Adaptive infusion of a glucagon-like peptide-1/glucagon receptor co-agonist G3215, in adults with overweight or obesity: Results from a phase 1 randomized clinical trial.

AIMS: To determine whether a continuous infusion of a glucagon-like peptide receptor (GLP-1R)/glucagon receptor (GCGR) co-agonist, G3215 is safe and well tolerated in adults with overweight or obesity. METHODS: A phase 1 randomized, double blind, placebo-controlled trial of G3215 in overweight or obese participants, with or without type 2 diabetes. RESULTS: Twenty-six participants were recruited and randomized with 23 completing a 14-day subcutaneous infusion of G3215 or placebo. The most common adverse events were nausea or vomiting, which were mild in most cases and mitigated by real-time adjustment of drug infusion. There were no cardiovascular concerns with G3215 infusion. The pharmacokinetic characteristics were in keeping with a continuous infusion over 14 days. A least-squares mean body weight loss of 2.39 kg was achieved with a 14-day infusion of G3215, compared with 0.84 kg with placebo infusion (p < .05). A reduction in food consumption was also observed in participants receiving G3215 and there was no deterioration in glycaemia. An improved lipid profile was seen in G3215-treated participants and consistent with GCGR activation, a broad reduction in circulating amino acids was seen during the infusion period. CONCLUSION: An adaptive continuous infusion of the GLP-1/GCGR co-agonist, G3215, is safe and well tolerated offering a unique strategy to control drug exposure. By allowing rapid, response-directed titration, this strategy may allow for mitigation of adverse effects and afford significant weight loss within shorter time horizons than is presently possible with weekly GLP-1R and multi-agonists. These results support ongoing development of G3215 for the treatment of obesity and metabolic disease.

Predictors of aspiration pneumonia: developing a new matrix for speech and language therapists.

INTRODUCTION: The contributing factors of aspiration pneumonia have been well documented. However, there are gaps in the literature regarding identifying the weight associated with each factor and the relationship between factors. METHOD: In this study, 20 potential predictors of aspiration pneumonia (with four additional variables) have been applied to historic Speech and Language Therapy records to greater understand the significance of each contributor of aspiration pneumonia. 152 cases with an oropharyngeal dysphagia, and a Speech and Language Therapy recommendation of eating and drinking with known aspiration and the associated potential risk of developing an aspiration pneumonia, were included in the data. These were inpatients and outpatients, and had various diagnoses but all had had a videofluoroscopy. RESULTS: Logistic regression analysis found seven factors that were individually significant in predicting the development of aspiration pneumonia with 84.93% sensitivity and 91.03% specificity DISCUSSION: Logistic regression and random forest analyses led to the proposal of a new matrix of predictors of aspiration pneumonia with respective scoring weights for individual and cumulative contributors (a direction for future research).

A clinical bulbar assessment scale (CBAS) for amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Comprehensive and valid bulbar assessment scales for use within amyotrophic lateral sclerosis (ALS) clinics are critically needed. The aims of this study are to develop the Clinical Bulbar Assessment Scale (CBAS) and complete preliminary validation. METHODS: The authors selected CBAS items from among the literature and expert opinion, and content validity ratio (CVR) was calculated. Following consent, the CBAS was administered to a pilot sample of English-speaking adults with El Escorial defined ALS (N = 54) from a multidisciplinary clinic, characterizing speech, swallowing, and extrabulbar features. Criterion validity was assessed by correlating CBAS scores with commonly used ALS scales, and internal consistency reliability was obtained. RESULTS: Expert raters reported strong agreement for the CBAS items (CVR = 1.00; 100% agreement). CBAS scores yielded a moderate, significant, negative correlation with ALS Functional Rating Scale-Revised (ALSFRS-R) total scores (r = -0.652, p < .001), and a strong, significant, negative correlation with ALSFRS-R bulbar subscale scores (r = -0.795, p < .001). There was a strong, significant, positive correlation with Center for Neurologic Studies Bulbar Function Scale (CNS-BFS) scores (r = 0.819, p < .001). CBAS scores were significantly higher for bulbar onset (mean = 38.9% of total possible points, SD = 22.6) than spinal onset (mean = 18.7%, SD = 15.8; p = .004). Internal consistency reliability (Cronbach's alpha) values were: (a) total CBAS, α = 0.889; (b) Speech subscale, α = 0.903; and (c) Swallowing subscale, α = 0.801. DISCUSSION: The CBAS represents a novel means of standardized bulbar data collection using measures of speech, swallowing, respiratory, and cognitive-linguistic skills. Preliminary evidence suggests the CBAS is a valid, reliable scale for clinical assessment of bulbar dysfunction.

