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DTNA encodes for α-dystrobrevin, a component of the macromolecular dystrophin-glycoprotein complex that binds to dystrophin/utrophin and α-syntrophin. Absence of α-dystrobrevin causes muscular dystrophy in mice but variants in DTNA in humans have not been associated with muscle disease. Here, we present nine individuals from two unrelated families with dominantly inherited DTNA variants. Affected individuals of family A showed a phenotype characterized by hyperCKaemia, myalgias and exercise intolerance, without weakness, that started in the second decade of life in most cases. One patient had an episode of rhabdomyolysis at 12 years old. The WBMRI performed in one patient was normal. All 4 affected individuals from family B had hyperCKaemia. The index case in family B showed also a progressive proximal weakness in lower limbs with onset at the age of 5. Muscle biopsies in five affected individuals showed a combination of myopathic and dystrophic pattern, characterized by variation in fiber size, increased internal nuclei, and slightly increased extracellular connective tissue. A patchy endomysial and perimysial inflammation was observed in one patient of family B. Immunohistochemical analysis of the four biopsies of affected individuals of family A showed a reduction in α-dystrobrevin as well as a variable reduction of several other proteins of the dystrophin-associated protein complex, including dystrophin, sarcoglycans and dystroglycans. The five affected individuals from family A harbored the heterozygous variant c.1585G>A; p.Glu529Lys while the four affected individuals from family B had a c.1567-1587del; p.Gln523_Glu529del. Both variants are located in the coiled-coil domain of α-dystrobrevin that mediates the interaction with dystrophin and utrophin, are absent from population databases, affect highly conserved residues, and have a pahogenic in silico prediction. This is the first description of variants in DTNA causing muscle disease. Our findings show variable expressivity of this new condition ranging from hyperCKemia to proximal muscle weakness making family studies very important for diagnosis. [ABSTRACT FROM AUTHOR]

Adenosine-to-inosine (A-to-I) RNA editing is a neurodevelopmentally regulated epigenetic modification shown to modulate complex behavior in animals. Little is known about human A-to-I editing, but it is thought to constitute one of many molecular mechanisms connecting environmental stimuli and behavioral outputs. Thus, comprehensive exploration of A-to-I RNA editing in human brains may shed light on gene-environment interactions underlying complex behavior in health and disease. Synaptic function is a main target of A-to-I editing, which can selectively recode key amino acids in synaptic genes, directly altering synaptic strength and duration in response to environmental signals. Here, we performed a high-resolution survey of synaptic A-to-I RNA editing in a human population, and examined how it varies in autism, a neurodevelopmental disorder in which synaptic abnormalities are a common finding. Using ultra-deep (>1000 × ) sequencing, we quantified the levels of A-to-I editing of 10 synaptic genes in postmortem cerebella from 14 neurotypical and 11 autistic individuals. A high dynamic range of editing levels was detected across individuals and editing sites, from 99.6% to below detection limits. In most sites, the extreme ends of the population editing distributions were individuals with autism. Editing was correlated with isoform usage, clusters of correlated sites were identified, and differential editing patterns examined. Finally, a dysfunctional form of the editing enzyme adenosine deaminase acting on RNA B1 was found more commonly in postmortem cerebella from individuals with autism. These results provide a population-level, high-resolution view of A-to-I RNA editing in human cerebella and suggest that A-to-I editing of synaptic genes may be informative for assessing the epigenetic risk for autism. [ABSTRACT FROM AUTHOR]

In patients with Duchenne muscular dystrophy (DMD), the absence of a functional dystrophin protein results in sarcolemmal instability, abnormal calcium signaling, cardiomyopathy, and skeletal muscle degeneration. Using the dystrophin-deficient sapje zebrafish model, we have identified microRNAs (miRNAs) that, in comparison to our previous findings in human DMD muscle biopsies, are uniquely dysregulated in dystrophic muscle across vertebrate species. MiR-199a-5p is dysregulated in dystrophin-deficient zebrafish, mdx5cv mice, and human muscle biopsies. MiR-199a-5p mature miRNA sequences are transcribed from stem loop precursor miRNAs that are found within the introns of the dynamin-2 and dynamin-3 loci. The miR-199a-2 stem loop precursor transcript that gives rise to the miR-199a-5p mature transcript was found to be elevated in human dystrophic muscle. The levels of expression of miR-199a-5p are regulated in a serum response factor (SRF)-dependent manner along with myocardin-related transcription factors. Inhibition of SRF-signaling reduces miR-199a-5p transcript levels during myogenic differentiation. Manipulation of miR-199a-5p expression in human primary myoblasts and myotubes resulted in dramatic changes in cellular size, proliferation, and differentiation. MiR-199a-5p targets several myogenic cell proliferation and differentiation regulatory factors within the WNT signaling pathway, including FZD4, JAG1, and WNT2. Overexpression of miR-199a-5p in the muscles of transgenic zebrafish resulted in abnormal myofiber disruption and sarcolemmal membrane detachment, pericardial edema, and lethality. Together, these studies identify miR-199a-5p as a potential regulator of myogenesis through suppression of WNT-signaling factors that act to balance myogenic cell proliferation and differentiation. [ABSTRACT FROM AUTHOR]

