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Clinical social workers are psychosocial care experts who provide interventions that aim to address the emotional, relational, financial, and logistical challenges that arise throughout the hematopoietic cell transplantation (HCT) treatment and recovery process. Interventions that contribute to better patient outcomes can include cognitive behavioral therapy and counseling for adaptation to illness, family planning for 24/7 caregiver availability and strategies to support patient activities of daily living, instruction on guided imagery and relaxation techniques for symptom management and to decrease anxiety, psychoeducation on the treatment trajectory, and linkage with financial resources. A Social Work Workforce Group (SWG) was established through the System Capacity Initiative, led by the National Marrow Donor Program/Be The Match, to characterize the current social work workforce capacity and challenges. The SWG conducted a web-based survey of HCT clinical social workers in the United States. The response rate was 57% (n = 90), representing 76 transplant centers. Survey results indicated that the clinical social worker role and scope of practice varies significantly between centers; less than half of respondents reported that their clinical social work expertise was used to its fullest potential. With an estimated 3-fold increase in HCT patient volume by 2020, the need for specialized psychosocial health services will increase. The SWG makes recommendations to build capacity for the psychosocial care of HCT patients and to more fully integrate the social worker as a core member of the HCT team. The SWG created a Blood and Marrow Transplant (BMT) Clinical Social Worker role description that can be used by transplant centers to educate healthcare professionals, benchmark utilization of clinical social workers, and improve comprehensive psychosocial health programs.

Project-based learning (PBL) involves a highly complex and learner-centered approach. It relies on formative assessment (FA) with ongoing feedback to help learners move through the PBL process to the eventual co-construction of a shared artefact. Conversation and discussion are central to the process. However, in a face-to-face context of learning, they are difficult to capture for later review or reflection as part of FA. This study investigates the role that technology might play in addressing this limitation using online PBL and FA in a media-creation course in a Thai university. Participants were undergraduate, pre-service teachers preparing to teach English as a foreign language. Objectives included the local design and implementation of online PBL and FA; identification of pre-service teachers’ (n = 28) post-implementation perceptions of the convenience, benefits and barriers of this form of learning; perceptions of their PBL skills and; post-implementation measures of PBL knowledge and skills compared with learners participating in a face-to-face section of the course (n = 30). Results revealed that the technology provided a foundational scaffold to support both the learners’ and the instructor’s activity and interaction. The design of a simple learning management system with communication and file-sharing tools supported not only the learners, but the instructor, not only the assessment, but the learning. Learners’ perceptions were positive and post-implementation measures of PBL knowledge and skill were significantly higher for the online section.

Summary Energy metabolism is a key aspect of cardiomyocyte biology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising tool for biomedical application, but they are immature and have not undergone metabolic maturation related to early postnatal development. To assess whether cultivation of hiPSC-CMs in 3D engineered heart tissue format leads to maturation of energy metabolism, we analyzed the mitochondrial and metabolic state of 3D hiPSC-CMs and compared it with 2D culture. 3D hiPSC-CMs showed increased mitochondrial mass, DNA content, and protein abundance (proteome). While hiPSC-CMs exhibited the principal ability to use glucose, lactate, and fatty acids as energy substrates irrespective of culture format, hiPSC-CMs in 3D performed more oxidation of glucose, lactate, and fatty acid and less anaerobic glycolysis. The increase in mitochondrial mass and DNA in 3D was diminished by pharmacological reduction of contractile force. In conclusion, contractile work contributes to metabolic maturation of hiPSC-CMs., Graphical Abstract, Highlights • Higher mitochondrial mass, protein, and DNA content in 3D versus 2D hiPSC-CMs • Similarity of mitochondrial proteomes between 3D hiPSC-CMs and adult human heart • Preference for oxidative metabolism in favor of anaerobic glycolysis in 3D hiPSC-CMs, Ulmer et al. show that 3D-cultured human iPSC-derived cardiomyocytes replicate metabolic aspects of developmental hypertrophy, indicating maturation of hiPSC-derived cardiomyocytes.

