups were explored with a general linear model covarying for confounders, in addition to follow-up analyses in patient groups controlling for clinical characteristics such as antipsychotic medication, duration of illness and illicit substance use. SCZ-V had smaller total hippocampal volume and smaller CA1, HATA, fimbria, and molecular layer of DG volumes compared to HC. Total amygdala volume together with basal nucleus, accessory basal nucleus, CTA, and paralaminar nucleus volumes were smaller in SCZ-V compared to HC. In SCZ-NV, compared to HC, the observed smaller volumes were limited to basal and paralaminar nucleus. There were no significant differences in hippocampal subfield and amygdala nuclei volumes between SCZ-V and SCZ-NV. Follow-up analyses showed that the results in patient groups were not affected by clinical characteristics. The results suggest that smaller hippocampal subfield and amygdala nuclei volumes may be relevant to violence risk in SCZ. However, the neurobiological signature of violence in SCZ should be further investigated in larger cohorts.

Pathogenic Pathways in Early-Onset Autosomal Recessive Parkinson's Disease Discovered Using Isogenic Human Dopaminergic Neurons.

Parkinson's disease (PD) is a complex and highly variable neurodegenerative disease. Familial PD is caused by mutations in several genes with diverse and mostly unknown functions. It is unclear how dysregulation of these genes results in the relatively selective death of nigral dopaminergic neurons (DNs). To address this question, we modeled PD by knocking out the PD genes PARKIN (PRKN), DJ-1 (PARK7), and ATP13A2 (PARK9) in independent isogenic human pluripotent stem cell (hPSC) lines. We found increased levels of oxidative stress in all PD lines. Increased death of DNs upon differentiation was found only in the PARKIN knockout line. Using quantitative proteomics, we observed dysregulation of mitochondrial and lysosomal function in all of the lines, as well as common and distinct molecular defects caused by the different PD genes. Our results suggest that precise delineation of PD subtypes will require evaluation of molecular and clinical data.

Fall Ascertainment and Development of a Risk Prediction Model Using Electronic Medical Records.

OBJECTIVES: To examine the use of electronic medical record (EMR) data to ascertain falls and develop a fall risk prediction model in an older population. DESIGN: Retrospective longitudinal study using 10 years of EMR data (2004-2014). A series of 3-year cohorts included members continuously enrolled for a minimum of 3 years, requiring 2 years pre-fall (no previous record of a fall) and a 1-year fall risk period. SETTING: Kaiser Permanente Hawaii, an ambulatory setting. PARTICIPANTS: A total of 57 678 adults, age 60 years and older. MEASUREMENTS: Initial EMR searches were guided by current literature and geriatricians to understand coding sources of falls as our outcome. Falls were captured by two coding sources: International Classification of Diseases, Ninth Revision (ICD-9) codes (E880-889) and/or a fall listed as a "primary reason for visit." A comprehensive list of EMR predictors of falls were included into prediction models enabling statistical subset selection from many variables and modeling by logistic regression. RESULTS: Although 72% of falls in the training data set were coded as "primary reason for visit," 22% of falls were coded as ICD-9 and 6% coded as both. About 80% were reported in face-to-face encounters (eg, emergency department). A total of 2164 individuals had a fall in the risk period. Using the 13 key predictors (age, comorbidities, female sex, other mental disorder, walking issues, Parkinson's disease, urinary incontinence, depression, polypharmacy, psychotropic and anticonvulsant medications, osteoarthritis, osteoporosis) identified through LASSO regression, the final model had a sensitivity of 67%, specificity of 69%, positive predictive value of 8%, negative predictive value of 98%, and area under the curve of .74. CONCLUSION: This study demonstrated how the EMR can be used to ascertain falls and develop a fall risk prediction model with moderate sensitivity/specificity. Concurrent work with clinical providers to enhance fall documentation will improve the ability of the EMR to capture falls and consequently may improve the model to predict fall risk.

Perceived social support and the risk of cardiovascular disease and all-cause mortality in the Women's Health Initiative Observational Study.

