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BackgroundArbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS.MethodsTwo phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12-50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5-11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-CFX). Secondary outcomes included other ABC-CFX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score.ResultsA total 119 of 125 randomized subjects completed the adolescent/adult study (n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations (n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-CFX Irritability subscale (p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-CFX Social Avoidance and Hyperactivity subscales (both p

Several lines of emerging data point to an imbalance between neuronal excitation and inhibition in at least a subgroup of individuals with autism spectrum disorder (ASD), including in those with fragile X syndrome (FXS), one of the most common genetic syndromes within ASD. In animal models of FXS and of ASD, GABA-B agonists have improved both brain and behavioral phenotypes, including social behavior. A phase 2 randomized, placebo-controlled, crossover trial found that the GABA-B agonist arbaclofen improved social avoidance symptoms in FXS. A pilot open-label trial of arbaclofen suggested similar benefits in ASD. We therefore evaluated arbaclofen in a randomized, placebo-controlled, phase 2 study of 150 participants, aged 5-21 years, with ASD. No difference from placebo was detected on the primary outcome measure, the parent-rated Aberrant Behavior Checklist Social Withdrawal/Lethargy subscale. However, a specified secondary analysis found improvement on the clinician-rated Clinical Global Impression of Severity. An exploratory post hoc analysis of participants with a consistent rater across the trial revealed greater improvement in the Vineland Adaptive Behavior Scales II socialization domain in participants receiving arbaclofen. Affect lability (11%) and sedation (9%) were the most common adverse events. In this exploratory study, secondary analyses suggest that arbaclofen may have the potential to improve symptoms in some children with ASD, but further study will be needed to replicate and extend these initial findings.

STX209 (arbaclofen), a selective GABA-B agonist, is hypothesized to modulate the balance of excitatory to inhibitory neurotransmission, and has shown preliminary evidence of benefit in fragile X syndrome. We evaluated its safety, tolerability, and efficacy in non-syndromic autism spectrum disorders, in an 8-week open-label trial enrolling 32 children and adolescents with either Autistic Disorder or Pervasive Developmental Disorder-Not Otherwise Specified, and a score =17 on the Aberrant Behavior Checklist (ABC)-Irritability subscale. STX209 was generally well-tolerated. The most common adverse events were agitation and irritability, which typically resolved without dose changes, and were often felt to represent spontaneous variation in underlying symptoms. Improvements were observed on several outcome measures in this exploratory trial, including the ABC-Irritability (the primary endpoint) and the Lethargy/Social Withdrawal subscales, the Social Responsiveness Scale, the CY-BOCS-PDD, and clinical global impression scales. Placebo-controlled study of STX209 is warranted.

Recognition and escalation of the deteriorating patient is multifaceted and relevant to all clinicians involved. However, little evidence exists exploring how clinicians from different professions make decisions about early signs of clinical deterioration and how this affects their actions. The aim of this study was to explore interprofessional clinicians' and students' experiences of responding to and escalating care of deteriorating patients. A convenience sample of clinicians and students from acute hospital settings in regional Australia participated in focus groups. Participants were able to identify barriers, facilitators, and strategies for improvement during the recognition and escalation of the deteriorating patient. Four themes were detected throughout the 38 focus group discussions: a Standardized Approach, Workplace Culture and Teamwork, Confidence and Experience, and Communication. Although standardization of systems and processes supported clinician's recognition and escalation of the deteriorating patient, use and misuse of the systems by some participants were identified as barriers to seeking assistance. Positive workplace culture and teamwork were important to promoting the escalation of care. Participants identified that experience in recognizing and responding to deteriorating patients increased their confidence. [ABSTRACT FROM AUTHOR]

STX209 (arbaclofen), a selective GABA-B agonist, is hypothesized to modulate the balance of excitatory to inhibitory neurotransmission, and has shown preliminary evidence of benefit in fragile X syndrome. We evaluated its safety, tolerability, and efficacy in non-syndromic autism spectrum disorders, in an 8-week open-label trial enrolling 32 children and adolescents with either Autistic Disorder or Pervasive Developmental Disorder--Not Otherwise Specified, and a score [greater than or equal to]17 on the Aberrant Behavior Checklist (ABC)--Irritability subscale. STX209 was generally well-tolerated. The most common adverse events were agitation and irritability, which typically resolved without dose changes, and were often felt to represent spontaneous variation in underlying symptoms. Improvements were observed on several outcome measures in this exploratory trial, including the ABC-Irritability (the primary endpoint) and the Lethargy/Social Withdrawal subscales, the Social Responsiveness Scale, the CY-BOCSPDD, and clinical global impression scales. Placebo-controlled study of STX209 is warranted. Keywords STX209 * Arbaclofen * Gamma-aminobutyric acid (GABA) * Autism spectrum disorder * Clinical trial, Introduction Although the number of children and adults diagnosed with autism spectrum disorders (ASD) has increased over the last decade, (CDC 2012) only two pharmacologic agents (risperidone and aripiprazole) are [...]

The article focuses on Sadelers may be famous for their production of superior engravings for elite patrons, as well as numerous additional projects and known to have made numerous book illustrations, their self-identification as booksellers and publication of various illustrated texts.

The article reports that when the engraver Charles de Mallery was 60 years old, Anthony van Dyck portrayed him at least three times in a black chalk drawing, an oil sketch and a large painting and his oil sketch served as the basis for Lucas Vorsterman engraving of De Mallery in Van Dyck's potrait.