Background: Phosphoinositide 3-kinase inhibitors (PI3Ki) are a new class of medications used to treat HR positive, HER2 negative, PIK3CA mutated advanced or metastatic breast cancer. Inhibition of PI3K, a key enzyme in the insulin signaling pathway, leads to disruption of glucose metabolism and frequently hyperglycemia. Here we present a case of difficult to treat PI3Ki-induced hyperglycemia from alpelisib. Case: 78 yo woman with metastatic breast cancer and NASH cirrhosis was referred for new hyperglycemia after starting alpelisib. Baseline HbA1c was 6%. She was initially started on metformin and glipizide without any blood glucose (BG) improvement. After 6 days, alpelisib was held with BG recovery. Alpelisib was restarted 1 month later, again resulting in hyperglycemia. Dapagliflozin treatment quickly improved BG to Within days, she was admitted with encephalopathy and a UTI which improved with antibiotics and lactulose. Alpelisib, initially held, was restarted on day 2 resulting in worsening hyperglycemia. Inpatient BG ranges on alpelisib were: fasting 191–358, pre-lunch 260–383, pre-dinner 308–404, and bedtime 330–355, despite a rapid increase of basal-bolus insulin and initiation of metformin, pioglitazone, and a ketogenic diet. Total daily insulin needs went from 18u, to 124u by day 5 of alpelisib. Imaging revealed new bone and hepatic metastases. With difficult to control hyperglycemia and cancer progression, alpelisib was discontinued with rapid improvement of hyperglycemia. Discussion: Hyperglycemia is a common adverse and on target effect of PI3Ki use. PI3K inhibition leads to acute hyperglycemia within hours. The pancreas responds by increasing insulin release. Transient hyperglycemia can occur in all patients, but may become persistent with underlying insulin resistance, as seen in our patient. T2DM (with HbA1c >6.5%) and all T1DM patients were excluded in alpelisib trials yet diabetes is not a formal contraindication. Providers should be vigilant for this complication in patients with diabetes and prediabetes. It has been suggested that exogenous insulin and medications that increase endogenous insulin secretion may be counterproductive because they overcome PI3Ki-induced insulin signaling disruption and compromise anti-tumor effectiveness of PI3Ki. Thus, the preferred and most effective treatment may be an SGLT2i as was the case in our patient. Insulin sensitizers and a ketogenic diet can potentially also be effective. Increasing insulin may have limited efficacy as seen with our patient. Future studies are needed to determine the best way to manage PI3Ki-induced hyperglycemia and the effect of potential treatments on anti-tumor efficacy.

When Franklin D. Roosevelt, a Democrat, was elected president in 1932, most African Americans did not support him since they were still loyal to the Republican Party. Moreover, New Deal policies, especially the Social Security Act in 1935, excluded farmers and domestics, and thus, most African Americans. One of the people who encouraged black voters to switch to the Democratic Party was Elizabeth McDuffie, a black servant in the Roosevelt White House. In the 1936 election, McDuffie went on the campaign trail and toured Chicago, Cleveland, Springfield, and St. Louis. As a domestic servant, McDuffie was a familiar face to southern migrants, and she convinced many black voters to switch to the Democratic Party. After her campaign tour concluded, McDuffie became acquainted with the large black population in Washington, D.C. McDuffie worked alongside middle-class activists to increase economic opportunities for women workers by sponsoring training programs for servants. But, as this article demonstrates, most black servants did not want training programs; they desired higher wages, better jobs, and inclusion in the Social Security Act. Working-class women in Washington wrote letters to the newspaper and in 1938, 10,000 rioted for jobs as federal charwomen, jobs that paid higher wages and offered savings for retirement. After McDuffie witnessed these events, she became a vocal critic of the limitations of New Deal programs while continuing to praise Roosevelt and the Democratic Party. This article argues that Elizabeth McDuffie’s career in Washington illuminates the contradictions of New Deal politics for black women workers.

Social media (SM) support new approaches to learning that rely on voluntary, peer-to-peer communication using devices and software provided and managed by students rather than on institutional course management systems. We present one case of such an approach with first-year university students (n = 86) in Thailand using SM for asking and answering questions between peers in a face-to-face computer-programming course. Encouraging students to ask questions about course content can result in improved performance. In general, understanding how students participate and what drives them to participate can provide insights into how universities and instructors can be socially ready. Students used SM during 10 weeks of an 18-week course. Each of four sections selected one form of SM as follows: Facebook [n = 33], Instagram [n = 21], Twitter [n = 21], and Line [n = 11]. The mixed-methods case study involved quantitative measures of how students participated and quantitative and qualitative measures of students’ perceptions of what drives or discourages their participation. Results revealed patterns in participation as follows: participation and motivation; passive and active participation; participation and sample size; participation and type of SM and; participation and student demographics. Implications for practice relate to the value of instructors’ understanding of the social incentives for student participation such as social recognition, gratification of needs and convenience. Implications for research focus on the value of investigating new forms of participation available to read-only participants and ‘lurkers’ using features of SM such as ‘liking’ and sharing.

Motivation and success in computer-science courses are influenced by the strength of students' self-efficacy (SE) beliefs in their learning abilities. Students with weak SE may struggle to be successful in a computer-science course. This study investigated the factors that enhance or impede the computer self-efficacy (CSE) of computer-science students. Data collection involved a survey of 524 undergraduate computer-science students from 10 Thai universities. The survey measured four items of CSE, 13 items pertaining to the classroom learning environment (CLE), and 14 items related to information sources of SE. Results revealed that perceptions of a CLE with autonomy, meaningfulness, and involvement were positively associated with strong CSE. In addition, perceptions of social persuasions such as meaningful and encouraging feedback or judgment from influential people demonstrated a statistically positive relationship with CSE. Perceptions of vicarious experiences whereby students determine and compare their own abilities with observational experiences of role models also demonstrated a statistically positive relationship with CSE. Perceived physiological and affective states such as anxiety and stress demonstrated a negative influence CSE. Implications for practice relate to students' perceptions of autonomous learning, the value of positive feedback, students' input into learning content and activities, role models for students and observation of how peers perform tasks better or worse.

Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

This study’s purpose was to make sense of divides and disconnects in a teacher education program that included university-based courses combined with school-based field experiences. The study took place in Québec, Canada, which has the longest practicum of all provinces and programs designed to develop professional autonomy and competency. Data collection relied on documents, interviews, surveys, and focus groups with 44 preservice teachers along with field supervisors and instructors. Analysis relied on cultural historical activity theory and its principle of contradictions. Findings revealed that contradictions resulted in unintended and unfavourable outcomes such as teacher candidates feeling unprepared and untouched by the program. Resolution of contradictions may be realized through expansion of the division of labour to include more peer and self-assessment and through expansion of tools to support boundary crossing between theory, practice, schools, and university. Keywords: Preservice teacher education; cultural historical activity theory; contradictions; school-university partnerships; divides and disconnects

Steroid hormone receptors including estrogen receptors (ER) classically function as ligand-regulated transcription factors. However, estrogens also elicit cellular effects through binding to extra-nuclear ER (ERα, ERβ, and G protein-coupled ER or GPER) that are coupled to kinases. How extra-nuclear ER actions impact cardiac ischemia-reperfusion (I/R) injury is unknown. We treated ovariectomized wild-type female mice with estradiol or an estrogen-dendrimer conjugate (EDC), which selectively activates extra-nuclear ER, or vehicle interventions for two weeks. I/R injury was then evaluated in isolated Langendorff perfused hearts. Two weeks of treatment with estradiol significantly decreased infarct size and improved post-ischemic contractile function. Similarly, EDC treatment significantly decreased infarct size and increased post-ischemic functional recovery compared to vehicle-treated hearts. EDC also caused an increase in myocardial protein S-nitrosylation, consistent with previous studies showing a role for this post-translational modification in cardioprotection. In further support of a role for S-nitrosylation, inhibition of nitric oxide synthase, but not soluble guanylyl cyclase blocked the EDC mediated protection. The administration of ICI182,780, which is an agonist of G-protein coupled estrogen receptor (GPER) and an antagonist of ERα and ERβ, did not result in protection; however, ICI182,780 significantly blocked EDC-mediated cardioprotection, indicating participation of ERα and/or ERβ. In studies determining the specific ER subtype and cellular target involved, EDC decreased infarct size and improved functional recovery in mice lacking ERα in cardiomyocytes. In contrast, protection was lost in mice deficient in endothelial cell ERα. Thus, extra-nuclear ERα activation in endothelium reduces cardiac I/R injury in mice, and this likely entails increased protein S-nitrosylation. Since EDC does not stimulate uterine growth, in the clinical setting EDC-like compounds may provide myocardial protection without undesired uterotrophic and cancer-promoting effects.

BACKGROUNDThe Centers for Medicare and Medicaid Services Innovation Center introduced the Bundled Payments for Care Improvement (BPCI) initiative in 2011 as 1 strategy to encourage healthcare organizations and clinicians to improve healthcare delivery for patients, both when they are in the hospital

The regulatory control of cardiac endoplasmic reticulum (ER) stress is incompletely characterized. As ER stress signaling upregulates the E3-ubiquitin ligase Parkin, we investigated the role of Parkin in cardiac ER stress. Parkin knockout mice exposed to aortic constriction-induced cardiac pressure-overload or in response to systemic tunicamycin (TM) developed adverse ventricular remodeling with excessive levels of the ER regulatory C/EBP homologous protein CHOP. CHOP was identified as a Parkin substrate and its turnover was Parkin-dose and proteasome-dependent. Parkin depletion in cardiac HL-1 cells increased CHOP levels and enhanced susceptibility to TM-induced cell death. Parkin reconstitution rescued this phenotype and the contribution of excess CHOP to this ER stress injury was confirmed by reduction in TM-induced cell death when CHOP was depleted in Parkin knockdown cardiomyocytes. Isogenic Parkin mutant iPSC-derived cardiomyocytes showed exaggerated ER stress induced CHOP and apoptotic signatures and myocardium from subjects with dilated cardiomyopathy showed excessive Parkin and CHOP induction. This study identifies that Parkin functions to blunt excessive CHOP to prevent maladaptive ER stress-induced cell death and adverse cardiac ventricular remodeling. Additionally, Parkin is identified as a novel post-translational regulatory moderator of CHOP stability and uncovers an additional stress-modifying function of this E3-ubiquitin ligase.