This phase 2 study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of carfilzomib, a selective proteasome inhibitor, in patients with multiple myeloma and varying degrees of renal impairment, including patients on chronic hemodialysis. Patients were grouped by creatinine clearance: >80 ml/min, 50-80 ml/min, 30-49 ml/min, <30 ml/min and chronic hemodialysis. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 in 28-day cycles: 15 mg/m2 (Cycle 1), 20 mg/m2 (Cycle 2) and 27 mg/m2 (Cycles 3+). There were no differences in carfilzomib clearance or exposure among patients with normal renal function and any group with renal impairment. Grade 3/4 adverse events (AEs) included anemia (28.0%), thrombocytopenia (20.0%), lymphopenia (18.0%) and fatigue (14.0%). AEs were similar among groups. At 15 mg/m2, proteasome inhibition up to 85% was observed and did not differ among groups. Although nearly 50% of patients were refractory to both bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 months median duration of response. In conclusion, the pharmacokinetics and safety of carfilzomib were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and carfilzomib was well tolerated and demonstrated promising efficacy. [ABSTRACT FROM AUTHOR]

In order to improve leukemia-free survival we evaluated the feasibility and efficacy of autologous transplantation of interleukin-2 (IL-2)-mobilized peripheral blood progenitor cells for adult patients with acute myelogenous leukemia in first remission. Forty-nine consecutive patients (median age 49, range 21-70) with acute myelogenous leukemia in first remission were enrolled on a study of high-dose cytarabine/mitoxantrone consolidation chemotherapy with post-recovery IL-2 used as a method of in vivo purging for the purpose of autologous peripheral blood progenitor cell transplantation. A median of 2.08 x 10(6) CD34+ peripheral blood progenitor cells/kg were infused 1 day after preparative conditioning with 11.25 Gy total body irradiation and cyclophosphamide (120 mg/kg). Forty-one patients received myeloablative chemoradiotherapy followed by the infusion of IL-2-mobilized autologous peripheral blood progenitor cells. The median times to both neutrophil and platelet recovery were 16 days (range, 2-43) and 23 days (8-318+ days), respectively. Twenty-seven patients remain alive with 24 in continued first complete remission. Median remission duration for all eligible patients is 8 months, and actuarial leukemia-free survival is 49+/-15%. The actuarial risk of relapse is 43+/-16%. Toxicity of autologous peripheral blood progenitor cell transplant included treatment-related death in three patients and serious organ toxicity in 12. Advanced age was a negative prognostic factor for leukemia-free survival. Results were compared to an age-matched historical control treated with autologous transplantation of chemotherapy-mobilized progenitor cells; no significant difference in favor of IL-2 mobilization could be demonstrated. Our results demonstrate that autologous transplantation of IL-2-mobilized peripheral blood progenitor cells is feasible in an unselected population of adult patients with acute myelogenous leukemia in first remission with minimal toxicity but no clear evidence of benefit in leukemia-free survival. [ABSTRACT FROM AUTHOR]

FilaminC (FLNc) is the muscle-specific member of a family of actin binding proteins. Although it interacts with many proteins involved in muscular dystrophies, its unique role in muscle is poorly understood. To address this, two models were developed. First, FLNc expression was stably reduced in C2C12 myoblasts by RNA interference. While these cells start differentiation normally, they display defects in differentiation and fusion ability and ultimately form multinucleated "myoballs" rather than maintain elongated morphology. Second, a mouse model carrying a deletion of last 8 exons of Flnc was developed. FLNc-deficient mice die shortly after birth, due to respiratory failure, and have severely reduced birth weights, with fewer muscle fibers and primary myotubes, indicating defects in primary myogenesis. They exhibit variation in fiber size, fibers with centrally located nuclei, and some rounded fibers resembling the in vitro phenotype. The similarity of the phenotype of FLNc-deficient mice to the filamin-interacting TRIO null mice was further confirmed by comparing FLNc-deficient C2C12 cells to TRIO-deficient cells. These data provide the first evidence that FLNc has a crucial role in muscle development and maintenance of muscle structural integrity and suggest the presence of a TRIO-FLNc-dependent pathway in maintaining proper myotube structure. [ABSTRACT FROM AUTHOR]