Safety and efficacy of an extended-release peptide YY analogue for obesity: A randomized, placebo-controlled, phase 1 trial.

AIM: To report the results from a Phase 1 trial of an extended-release peptide YY analogue, Y14, developed for the treatment of obesity. METHODS: Y14 was evaluated in overweight/obese volunteers in a Phase 1 randomized placebo-controlled trial, conducted in a clinical trial unit in the United Kingdom. Part A was a blinded single-ascending-dose study evaluating doses up to 36 mg. Part B was double-blinded and tested multiple ascending doses between 9 and 36 mg, given at 7- to 14-day intervals, over the course of 28 days, with up to five doses given per participant. The primary outcome was safety and tolerability; the secondary outcome was assessment of pharmacokinetic (PK) characteristics. Exploratory outcomes included food intake, body weight change and glucose tolerance after multiple doses. RESULTS: Between April 11, 2017 and December 24, 2018, 53 participants were enrolled into Part A and 24 into Part B of the trial. The PK characteristics were compatible with administration every 7 to 14 days. The most common adverse events (AEs) were nausea, vomiting or administration site reactions, which were mild in most cases and settled with time. No serious AE occurred. Participants given multiple doses of Y14 lost between -2.87 and -3.58 kg body weight compared with placebo (P <0.0001) at 31 days from the first dose, with profound reductions in food intake of 38% to 55% (P <0.0001, compared to placebo) and there was no evidence of tachyphylaxis. CONCLUSIONS: Our results support the continued development of Y14 as a novel treatment for obesity.

Risk factors of infective endocarditis in persons who inject drugs.

BACKGROUND: The rising incidence of infective endocarditis (IE) among people who inject drugs (PWID) has been a major concern across North America. The coincident rise in IE and change of drug preference to hydromorphone controlled-release (CR) among our PWID population in London, Ontario intrigued us to study the details of injection practices leading to IE, which have not been well characterized in literature. METHODS: A case-control study, using one-on-one interviews to understand risk factors and injection practices associated with IE among PWID was conducted. Eligible participants included those who had injected drugs within the last 3 months, were > 18 years old and either never had or were currently admitted for an IE episode. Cases were recruited from the tertiary care centers and controls without IE were recruited from outpatient clinics and addiction clinics in London, Ontario. RESULTS: Thirty three cases (PWID IE+) and 102 controls (PWID but IE-) were interviewed. Multivariable logistic regressions showed that the odds of having IE were 4.65 times higher among females (95% CI 1.85, 12.28; p = 0.001) and 5.76 times higher among PWID who did not use clean injection equipment from the provincial distribution networks (95% CI 2.37, 14.91; p < 0.001). Injecting into multiple sites and heating hydromorphone-CR prior to injection were not found to be significantly associated with IE. Hydromorphone-CR was the most commonly injected drug in both groups (90.9% cases; 81.4% controls; p = 0.197). DISCUSSION: Our study highlights the importance of distributing clean injection materials for IE prevention. Furthermore, our study showcases that females are at higher risk of IE, which is contrary to the reported literature. Gender differences in injection techniques, which may place women at higher risk of IE, require further study. We suspect that the very high prevalence of hydromorphone-CR use made our sample size too small to identify a significant association between its use and IE, which has been established in the literature.

Validation of an Algorithm to Identify Infective Endocarditis in People Who Inject Drugs.