As a simple and versatile method, diffusion driven Layer-by-Layer assembly (dd-LbL) is developed to assemble graphene oxide (GO) into three-dimensional (3D) structure. The assembled GO macrostructure can be reduced through a hydrothermal treatment and used as a high volumetric capacitance electrode in supercapacitors. In this report we use rGO framework created from dd-LbL as a scaffold for in situ polymerization of aniline within the pores of the framework to form rGO/polyaniline (rGO/PANI) composite. The rGO/PANI composite affords a robust and porous structure, which facilitates electrolyte diffusion and exhibits excellent electrochemical performance as binder-free electrodes in a sandwich-configuration supercapacitor. Combining electric double layer capacitance and pseudo-capacitance, rGO/PANI electrodes exhibit a specific capacitance of 438.8 F g −1 at discharge rate of 5 mA (mass of electrodes were 10.0 mg, 0.5 A g −1 ) in 1 mol L −1 H 2 SO 4 electrolyte; furthermore, the generated PANI nanoparticles in rGO template achieve a higher capacitance of 763 F g −1 . The rGO/PANI composite electrodes also show an improved recyclability, 76.5% of capacitance retains after recycled 2000 times.

Aims and objectives To evaluate the effect of an ‘insulin introduction’ group visit on insulin initiation and A1C in adults with type 2 diabetes. Background The clinical course of type 2 diabetes involves eventual beta-cell failure and the need for insulin therapy. Patient psychological insulin resistance, provider-related delays and system barriers to timely initiation of insulin are common. Group visits are widely accepted by patients and represent a potential strategy for improving insulin initiation. Design A single two-hour group visit in English or Spanish, facilitated by advanced practice nurses, addressed psychological insulin resistance and encouraged mock injections to overcome needle anxiety. Methods A retrospective review of 273 patients referred from 2008–2012, determined characteristics of group attenders, rates of mock self-injection, rates of insulin initiation and changes in A1C from baseline to 2–6 and 7–12 months postgroup. Change in A1C was compared to patients referred to the group who did not attend (‘nonattenders’). Results Of 241 patients eligible for analysis, 87·6% were racial/ethnic minorities with an average A1C of 9·99%. Group attendance rate was 66%; 92% performed a mock injection, 55% subsequently started insulin. By 2–6 months, A1C decreased by 1·37% among group attenders, and by 1·6% in those who did a mock injection and started insulin. Fewer nonattenders started insulin in primary care (40%), experiencing an A1C reduction of 0·56% by 2–6 months. A1C improvements were sustained by 7–12 months among group attenders and nonattenders who started insulin. Relevance to clinical practice Nurses can effectively address patient fears and engage patients in reframing insulin therapy within group visits. Conclusions This one-time nurse-facilitated group visit addressing psychological barriers to insulin in a predominantly minority patient population resulted in increased insulin initiation rates and clinically meaningful A1C reductions.

This study aimed to confirm the factor structure of the Beliefs about Paranoia Scale (BaPS), a self-report measure to assess metacognitive beliefs about paranoia, and to test hypotheses of a metacognitive model. We hypothesised that positive and negative beliefs about paranoia would be associated with severity of suspiciousness, and that the co-occurrence of positive and negative beliefs would be associated with increased suspiciousness. A total of 335 patients meeting criteria for a schizophrenia spectrum disorder completed the BaPS, the Positive and Negative Syndromes Scale (PANSS), and the Psychotic Symptom Rating Scales (PSYRATS). Confirmatory factor analysis verified that the three BaPS subscales (negative beliefs about paranoia, paranoia as a survival strategy, and normalizing beliefs) were an adequate fit of the data. Ordinal regression showed that positive beliefs about paranoia as a survival strategy and negative beliefs were both associated with severity of suspiciousness. This was the first study to show that the co-occurrence of positive and negative beliefs was associated with increased suspiciousness. All hypotheses were confirmed, suggesting that a metacognitive approach has utility for the conceptualization of paranoia. Clinical implications suggest a role for metacognitive therapy, including strategies such as detached mindfulness and worry postponement.

Article as accepted for publication in Philosophy, Psychiatry, and Psychology published by John Hopkins University Press

Successful critiques of health policies for people with impaired cognition identify a need for alternatives that go beyond individualism. ‘Choice’ policy was examined as young people with severe intellectual disabilities moved from special schools to adult services. We draw on three cases from a longitudinal cohort study to examine the way decisions with and for these young people were made and accounted for. It was not a simple matter of parents and transition workers hearing about these young people’s choices and facilitating what they wanted. The data raise questions about discourses of choice in ID when referring to people with severe intellectual disabilities: few ‘choices’ could be considered informed nor made by young people with capacity to make them and many decisions were informed by other ethics. Findings were interpreted through a Deleuzean ethical–relational lens. We identify implications for theory and practice to show how Deleuzean thinking can reinvigorate intellectual disability.