The empirical success of Generative Adversarial Networks (GANs) caused an increasing interest in theoretical research. The statistical literature is mainly focused on Wasserstein GANs and generalizations thereof, which especially allow for good dimension reduction properties. Statistical results for Vanilla GANs, the original optimization problem, are still rather limited and require assumptions such as smooth activation functions and equal dimensions of the latent space and the ambient space. To bridge this gap, we draw a connection from Vanilla GANs to the Wasserstein distance. By doing so, existing results for Wasserstein GANs can be extended to Vanilla GANs. In particular, we obtain an oracle inequality for Vanilla GANs in Wasserstein distance. The assumptions of this oracle inequality are designed to be satisfied by network architectures commonly used in practice, such as feedforward ReLU networks. By providing a quantitative result for the approximation of a Lipschitz function by a feedforward ReLU network with bounded Hölder norm, we conclude a rate of convergence for Vanilla GANs as well as Wasserstein GANs as estimators of the unknown probability distribution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The role of direct oral anticoagulants (DOACs) in chronic limb-threatening ischemia after revascularization is unknown. Current evidence-based guidelines do not provide clear guidance on the role of anticoagulation or the selection of anticoagulant. Current practice is highly varied and based on provider and patient preference. The purpose of this study was to measure the impact of different anticoagulants on the incidence of major adverse limb events (MALEs) after revascularization for chronic limb-threatening ischemia, major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for major bleeding events., Methods: This was a single-center, observational, retrospective cohort study. Subjects were eligible if they were 18 years or older; underwent endovascular or open revascularization for chronic limb-threatening ischemia, rest pain, or tissue loss; and were subsequently prescribed apixaban, rivaroxaban, or warfarin. The primary end point was the incidence of MALEs, including above-ankle amputation or major index-limb reintervention, within 1 year of index event. Secondary end points included the rate of all-cause mortality, MACEs, and incidence of International Society on Thrombosis and Haemostasis (ISTH) major bleeding., Results: From January 1, 2017, to September 20, 2022, 141 patients met the inclusion and exclusion criteria and were reviewed. The median age was 67 years, with 92 patients prescribed apixaban or rivaroxaban and 49 patients prescribed warfarin. Of these, 42 patients were prescribed triple antithrombotic therapy, 88 dual antithrombotic therapy, and 13 anticoagulant monotherapy. The primary outcome of 1-year MALEs occurred in 36.7% of the warfarin group and 33.7% of the DOAC group (relative risk [RR], 1.09; 95% CI, 0.53-2.25; P = .72). Secondary outcomes of 1-year MACEs (10.2% vs 4.3%; RR, 2.35; 95% CI, 0.60-9.18; P = .18) and 1-year all-cause mortality (26.5% vs 16.3%; RR, 1.63; 95% CI, 0.70-3.78; P = .15) did not differ between the groups. The secondary safety outcome of 1-year ISTH major bleeding occurred in 16.3% of the warfarin group and 4.3% of the DOAC group (RR, 3.76; 95% CI, 1.07-13.19; P = .015)., Conclusions: In patients with chronic limb-threatening ischemia who were revascularized and prescribed anticoagulation with apixaban, rivaroxaban, or warfarin on discharge, no difference in MALEs, MACEs, or all-cause mortality was found. However, 1-year admissions for ISTH major bleeding were significantly higher among patients prescribed warfarin. A randomized trial may confirm these findings., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain disorder causing symptoms of urinary frequency, urgency, and bladder discomfort or pain. Although this condition affects a large population, little is known about its etiology. Genetic analyses of whole exome sequencing are performed on 109 individuals with IC/BPS. One family has a previously reported  SIX5  variant (ENST00000317578.6:c.472G>A, p.Ala158Thr), consistent with Branchiootorenal syndrome 2 (BOR2). A likely pathogenic heterozygous variant in  ATP2A2  (ENST00000539276.2:c.235G>A, p.Glu79Lys) is identified in two unrelated probands, indicating possible Darier-White disease. Two private heterozygous variants are identified in  ATP2C1  (ENST00000393221.4:c.2358A>T, p.Glu786Asp (VUS/Likely Pathogenic) and ENST00000393221.4:c.989C>G, p.Thr330Ser (likely pathogenic)), indicative of Hailey-Hailey Disease. Sequence kernel association test analysis finds an increased burden of rare  ATP2C1  variants in the IC/BPS cases versus a control cohort ( p = 0.03, OR = 6.76), though does not survive Bonferroni correction. The data suggest that some individuals with IC/BPS may have unrecognized Mendelian syndromes. Comprehensive phenotyping and genotyping aid in understanding the range of diagnoses in the population-based IC/BPS cohort. Conversely,  ATP2C1, ATP2A2 , and  SIX5  may be candidate genes for IC/BPS. Further evaluation with larger numbers is needed. Genetically screening individuals with IC/BPS may help diagnose and treat this painful disorder due to its heterogeneous nature., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Advanced Genetics published by Wiley Periodicals LLC.)