OBJECTIVE: Previous studies have shown social support to be inversely associated with cardiovascular disease (CVD) in men, whereas fewer studies have assessed the relationship in women. The purpose of this study was to evaluate the relationship between perceived social support and cardiovascular outcomes among postmenopausal women enrolled in the Women's Health Initiative Observational Study. METHODS: We examined the relationships between perceived social support and (1) incident coronary heart disease (CHD), (2) total CVD, and (3) all-cause mortality. Participants were Women's Health Initiative Observational Study women, ages 50 to 79 years, enrolled between 1993 and 1998 and followed for up to 10.8 years. Social support was ascertained at baseline via nine questions measuring the following functional support components: emotional/informational, tangible, positive social interaction, and affectionate support. RESULTS: Among women with prior CVD (n = 17,351) and no prior CVD (n = 73,421), unadjusted hazard ratios ranged from 0.83 to 0.93 per standard deviation increment of social support. Adjustment for potential confounders, such as smoking and physical activity levels, eliminated the statistical significance of the associations with CHD and CVD. However, for all-cause mortality and among women free of baseline CVD, the association was modest but remained statistically significant after this adjustment (hazard ratio = 0.95 [95% confidence interval, 0.91-0.98]). No statistically significant association was observed among women with a history of CVD. CONCLUSIONS: After controlling for potential confounding variables, higher perceived social support is not associated with incident CHD or CVD. However, among women free of CVD at baseline, perceived social support is associated with a slightly lower risk of all-cause mortality.

Ryanodine channel complex stabilizer compound S48168/ARM210 as a disease modifier in dystrophin-deficient mdx mice: proof-of-concept study and independent validation of efficacy.

Muscle fibers lacking dystrophin undergo a long-term alteration of Ca2+ homeostasis, partially caused by a leaky Ca2+ release ryanodine (RyR) channel. S48168/ARM210, an RyR calcium release channel stabilizer (a Rycal compound), is expected to enhance the rebinding of calstabin to the RyR channel complex and possibly alleviate the pathologic Ca2+ leakage in dystrophin-deficient skeletal and cardiac muscle. This study systematically investigated the effect of S48168/ARM210 on the phenotype of mdx mice by means of a first proof-of-concept, short (4 wk), phase 1 treatment, followed by a 12-wk treatment (phase 2) performed in parallel by 2 independent laboratories. The mdx mice were treated with S48168/ARM210 at two different concentrations (50 or 10 mg/kg/d) in their drinking water for 4 and 12 wk, respectively. The mice were subjected to treadmill sessions twice per week (12 m/min for 30 min) to unmask the mild disease. This testing was followed by in vivo forelimb and hindlimb grip strength and fatigability measurement, ex vivo extensor digitorum longus (EDL) and diaphragm (DIA) force contraction measurement and histologic and biochemical analysis. The treatments resulted in functional (grip strength, ex vivo force production in DIA and EDL muscles) as well as histologic improvement after 4 and 12 wk, with no adverse effects. Furthermore, levels of cellular biomarkers of calcium homeostasis increased. Therefore, these data suggest that S48168/ARM210 may be a safe therapeutic option, at the dose levels tested, for the treatment of Duchenne muscular dystrophy (DMD).-Capogrosso, R. F., Mantuano, P., Uaesoontrachoon, K., Cozzoli, A., Giustino, A., Dow, T., Srinivassane, S., Filipovic, M., Bell, C., Vandermeulen, J., Massari, A. M., De Bellis, M., Conte, E., Pierno, S., Camerino, G. M., Liantonio, A., Nagaraju, K., De Luca, A. Ryanodine channel complex stabilizer compound S48168/ARM210 as a disease modifier in dystrophin-deficient mdx mice: proof-of-concept study and independent validation of efficacy.

What's the Plan? Needing Assistance with Plan of Care Is Associated with In-Hospital Death for ICU Patients Referred for Palliative Care Consultation.

To inform earlier identification of intensive care unit (ICU) patients needing palliative care, we examined factors associated with in-hospital death among ICU patients (N=260) receiving palliative care consultations at a 542-bed tertiary care hospital (2005-2009). High pre-consultation length of stay (LOS, ≥7 days) (adjusted odds ratio (aOR)=5.0, 95% confidence interval (95% CI)=2.5-9.9, P<.01) and consultations for assistance with plan of care (aOR=11.6, 95% CI=5.6-23.9, P<.01) were independently associated with in-hospital death. Patients with both consultation for plan of care and high pre-consult LOS had the highest odds of in-hospital death (aOR=36.3, 95% CI=14.9-88.5, P<.001), followed by patients with consultation for plan of care and shorter pre-consult LOS (aOR=9.8, 95% CI=4.3-22.1, P<.001), and patients with long pre-consult LOS but no consultation for plan of care (aOR=4.7, 95% CI=1.8-12.4, P=.002). Our findings suggest that ICU patients who require assistance with plan of care need to be identified early to optimize end-of-life care and avoid in-hospital death.