The clinical course of patients with recently diagnosed early stage chronic lymphocytic leukemia (CLL) is highly variable. We examined the relationship between CLL-cell birth rate and treatment-free survival (TFS) in 97 patients with recently diagnosed, Rai stage 0-II CLL in a blinded, prospective study, using in vivo 2H2O labeling. Birth rates ranged from 0.07 to 1.31% new cells per day. With median follow-up of 4.0 years, 33 subjects (34%) required treatment by NCI criteria. High-birth rate was observed in 44% of subjects and was significantly associated with shorter TFS, unmutated IGHV status and expression of ZAP70 and of CD38. In multivariable modeling considering age, gender, Rai stage, expression of ZAP70 or CD38, IGHV mutation status and FISH cytogenetics, only CLL-cell birth rate and IGHV mutation status met criteria for inclusion. Hazard ratios were 3.51 (P=0.002) for high-birth rate and 4.93 (P

Background Cryptococcal meningoencephalitis (CM) is a major cause of mortality in HIV/AIDS, transplant recipients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with poor clinical response despite prior amphotericin therapy and CSF culture conversion. Data on effective treatment is limited. Methods Between March 2015 and March 2020, 15 patients with CM/PIIRS were treated with adjunctive pulse – taper corticosteroid therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/d, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky Performance scores, MRI brain scans, eye and audiologic exams were conducted at baseline and after pulse completion. CSF parameters were assessed prior to and after the pulse. Results 80% of patients were male, median age 51 years. Median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were progressive deterioration in mental status and vision changes. There was a significant improvement in MOCA(n=14) and Karnofsky(n=15) scores at 3 weeks (p< 0.0003), which was accompanied by improvements in CSF: serum, glucose ratios, CSF WBC, protein and activated CD4 T cells (n=14) post-pulse (p< 0.003). Additionally, soluble CSF IL-6 and sCD25 levels improved (p = 0.03). Neurofilament light chain levels (NFL), a biomarker of axonal damage, showed significant reductions over a 30-month period (Generalized Estimating Equation coefficient = 0.128) and a negative correlation with post pulse MOCA scores (r = - 0.8; p = 0.01). Papilledema (n=8) and visual field deficits (n=11) improved significantly (p< 0.0005) after 2 months of pulse completion. Brain MRI showed improvement of radiological findings in 11 patients (p=0.001). Five out of 7 patients who underwent audiological testing demonstrated hearing improvement after 3 weeks post-pulse. CSF cultures remained negative. Conclusion PCT in this small cohort of PIIRS patients was associated with persistent improvements in CM-related complications with minimal toxicity and no recurrence of infection. Disclosures All Authors: No reported disclosures

Background Translocation of miR‐181c into cardiac mitochondria downregulates the mitochondrial gene, mt‐ COX 1. miR‐181c/d −/− hearts experience less oxidative stress during ischemia/reperfusion (I/R) and are protected against I/R injury. Additionally, miR‐181c overexpression can increase mitochondrial matrix Ca 2+ ([Ca 2+ ] m ), but the mechanism by which miR‐181c regulates [Ca 2+ ] m is unknown. Methods and Results By RNA sequencing and analysis, here we show that hearts from miR‐181c/d −/− mice overexpress nuclear‐encoded Ca 2+ regulatory and metabolic pathway genes, suggesting that alterations in miR‐181c and mt‐ COX 1 perturb mitochondria‐to‐nucleus retrograde signaling and [Ca 2+ ] m regulation. Quantitative polymerase chain reaction validation of transcription factors that are known to initiate retrograde signaling revealed significantly higher Sp1 (specificity protein) expression in the miR‐181c/d −/− hearts. Furthermore, an association of Sp1 with the promoter region of MICU 1 was confirmed by chromatin immunoprecipitation‐quantitative polymerase chain reaction and higher expression of MICU 1 was found in the miR‐181c/d −/− hearts. Conversely, downregulation of Sp1 by small interfering RNA decreased MICU 1 expression in neonatal mouse ventricular myocytes. Changes in PDH activity provided evidence for a change in [Ca 2+ ] m via the miR‐181c/ MICU 1 axis. Moreover, this mechanism was implicated in the pathology of I/R injury. When MICU 1 was knocked down in the miR‐181c/d −/− heart by lentiviral expression of a short‐hairpin RNA against MICU 1, cardioprotective effects against I/R injury were abrogated. Furthermore, using an in vitro I/R model in miR‐181c/d −/− neonatal mouse ventricular myocytes, we confirmed the contribution of both Sp1 and MICU 1 in ischemic injury. Conclusions miR‐181c regulates mt‐ COX 1, which in turn regulates MICU 1 expression through the Sp1‐mediated mitochondria‐to‐nucleus retrograde pathway. Loss of miR‐181c can protect the heart from I/R injury by modulating [Ca 2+ ] m through the upregulation of MICU 1.

Background Heart failure is one of the leading causes of death in Western countries, and there is a need for new therapeutic approaches. Relaxin‐2 is a peptide hormone that mediates pleiotropic cardiovascular effects, including antifibrotic, angiogenic, vasodilatory, antiapoptotic, and anti‐inflammatory effects in vitro and in vivo. Methods and Results We developed RELAX 10, a fusion protein composed of human relaxin‐2 hormone and the Fc of a human antibody, to test the hypothesis that extended exposure of the relaxin‐2 peptide could reduce cardiac hypertrophy and fibrosis. RELAX 10 demonstrated the same specificity and similar in vitro activity as the relaxin‐2 peptide. The terminal half‐life of RELAX 10 was 7 days in mouse and 3.75 days in rat after subcutaneous administration. We evaluated whether treatment with RELAX 10 could prevent and reverse isoproterenol‐induced cardiac hypertrophy and fibrosis in mice. Isoproterenol administration in mice resulted in increased cardiac hypertrophy and fibrosis compared with vehicle. Coadministration with RELAX 10 significantly attenuated the cardiac hypertrophy and fibrosis compared with untreated animals. Isoproterenol administration significantly increased transforming growth factor β1 (TGF‐β1)–induced fibrotic signaling, which was attenuated by RELAX 10. We found that RELAX 10 also significantly increased protein kinase B/endothelial NO synthase signaling and protein S‐nitrosylation. In the reversal study, RELAX 10‐treated animals showed significantly reduced cardiac hypertrophy and collagen levels. Conclusions These findings support a potential role for RELAX 10 in the treatment of heart failure.