From an early age, children are willing to pay a personal cost to punish others for violations that do not affect them directly. Various motivations underlie such "costly punishment": People may punish to enforce cooperative norms (amplifying punishment of in-groups) or to express anger at perpetrators (amplifying punishment of out-groups). Thus, group-related values and attitudes (e.g., how much one values fairness or feels out-group hostility) likely shape the development of group-related punishment. The present experiments ( N = 269, ages 3-8 from across the United States) tested whether children's punishment varies according to their parents' political ideology-a possible proxy for the value systems transmitted to children intergenerationally. As hypothesized, parents' self-reported political ideology predicted variation in the punishment behavior of their children. Specifically, parental conservatism was associated with children's punishment of out-group members, and parental liberalism was associated with children's punishment of in-group members. These findings demonstrate how differences in group-related ideologies shape punishment across generations.

Background: In Vietnam, access to medications for opioid use disorder (MOUD) for people living with HIV has rapidly expanded, but MOUD use over time remains low. We sought to assess factors associated with days of MOUD treatment exposure., Methods: From 2015 to 2019, patients with OUD in six Northern Vietnamese HIV clinics were randomized to receive HIV clinic-based buprenorphine (BUP/NX) or referral for methadone maintenance therapy (MMT) and followed for 12 months. All MOUD doses were directly observed and abstracted from dosing logs. The primary outcome was days of MOUD treatment exposure (buprenorphine or methadone) received over 12 months. Negative binomial regression modelled associations with days of MOUD exposure., Results: Of 281 participants, 264 (94%) were eligible for analysis. Participants were primarily male (97%), unmarried (61%), employed (54%), and previously arrested (83%). Participants had a mean 187 (SD 150) days of MOUD exposure with 134 (51%) having at least 180 days, and 35 (13.2%) having at least 360 days of MOUD exposure. Age (IRR 1.26, 95% CI 1.02-1.55), income (IRR 0.96, 95% CI 0.93-1.001), and methadone (IRR 1.88, 95% CI 1.51-2.42) were associated with MOUD exposure in multivariate models. Multivariate models predicted 127 (95% CL 109-147) days of MOUD exposure for HIV clinic based-buprenorphine vs 243 (95% CL 205-288) for MMT., Conclusion: MOUD treatment exposure was suboptimal among patients with HIV and OUD in Northern Vietnam and was influenced by several factors. Interventions to support populations at risk of lower MOUD exposure as well programs administering MOUD should be considered in countries seeking to expand access to MOUD., Competing Interests: Declarations of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Lithium, one of the few effective treatments for bipolar depression (BPD), has been hypothesized to work by enhancing serotonergic transmission. Despite preclinical evidence, it is unknown whether lithium acts via the serotonergic system. Here we examined the potential of serotonin transporter (5-HTT) or serotonin 1A receptor (5-HT 1A ) pre-treatment binding to predict lithium treatment response and remission. We hypothesized that lower pre-treatment 5-HTT and higher pre-treatment 5-HT 1A binding would predict better clinical response. Additional analyses investigated group differences between BPD and healthy controls and the relationship between change in binding pre- to post-treatment and clinical response. Twenty-seven medication-free patients with BPD currently in a depressive episode received positron emission tomography (PET) scans using 5-HTT tracer [ 11 C]DASB, a subset also received a PET scan using 5-HT 1A tracer [ 11 C]-CUMI-101 before and after 8 weeks of lithium monotherapy. Metabolite-corrected arterial input functions were used to estimate binding potential, proportional to receptor availability. Fourteen patients with BPD with both [ 11 C]DASB and [ 11 C]-CUMI-101 pre-treatment scans and 8 weeks of post-treatment clinical scores were included in the prediction analysis examining the potential of either pre-treatment 5-HTT or 5-HT1A or the combination of both to predict post-treatment clinical scores., Results: We found lower pre-treatment 5-HTT binding (p = 0.003) and lower 5-HT 1A binding (p = 0.035) were both significantly associated with improved clinical response. Pre-treatment 5-HTT predicted remission with 71% accuracy (77% specificity, 60% sensitivity), while 5-HT 1A binding was able to predict remission with 85% accuracy (87% sensitivity, 80% specificity). The combined prediction analysis using both 5-HTT and 5-HT 1A was able to predict remission with 84.6% accuracy (87.5% specificity, 60% sensitivity). Additional analyses BPD and controls pre- or post-treatment, and the change in binding were not significant and unrelated to treatment response (p > 0.05)., Conclusions: Our findings suggest that while lithium may not act directly via 5-HTT or 5-HT 1A to ameliorate depressive symptoms, pre-treatment binding may be a potential biomarker for successful treatment of BPD with lithium., Clinical Trial Registration: PET and MRI Brain Imaging of Bipolar Disorder Identifier: NCT01880957; URL: https://clinicaltrials.gov/ct2/show/NCT01880957.