Globally, the impact of COVID‐19 on healthcare workers' mental health has been a major focus of recent research. However, Australian research involving nurses, particularly across the acute care sector, is limited. This cross‐sectional research aimed to explore the impact of pandemic‐related stress on psychological adjustment outcomes and potential protective factors for nurses (n = 767) working in the Australian acute care sector during the COVID‐19 pandemic. Nurses completed an online questionnaire with psychometrically validated measures of pandemic‐related stress, psychological adjustment outcomes (depression, anxiety, and subjective well‐being), and protective factors (posttraumatic growth and self‐compassion). Descriptive analyses revealed that pandemic‐related stress was reported by 17.7% of the participants. Psychological adjustment outcome scores above normal for depression (27.5%) and anxiety (22.0%) were found, and 36.4% of the participants reported poor subjective well‐being. Regression analyses suggest that pandemic‐related stress predicted greater depression (B = 0.32, SE = 0.02, 95% confidence interval [0.28, 0.35]) and anxiety (B = 0.26, SE = 0.01, 95% confidence interval [0.24, 0.29]) and less subjective well‐being (B = −0.14, SE = 0.01, 95% confidence interval [−0.16, −0.12]). Self‐compassion weakened the relationship between pandemic‐related stress and greater depression, however, exacerbated the relationship between pandemic‐related stress and less subjective well‐being. Posttraumatic growth reduced the negative relationship between pandemic‐related stress and psychological adjustment outcomes. These findings will inform strategies to facilitate psychological resources that support nurses' psychological adjustment, enabling better pandemic preparedness at both an individual and organizational level. [ABSTRACT FROM AUTHOR]

A treatment combining standard antibiotics, such as vancomycin hydrochloride or metronidazole, with the fungus Saccharomyces boulardii appears to be effective at reducing the recurrence of Clostridium difficile disease (CDD). Clostridium difficile is a bacteria responsible for causing an inflammation of the large intestine often associated with prolonged use of antibiotics. A total of 124 patients were studied, of whom 64 were experiencing their first episode of CDD and 60 were experiencing a recurrence. The combined treatment of S. boulardii and antibiotics was significantly more effective than antibiotics alone for those with recurrent CDD. However, the combined treatment was statistically no better than straight antibiotics at treating those with an initial episode of CDD. No adverse reactions to S. boulardii were noted., Objective. - To determine the safety and efficacy of a new combination treatment for patients with Clostridium difficile-associated disease (CDD). The treatment combines the yeast Saccharomyces boulardii with an antibiotic (vancomycin hydrochloride or metronidazole). Design. - A double-blind, randomized, placebo-controlled, parallel-group intervention study in patients with active CDD. Patients received standard antibiotics and S boulardii or placebo for 4 weeks, and were followed up for an additional 4 weeks after therapy. Effectiveness was determined by comparing the recurrence of CDD in the two groups using multivariate analysis to control for other risk factors for CDD. Setting. - National referral study of ambulatory or hospitalized patients from three main study coordinating centers. Patients. - A total of 124 eligible consenting adult patients, including 64 who were enrolled with an initial episode of CDD, and 60 who had a history of at least one prior CDD episode. Patients who were immunosuppressed due to acquired immunodeficiency syndrome or cancer chemotherapy within 3 months were not eligible. Intervention. - Treatment with oral S boulardii (1 g/d for 4 weeks) or placebo in combination with a standard antibiotic. Main Outcome Measure. - Recurrence of active CDD. Results. - A history of CDD episodes dramatically increased the likelihood of further recurrences. Multivariate analysis revealed that patients treated with S boulardii and standard antibiotics had a significantly lower relative risk (RR) of CDD recurrence (RR, 0.43; 95% confidence interval, 0.20 to 0.97) compared with placebo and standard antibiotics. The efficacy of S boulardii was significant (recurrence rate 34.6%, compared with 64.7% on placebo; P=.04) in patients with recurrent CDD, but not in patients with initial CDD (recurrence rate 19.3% compared with 24.2% on placebo; P=.86). There were no serious adverse reactions associated with S boulardii. Conclusions. - The combination of standard antibiotics and S boulardii was shown to be an effective and safe therapy for these patients with recurrent CDD; no benefit of S boulardii was demonstrated for those with an initial episode of CDD.

MW01‐6‐189WH (MW189) is a novel central nervous system–penetrant small‐molecule drug candidate that selectively attenuates stressor‐induced proinflammatory cytokine overproduction and is efficacious in intracerebral hemorrhage and traumatic brain injury animal models. We report first‐in‐human, randomized, double‐blind, placebo‐controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous doses of MW189 in healthy adult volunteers. MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. The most common drug‐related treatment‐emergent adverse event was infusion‐site reactions, likely related to drug solution acidity. No clinically concerning changes were seen in vital signs, electrocardiograms, physical or neurological examinations, or safety laboratory results. PK analysis showed dose‐proportional increases in plasma concentrations of MW189 after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. Steady state was achieved by dose 3 for all dosing cohorts. A pilot pharmacodynamic study administering low‐dose endotoxin to induce a systemic inflammatory response was done to evaluate the effects of a single intravenous dose of MW189 on plasma cytokine levels. MW189 treatment resulted in lower levels of the proinflammatory cytokine TNF‐α and higher levels of the anti‐inflammatory cytokine IL‐10 compared with placebo treatment. The outcomes are consistent with the pharmacological mechanism of MW189. Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute brain injury. [ABSTRACT FROM AUTHOR]