Background There is limited research defining the true prevalence of anal incontinence (AI) in women of childbearing age. Understanding the limitations of the current assessment tools in the identification of AI is paramount for identifying the prevalence of AI and improving the care and management for women of childbearing age. The aim of this research was to explore and develop an understanding of women’s experiences in disclosing AI when completing a new bowel-screening questionnaire when compared to two established AI tools. Methods A phenomenological qualitative research study was undertaken in a maternity setting in a large tertiary hospital. Parous women in the first trimester of a subsequent pregnancy were recruited to complete a specifically designed screening tool (BSQ), St Marks Faecal incontinence score (Vaizey) and Cleveland (Wexner) score. Qualitative semi-structured interviews were utilised to identify experiences in disclosing AI. Results Women (n = 16, 22–42 years) with a history of anal incontinence either following the first birth (n = 12) or the second (n = 4) provided differing responses between the three assessment tools. All women answered the BSQ while the Vaizey and Wexner scores were more difficult to complete due to clinical language and participants level of comprehension. Women identified three major themes that were barriers for disclosing incontinence, which included social expectations, trusted space and confusion. Conclusion There are barriers for disclosing AI in the pregnant and post-natal population, which can be improved with the use of an easy assessment tool. The BSQ may facilitate discussion on AI between the patient and health professional leading to earlier identification and improvement in short and long-term health outcomes.

While much work has been done in associating differentially methylated positions (DMPs) to type 2 diabetes (T2D) across different populations, not much attention has been placed on identifying its possible functional consequences. We explored methylation changes in the peripheral blood of Filipinos with T2D and identified 177 associated DMPs. Most of these DMPs were associated with genes involved in metabolism, inflammation and the cell cycle. Three of these DMPs map to the TXNIP gene body, replicating previous findings from epigenome-wide association studies (EWAS) of T2D. The TXNIP downmethylation coincided with increased transcription at the 3’-UTR, H3K36me3 histone markings, and Sp1 binding, suggesting spurious transcription initiation at the TXNIP 3’-UTR as a functional consequence of T2D methylation changes. We also explored potential epigenetic determinants to increased incidence of T2D in Filipino immigrants in the United States and found 3 DMPs associated with the interaction of T2D and immigration. Two of these DMPs were located near MAP 2 K7 and PRMT1, which may point towards dysregulated stress response and inflammation as a contributing factor to T2D among Filipino immigrants.

Objective There is an ongoing debate about excluding patient's global assessment (PtGA) from composite and Boolean-based definitions of rheumatoid arthritis (RA) remission. This study aimed at determining the influence of PtGA on RA disease states, exploring differences across countries, and understanding the association between PtGA, measures of disease impact (symptoms), and markers of disease activity (inflammation). Methods Cross-sectional data from the Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology international database were used. We calculated the proportion of patients failing American College of Rheumatology/European League Against Rheumatism Boolean-based remission (4-variable remission) solely due to PtGA (PtGA-near-remission) in the overall sample and in the most representative countries (i.e., those with >3,000 patients in the database). Multivariable linear regression models were used to identify the main determinants of PtGA, grouped in predominantly inflammatory impact factors (28 tender joint counts, 28 swollen joint counts, and C-reactive protein level) and disease impact factors (pain and function). Results This study included 27,768 patients. Excluding PtGA from the Boolean-based definition (3-variable remission) increased the remission rate from 5.8% to 15.8%. The rate of PtGA-near-remission varied considerably between countries, from 1.7% in India to 17.9% in Portugal. One-third of the patients in PtGA-near-remission group scored PtGA >4 of 10. Pain and function were the main correlates of PtGA, with inflammation-related variables contributing less to the model (R2 = 0.57). Conclusion PtGA is moderately related to joint inflammation overall, but only weakly so in low levels of disease activity. A considerable proportion of patients otherwise in biologic remission still perceive high PtGA, putting them at risk of excessive immunosuppressive treatment.