Background: Little is known about patient characteristics that contribute to initiating antiretroviral therapy (ART) and achieving viral suppression among HIV people with opioid use disorder in Vietnam. The primary objective of this analysis was to evaluate associations between participant characteristics and the critical steps in the HIV care continuum of ART initiation and HIV viral suppression among people with opioid use disorder and HIV in Vietnam., Methods: We assessed baseline participant characteristics, ART status, and HIV viral suppression (HIV RNA PCR < 200 copies/mL) enrolled in a clinical trial of HIV clinic-based buprenorphine versus referral for methadone among people with opioid use disorder in Vietnam. We developed logistic regression models to identify characteristics associated with ART status and HIV viral suppression., Results: Among 283 study participants, 191 (67.5%) were prescribed ART at baseline, and 168 of those on ART (90%) were virally suppressed. Years since HIV diagnosis (aOR = 1.12, 95% CI 1.06, 1.19) and being married (aOR = 2.83, 95% CI 1.51, 5.34) were associated with an increased likelihood of current prescription for ART at baseline. Greater depression symptoms were negatively associated with receipt of ART (aOR = 0.97, 95% CI = (0.94, 0.9963)). In the HIV suppression model, once adjusting for all included covariates, only receipt of ART was associated with viral suppression (aOR = 25.9, 95% CI = (12.5, 53.8). In bivariate analyses, methamphetamine was negatively correlated with ART prescription (p = 0.07) and viral suppression (p = 0.08)., Conclusion: While fewer than 90% of participants had received ART, 90% of those on ART had achieved HIV viral suppression at baseline, suggesting that interventions to improve uptake of ART in Vietnam are essential for achieving UNAIDS 90-90-90 goals in people who use heroin in Vietnam. Social determinants of health associated with ART and HIV viral suppression suggest that social support may be a key to facilitating both of these steps in the HIV care continuum.

Facioscapulohumeral dystrophy type 1 (FSHD-1) is the most common autosomal dominant form of muscular dystrophy with a prevalence of ∼1 in 8000 individuals. It is considered a late-onset form of muscular dystrophy and leads to asymmetric muscle weakness in the facial, scapular, trunk and lower extremities. The prevalent hypothesis on disease pathogenesis is explained by misexpression of a germ line, primate-specific transcription factor DUX4-fl (double homeobox 4, full-length isoform) linked to the chromosome 4q35. In vitro and in vivo studies have demonstrated that very low levels of DUX4-fl expression are sufficient to induce an apoptotic and/or lethal phenotype, and therefore modeling of the disease has proved challenging. In this study, we expand upon our previously established injection model of DUX4 misexpression in zebrafish and describe a DUX4-inducible transgenic zebrafish model that better recapitulates the expression pattern and late onset phenotype characteristic of FSHD patients. We show that an induced burst of DUX4 expression during early development results in the onset of FSHD-like phenotypes in adulthood, even when DUX4 is no longer detectable. We also utilize our injection model to study long-term consequences of DUX4 expression in those that fail to show a developmental phenotype. Herein, we introduce a hypothesis that DUX4 expression during developmental stages is sufficient to induce FSHD-like phenotypes in later adulthood. Our findings point to a developmental role of DUX4 misexpression in the pathogenesis of FSHD and should be factored into the design of future therapies.

Group B streptococcus (GBS) is a leading bacterial cause of neonatal sepsis and meningitis in many countries as well as an important cause of disease in pregnant women. Currently, serotype-specific conjugate vaccines are being developed. We conducted an epidemiological analysis of health administrative data to estimate the burden of infant GBS disease in Ontario, Canada and combined these estimates with literature on serotype distribution to estimate the burden of disease likely to be vaccine-preventable. Between 1st January 2005 and 31st December 2015, 907 of 64320 health care encounters in Ontario in patients under 1 year old had codes specifically identifying GBS as the cause of the disease, of which 717 were under one month of age. In addition, application of epidemiological data to the remaining patients allowed us to estimate a further 2322 cases and among them 1822 were under one month of age. In the same period, 579 confirmed neonatal invasive GBS cases in patients up to one month of age were reported to public health. Depending on serotype distribution, vaccination coverage and early versus late onset disease (0-6 days and 7-90 days of age respectively), the preventable fraction ranged widely. With a vaccine that is 90% effective and 60% immunization coverage, up to 52% of early and late onset disease could be prevented by forthcoming vaccines. GBS is under-reported in Ontario. Uncertainty about the potential impact of vaccine indicates that further analysis and research may be needed to prepare for policy-decision making, including clinical validation studies and an economic evaluation of GBS vaccination in Ontario.

Regulatory T (Treg) cells play a central role in immune tolerance and prevention of aberrant immune responses. Several studies have suggested that the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) can be ameliorated by increasing Tregs. We have developed an approach of in vivo expansion of Tregs with RGI-2001, a novel liposomal formulation of a synthetic derivative of alpha-galactosylceramide, a naturally occurring ligand that binds to CD1 and activates and expands invariant natural killer cells. In preclinical studies, a single intravenous infusion of RGI-2001 expanded Treg and could ameliorate GVHD in a mouse model of allogeneic HCT. To explore the role of RGI-2001 in clinical HCT, we initiated a phase 2A clinical trial (n = 29), testing 2 different doses of RGI-2001 administered as a single infusion on day 0 of allogeneic HCT. RGI-2001 was well tolerated and without infusion reactions or cytokine release syndrome. A subset of patients (8 of 29, 28%) responded to RGI-2001 by inducing a markedly increased number of cells with a Treg phenotype. The Treg had a high Ki-67 index and were almost exclusively Helios + and Foxp3 + , indicating that their accumulation was due to expansion of natural Treg. Notably, the incidence of grade 2 to 4 GVHD in the 8 patients who responded to RGI-2001 was 12.5%, compared with 52.4% in the 21 patients who did not respond. No grade 3 or 4 GVHD was observed in the responder group, compared with a 9.5% incidence among nonresponders. Immunosuppression with sirolimus was also associated with a low incidence of GVHD, suggesting that RGI-2001 may have synergized with sirolimus to promote Treg expansion., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Duchenne muscular dystrophy is caused by mutations in the DYSTROPHIN gene. Although primarily associated with muscle wasting, a significant portion of patients (approximately 25%) are also diagnosed with autism spectrum disorder. We describe social behavioral deficits in dystrophin-deficient mice and present evidence of cerebellar deficits in cGMP production. We demonstrate therapeutic potential for selective inhibitors of the cGMP-specific PDE5A and PDE9A enzymes to restore social behaviors in dystrophin-deficient mice., Competing Interests: LMK is a consultant for Pfizer, Summit Corporation PLC and Sarepta Therapeutics for muscle disease drug therapies. MTP, CAM, all hold equity in Pfizer. MTP is a current employee of Autism Speaks. RJK is a consultant for Ironwood Pharmaceuticals. CJS, JFH and ELPC are employees of Pfizer. MS is on the Scientific Advisory Board of Sage Therapeutics and has received research support from Novartis and Shire. The remaining authors declare no conflict of interest.

Classical Hodgkin lymphoma treatment is evolving rapidly with high response rates from antibody-drug conjugates targeting CD30 and immune checkpoint antibodies. However, most patients do not achieve a complete response, therefore development of novel therapies is warranted to improve patient outcomes. In this phase II study, patients with relapsed or refractory Hodgkin lymphoma were treated with entinostat, an isoform selective histone deacetylase inhibitor. Forty-nine patients were enrolled: 33 patients on Schedule A (10 or 15 mg oral entinostat once every other week); 16 patients on Schedule B (15 mg oral entinostat once weekly in 3 of 4 weeks). Patients received a median of 3 prior treatments (range 1-10), with 80% of the patients receiving a prior stem cell transplant and 8% of patients receiving prior brentuximab vedotin. In the intention-to-treat analysis, the overall response rate was 12% while the disease control rate (complete response, partial response, and stable disease beyond 6 months) was 24%. Seven patients did not complete the first cycle due to progression of disease. Tumor reduction was observed in 24 of 38 (58%) evaluable patients. Median progression-free survival and overall survival was 5.5 and 25.1 months, respectively. The most frequent grade 3 or 4 adverse events were thrombocytopenia (63%), anemia (47%), neutropenia (41%), leukopenia (10%), hypokalemia (8%), and hypophosphatemia (6%). Twenty-five (51%) patients required dose reductions or delays. Pericarditis/pericardial effusion occurred in one patient after 12 cycles of therapy. Future studies are warranted to identify predictive biomarkers for treatment response and to develop mechanism-based combination strategies. (clinicaltrials.gov identifier: 00866333)., (Copyright© Ferrata Storti Foundation.)

Limb-girdle muscular dystrophy type 2C (LGMD2C) is considered one of the severe forms of childhood-onset muscular dystrophy. The geographical distribution of founder mutations in the SGCG gene has a prominent effect on the prevalence of LGMD2C in certain populations. The aim of this study was to confirm the hypothesis that the c.787G>A (p.E263K) mutation in the SGCG gene is a founder mutation among Puerto Rican Hispanics and to characterize the associated clinical and immunohistochemical phenotype. Genotyping of six polymorphic microsatellite markers internal to (D13S232) and flanking (D13S175, D13S292, D13S787, D13S1243, D13S283) the SGCG gene was performed on four unrelated Puerto Rican patients with LGMD2C. Preserved ambulation to the second decade of life was observed in at least two subjects. Immunostaining of skeletal muscle demonstrated absence of γ-sarcoglycan in all affected subjects. Two markers, D13S232 and D13S292, were highly informative and confirmed that all four families share the haplotype of the mutant allele. Our findings confirm that the E263K missense mutation in the SGCG gene is a founder mutation in Puerto Rican Hispanics. A slowly progressive disease course with prolonged preservation of ambulation can be seen in association with this mutation, providing evidence for phenotypic variability.