The mitochondrial calcium uniporter is widely accepted as the primary route of rapid calcium entry into mitochondria, where increases in matrix calcium contribute to bioenergetics but also mitochondrial permeability and cell death. Hence, regulation of uniporter activity is critical to mitochondrial homeostasis. The uniporter subunit EMRE is known to be an essential regulator of the channel-forming protein MCU in cell culture, but EMRE’s impact on organismal physiology is less understood. Here we characterize a mouse model of EMRE deletion and show that EMRE is indeed required for mitochondrial calcium uniporter function in vivo. EMRE(–/–) mice are born less frequently; however, the mice that are born are viable, healthy, and do not manifest overt metabolic impairment, at rest or with exercise. Finally, to investigate the role of EMRE in disease processes, we examine the effects of EMRE deletion in a muscular dystrophy model associated with mitochondrial calcium overload.

Cyclophilin-D (CypD) is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischemia/reperfusion (I/R) injury characterized by oxidative stress and calcium overload. However, the binding of CypD to the PTP is poorly understood. Cysteine 202 of CypD (C202) is highly conserved across species and can undergo redox-sensitive post-translational modifications. To study the importance of C202, we developed a knock-in mouse model using CRISPR where CypD-C202 was mutated to a serine (C202S). In a Langendorff perfused heart model, infarct size is reduced by 51% in CypD-C202S hearts compared to WT (n=4, p=0.003). Isolated cardiac mitochondria from CypD-C202S mice also have a 49% higher calcium retention capacity compared to WT (n=5, p=0.011). We hypothesized that oxidation of C202 might target CypD to the PTP and that the cardioprotection in CypD-C202S mice is due to a post-translational modification on C202. Indeed, isolated cardiac mitochondria subjected to oxidative stress exhibit less binding of CypD-C202S to the proposed PTP component ATP synthase by 48% compared to WT (p=0.012, n=4). We previously found C202 to be S-nitrosylated in ischemic preconditioning. Cysteines can also undergo S-acylation (attachment of a fatty acid), and C202 matched a S-acylation motif. To assess S-acylation of CypD-C202 we employed a resin-assisted capture. Lysates were treated with N-ethylmaleimide to block free cysteines, and then with hydroxylamine to free cysteines from fatty acids. Subsequently, free cysteines were captured by a sepharose resin, followed by western-blot of the eluate. CypD-C202 is abundantly S-acylated, but CypD-C202S hearts exhibit less S-acylation than WT by 63% (n=6, p

Translocation of miR-181c into heart-mitochondria downregulates the mitochondrial gene, mt-COX1. miR-181c/d -/- hearts experience less oxidative stress during I/R and are protected against I/R injury. Additionally, miR-181c overexpression can increase mitochondrial matrix Ca 2+ ([Ca 2+ ] m ); the mechanism is unknown. By RNA-Seq, here we show that hearts from miR-181c/d -/- mice overexpress nuclear-encoded Ca 2+ regulatory genes, suggesting that alterations in miR-181c and mt-COX1 perturb mitochondria-to-nucleus retrograde signaling and [Ca 2+ ] m regulation. qPCR validation of transcription factors that are known to initiate retrograde signaling revealed significantly higher Sp1 expression in the miR-181c/d -/- hearts. Furthermore, an association of Sp1 with the promoter region of MICU1 was confirmed by ChIP-qPCR and higher expression of MICU1 was found in the miR-181c/d -/- hearts. Conversely, downregulation of Sp1 by siRNA decreased MICU1 expression in NMVM. Changes in PDH activity provided evidence for a change in [Ca 2+ ] m via the miR-181c/MICU1 axis. Moreover, this mechanism was implicated in the pathology of I/R injury. When MICU1 was knocked down in the miR-181c/d -/- heart by lentiviral expression of an shRNA against MICU1, cardioprotective effects against I/R injury were abrogated. Furthermore, using an in vitro I/R model in miR-181c/d -/- NMVM, we confirmed the contribution of Sp1-MICU1 in ischemic injury. In summary, miR-181c regulates mt-COX1, which in turn regulates MICU1 through the Sp1-mediated mitochondria-to-nucleus retrograde pathway. Loss of miR-181c can protect the heart from I/R injury by modulating [Ca 2+ ] m through the upregulation of MICU1.

Background The economics of allogeneic hematopoietic cell transplantation (alloHCT) for older patients with acute myeloid leukemia (AML) affects clinical practice and public policy. To assess reimbursement, utilization, and overall survival (OS) up to 1 year post-alloHCT for Medicare beneficiaries aged 65 years or older with AML, a unique merged dataset of Medicare claims and national alloHCT registry data was analyzed. Methods Patients diagnosed with AML undergoing alloHCT from 2010 to 2011 were included for a retrospective cohort analysis with generalized linear model adjustment. One-year post-alloHCT reimbursement included Medicare, secondary payer, and beneficiary copayments (no coinsurance) (inflation adjusted to 2017 dollars). Cost-to-charge ratios were applied to estimate department-specific inpatient costs. Cox proportional hazards regression models were utilized to identify risk factors of 1-year OS post-alloHCT. Results A total of 250 patients met inclusion criteria. Mean total reimbursement was $230 815 (95% confidence interval [CI] = $214 381 to $247 249) 1 year after alloHCT. Pharmacy was the most- costly inpatient service category. Adjusted mean total reimbursement was statistically higher for patients who received cord blood grafts (P = .01), myeloablative conditioning (P Conclusions This merged dataset allowed adjustment for a richer set of patient- and HCT-related characteristics than claims data alone. The finding that nonmyeloablative conditioning was associated with lower reimbursement and improved OS 1 year post-alloHCT warrants further investigation.

Patient, caregiver, and family education and support was 1 of 6 key areas of interest identified by the National Marrow Donor Program/Be The Match 2-year project to prioritize patient-centered outcomes research (PCOR) goals for the blood and marrow transplantation (BMT) community. PCOR focuses on research to help patients and their caregivers make informed decisions about health care. Therefore, each area of interest was assigned to a working group with broad representation, including patients, caregivers, and clinicians. Each working group was charged with identifying gaps in knowledge and making priority recommendations for critical research to fill those gaps. The report from this working group presents a conceptual framework to address gaps in knowledge regarding patient and caregiver education in BMT and recommendations for priority research questions on this topic. ispartof: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION vol:25 issue:7 pages:1416-1423 ispartof: location:United States status: published

ObjectiveTo investigate associations between baseline presence of erosions and/or anti-citrullinated protein antibodies (ACPA) on functional ability, disease activity and treatment survival over time.MethodsReal life data from newly diagnosed rheumatoid arthritis patients were identified in the international METEOR registry. Patients were grouped according to presence/absence of ACPA and/or erosions at baseline. Associations between the presence of ACPA and/or erosions (four groups) with the change of Disease Activity Score (DAS) and Health Assessment Questionnaire (HAQ) over time were assessed using linear mixed models during maximum 6 or maximum 12 months from baseline. Treatment survival was assessed using multiple failure-times Cox regression.ResultsData were included from 701 ACPA‒/erosions‒, 334 ACPA‒/erosions+, 1585 ACPA+/erosions‒ and 1993 ACPA+/erosions+ patients. We found statistically significant differences in DAS and HAQ change over time between the four groups, both after maximum follow-up durations of 6 and of 12 months, but after stratification differences proved small and not clinically meaningful. Patients in the ACPA‒/erosions‒ group were less likely to switch treatment compared with the ACPA+/erosions‒ reference group (pConclusionsIn this analysis of worldwide real life data, we found statistically significant, but clinically irrelevant differences in treatment response to initial disease modifying anti-rheumatic drug therapies as measured by DAS and HAQ in ACPA‒/erosions‒, ACPA‒/erosions+, ACPA+/erosions‒ and ACPA+/erosions+ rheumatoid arthritis patients. However, after maximum follow-up durations of 6 and 12 months all groups had a similar response to initial treatment, but with a lower likelihood to switch treatment for ACPA‒/erosions‒ patients during the first year of follow-up.

Introduction HSE is estimated to occur in approximately 1 in 250,000 to 1 in 500, 000 individuals per year, with approximately one third of cases occurring in children and adolescents. Poorer prognosis and neurological sequelae are associated with delayed treatment of HSE. We retrospectively reviewed all cases of HSV meningoencephalitis admitted to our centre over a ten year period from Jan 2008 to Jan 2018. Four cases were identified based on PCR confirmation of HSV 1 or 2 in cerebrospinal fluid samples. Here we discuss the clinical presentation, as well as electroencelphalogram, neuroimaging and clinical outcomes, to highlight the importance of early recognition and timely treatment of such cases. Case series Case 1: Nineteen month old male infant presented with prolonged focal febrile seizure, on a preceding history of pyrexia and lethargy for one day, and cough for one week. EEG showed excess slowing over both posterior regions, more marked on the left posterior region, consistent with bilateral cerebral dysfunction without epileptiform discharges. MRI brain demonstrated deep white matter changes in the left parietal and posterior parietal/occipital regions and adjacent grey matter and two small punctate haemorrhages in the left midparietal region. Case 2: Four week old male infant presented with recurrent focal seizures. No pyrexia or preceding symptoms were documented. EEG recorded two seizures with origin near the right midline with spread to right motor cortex and right hemisphere. MRI brain showed right deep white matter changes and left subcortical lesion. Case 3: Eleven week old female infant admitted with pyrexia and lethargy. She had 6 episodes of febrile generalised tonic seizures over 48 hours, each less than 5 minutes in duration. EEG demonstrated some asymmetry and excess slow activities over right temporal region in sleep, with no epileptiform features. MRI brain was normal. Case 4: Thirteen month old female presented with febrile status epilepticus, on a background history of pyrexia and diarrhoea for 3 days. EEG showed three epileptic spasms with background continuous epileptiform discharges, which were multifocal; predominantly right posterior and some frontal discharges were seen in sleep. MRI brain showed subtle high signal white matter changes in the frontal lobes bilaterally and multiple high signal areas throughout corpus callosum. Discussion This case series demonstrates that HSV encephalitis should be considered in children with atypical febrile seizures which are prolonged, focal or recurrent. Timely recognition of HSE is essential to minimise patient morbidity and mortality.