A retrospective chart review was conducted to elucidate the clinical and medical characteristics of male youth admitted to a tertiary inpatient treatment center for eating disorders. A total of 23 male youth were identified who had received treatment between January 2003 and February 2014, and for whom charts were available. The majority of the sample (n = 19; 82.6%) received a diagnosis of anorexia nervosa, and the data suggest that these male youth were significantly medically compromised. The patterns in this data will be discussed in the context of previous published research on male youth with eating disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that results in behavioral, social and communication impairments. ASD has a substantial genetic component, with 88-95% trait concordance among monozygotic twins. Efforts to elucidate the causes of ASD have uncovered hundreds of susceptibility loci and candidate genes. However, owing to its polygenic nature and clinical heterogeneity, only a few of these markers represent clear targets for further analyses. In the present study, we used the linkage structure associated with published genetic markers of ASD to simultaneously improve candidate gene detection while providing a means of prioritizing markers of common genetic variation in ASD. We first mined the literature for linkage and association studies of single-nucleotide polymorphisms, copy-number variations and multi-allelic markers in Autism Genetic Resource Exchange (AGRE) families. From markers that reached genome-wide significance, we calculated male-specific genetic distances, in light of the observed strong male bias in ASD. Four of 67 autism-implicated regions, 3p26.1, 3p26.3, 3q25-27 and 5p15, were enriched with differentially expressed genes in blood and brain from individuals with ASD. Of 30 genes differentially expressed across multiple expression data sets, 21 were within 10 cM of an autism-implicated locus. Among them, CNTN4, CADPS2, SUMF1, SLC9A9, NTRK3 have been previously implicated in autism, whereas others have been implicated in neurological disorders comorbid with ASD. This work leverages the rich multimodal genomic information collected on AGRE families to present an efficient integrative strategy for prioritizing autism candidates and improving our understanding of the relationships among the vast collection of past genetic studies.

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental disorders with high heritability, yet a majority of genetic contribution to pathophysiology is not known. Siblings of individuals with ASD are at increased risk for ASD and autistic traits, but the genetic contribution for simplex families is estimated to be less when compared to multiplex families. To explore the genomic (dis-) similarity between proband and unaffected sibling in simplex families, we used genome-wide gene expression profiles of blood from 20 proband-unaffected sibling pairs and 18 unrelated control individuals. The global gene expression profiles of unaffected siblings were more similar to those from probands as they shared genetic and environmental background. A total of 189 genes were significantly differentially expressed between proband-sib pairs (nominal p < 0.01) after controlling for age, sex, and family effects. Probands and siblings were distinguished into two groups by cluster analysis with these genes. Overall, unaffected siblings were equally distant from the centroid of probands and from that of unrelated controls with the differentially expressed genes. Interestingly, five of 20 siblings had gene expression profiles that were more similar to unrelated controls than to their matched probands. In summary, we found a set of genes that distinguished probands from the unaffected siblings, and a subgroup of unaffected siblings who were more similar to probands. The pathways that characterized probands compared to siblings using peripheral blood gene expression profiles were the up-regulation of ribosomal, spliceosomal, and mitochondrial pathways, and the down-regulation of neuroreceptor-ligand, immune response and calcium signaling pathways. Further integrative study with structural genetic variations such as de novo mutations, rare variants, and copy number variations would clarify whether these transcriptomic changes are structural or environmental in origin.

Carfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m(2) intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m(2) for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238.

Unlabelled: Study Type - Aetiology (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Genetic linkage to distinguish loci for VUR has been previously described in several autosomal chromosomes. Although there are numerous explanations for the dissimilar findings, e.g. multifactorial etiology of VUR and hereditary miscellany among studied populations, clinical diversity between males and females may indicate a central gender-specific genetic susceptibility. Early studies suggested the presence of modified VUR gene(s) on the X-chromosome, accounting for the higher incidence of this disorder among female members in the pedigrees studied. On the other hand male-to-male transmission and a higher ratio of females to males argued against X-linked inheritance. More recently, additional chromosomal regions (i.e. chromosomes 1-7, 10-13, and 18-22) have been identified for VUR by using single nucleotide polymorphism-genome-wide linkage analysis. This is the first study to show that there is autosomal difference in VUR expression in males and females. This genotype variability may be the basis for the clinical differences between genders in children with VUR., Objective: To assess gender-specific genetic differences in the susceptibility loci for vesico-ureteric reflux (VUR) in families who have two or more affected children., Patients and Methods: A genome-wide linkage analysis of VUR with high-density single nucleotide polymorphisms was conducted in 98 families with two or more affected children. A total of 221 affected offspring (123 sibling pairs) were included in the analysis. Genomic DNA was extracted from blood or saliva from all the patients. Data was stratified and analysed according to clinical presentation and gender of the proband and affected siblings., Results: Using the affected sib-pair method, statistically significant peaks were found on chromosomes 1 (logarithm of odds, base10 [LOD] 4.4) and 5 (LOD 3.7) in males and on chromosomes 3 (LOD 3.5), 13 (LOD 4.5), and 15 (LOD 3.4) in females., Conclusion: This genotype variability might be the basis for the clinical differences between genders in children with VUR. Our data might be the first step to understanding the genetic background behind the gender-specific differences of VUR and more clearly defining the genetically different subgroups of VUR., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Objectives: Use electronic health records Autism Spectrum Disorder (ASD) to assess the comorbidity burden of ASD in children and young adults., Study Design: A retrospective prevalence study was performed using a distributed query system across three general hospitals and one pediatric hospital. Over 14,000 individuals under age 35 with ASD were characterized by their co-morbidities and conversely, the prevalence of ASD within these comorbidities was measured. The comorbidity prevalence of the younger (Age<18 years) and older (Age 18-34 years) individuals with ASD was compared., Results: 19.44% of ASD patients had epilepsy as compared to 2.19% in the overall hospital population (95% confidence interval for difference in percentages 13.58-14.69%), 2.43% of ASD with schizophrenia vs. 0.24% in the hospital population (95% CI 1.89-2.39%), inflammatory bowel disease (IBD) 0.83% vs. 0.54% (95% CI 0.13-0.43%), bowel disorders (without IBD) 11.74% vs. 4.5% (95% CI 5.72-6.68%), CNS/cranial anomalies 12.45% vs. 1.19% (95% CI 9.41-10.38%), diabetes mellitus type I (DM1) 0.79% vs. 0.34% (95% CI 0.3-0.6%), muscular dystrophy 0.47% vs 0.05% (95% CI 0.26-0.49%), sleep disorders 1.12% vs. 0.14% (95% CI 0.79-1.14%). Autoimmune disorders (excluding DM1 and IBD) were not significantly different at 0.67% vs. 0.68% (95% CI -0.14-0.13%). Three of the studied comorbidities increased significantly when comparing ages 0-17 vs 18-34 with p<0.001: Schizophrenia (1.43% vs. 8.76%), diabetes mellitus type I (0.67% vs. 2.08%), IBD (0.68% vs. 1.99%) whereas sleeping disorders, bowel disorders (without IBD) and epilepsy did not change significantly., Conclusions: The comorbidities of ASD encompass disease states that are significantly overrepresented in ASD with respect to even the patient populations of tertiary health centers. This burden of comorbidities goes well beyond those routinely managed in developmental medicine centers and requires broad multidisciplinary management that payors and providers will have to plan for.

The basis for vesicoureteral reflux (VUR) is considered to be primarily genetic, with a 30-50% incidence of VUR in first-degree relatives of patients. The search for the causative gene or genes has been elusive, likely because of VUR being genetically heterogeneous with complex inheritance patterns. In this study, a genome-wide analysis of VUR with high-density single nucleotide polymorphisms was conducted with the aim of identifying susceptibility loci for VUR in 98 families with two or more affected children. Using the affected sib-pair method of analysis in 150 sib-pairs, we identified a genome-wide statistically significant linkage peak with an LOD score greater than 4 on chromosome 5 and two linkage peaks with LOD scores greater than 3.6 on chromosomes 13 and 18 were identified in these 98 families. These results suggested that multiple genes are likely to contribute to the formation of VUR phenotype. Further mapping of these linkage peaks may help identify the causative genes.

Clonotypic B lymphocytes may underlie relapse of patients with multiple myeloma. Rituximab, a CD20 monoclonal antibody, may result in eradication of the monoclonal B cells. We conducted a phase II study of rituximab in combination with melphalan and prednisone therapy (MP) followed by rituximab maintenance in newly diagnosed multiple myeloma patients. Sixteen patients (35%) had CD20 positive bone marrow plasma cells, while 9 patients (20%) had unknown CD20 status. No patient had a complete remission, 26 patients (58%) had a partial response, 6 patients (13%) had a minimal response, and 8 patients (18%) had stable disease. The median event-free survival was 14 months, and the 7-year overall survival was 30%. The toxicity of the combination was overall manageable and consistent with what is generally noted with MP chemotherapy. The combination of rituximab to MP therapy did not result in improved response rate or event-free survival.