INTRODUCTION: Infective endocarditis is associated with high morbidity and mortality. Currently, there is concern that the incidence of infective endocarditis associated with people who inject drugs (PWID) is increasing. However, it is difficult to monitor population-wide trends in PWID-associated infective endocarditis, as there is no International Statistical Classification of Diseases, 10th Revision (ICD-10) code for injection drug use. To address this barrier, we sought to develop a validated algorithm using ICD-10 discharge diagnosis codes. MATERIALS AND METHODS: We constructed a cohort of patients whose hospital discharge diagnosis included infective endocarditis. We reviewed 100 patients with incident infective endocarditis from 2014 to 2016 for their infective endocarditis and injection drug use status. We calculated the operating characteristics for algorithms constructed using permutations of ICD-10 codes associated with injection drug use. We repeated this analysis in a cohort of 100 patients with incident infective endocarditis from 2009 to 2011 to examine the temporal stability of the operating characteristics of each algorithm. RESULTS: We found that a combination of hepatitis C virus, drug use, and mental/behavioral disorder codes yielded the highest sensitivity (93%) and positive predictive value (83%) of the algorithms analyzed. DISCUSSION: We have described the first algorithm, validated against chart review data, for identifying PWID-associated infective endocarditis cases using ICD-10 codes. The high sensitivity and positive predictive value indicate that this algorithm can be used for surveillance and research with confidence. CONCLUSIONS: This algorithm will enable researchers to examine epidemiological trends in PWID-associated infective endocarditis.

Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies.

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.

Use of At-Breast Supplementers to Facilitate Feeding Solely at the Breast for Infants with Retrognathia: Two Case Studies.

Objective: Infants with significant retrognathia often have difficulty forming a latch adequate to establish exclusive breastfeeding. This article describes the use of at-breast supplementers (ABSs) to facilitate extended breastfeeding relationships, even when supplementation is necessary for growth. Methods: Two cases are described where infants with severe retrognathia initially struggled with weight gain necessitating supplementation but were able to ultimately exclusively feed at-breast with the use of ABSs. Results: While the two cases differed in the form of supplemental milk used and duration of ABS use, both dyads breastfed for beyond 2 years. Conclusions: Feeding solely at the breast and subsequent extended breastfeeding may be possible even for infants who require supplementation, including those with anatomical or functional challenges such as retrognathia. The ABS is a relatively simple system that may be beneficial for difficulties such as poor latch and low milk supply. More awareness and education is needed so that clinicians consider supporting dyads with this approach.

Participant anxiety and presence of hyperfunction in stroboscopy.

OBJECTIVE: Excessive supraglottic and abnormal fine vibratory characteristics associated with vocal hyperfunction are identified even in individuals with normal laryngeal structure, function and vocal quality when they undergo stroboscopy, possibly due to anxiety. The purpose of this study is to (a) test for vocal hyperfunction in individuals with normal laryngeal structure and function and if present, (b) to track changes in vocal hyperfunction associated with anxiety when stroboscopy is repeated within 24-48 h. PARTICIPANTS AND METHODS: Thirty participants, naïve to stroboscopy, underwent the procedure and completed the State-Trait Anxiety Inventory 3 times over 24-48 h. RESULTS: 41.4% of participants demonstrated vocal hyperfunction in supraglottic and fine vibratory characteristics after the first trial. Vocal hyperfunction decreased to 27.6% after the third trial. RESULTS showed a significant main effect of time indicating that vocal hyperfunction decreased as participants repeated stroboscopy. Although the average anxiety score decreased across trials, state (anxiety) had no significant effect on change in vocal hyperfunction. CONCLUSIONS: In the real world, true representation of vocal function can be achieved by getting a patient acquainted to the presence of strobe in the oral cavity and practice the tasks that will be attempted during the procedure without introducing vocal hyperfunction and most importantly, without the use of a topical anesthetic.

Family impact of assistive technology scale: development of a measurement scale for parents of children with complex communication needs.

Young people use augmentative and alternative communication (AAC) systems to meet their everyday communication needs. However, the successful integration of an AAC system into a child's life requires strong commitment and continuous support from parents and other family members. This article describes the development and evaluation of the Family Impact of Assistive Technology Scale for AAC Systems - a parent-report questionnaire intended to detect the impact of AAC systems on the lives of children with complex communication needs and their families. The study involved 179 parents and clinical experts to test the content and face validities of the questionnaire, demonstrate its internal reliability and stability over time, and estimate its convergent construct validity when compared to a standardized measure of family impact.

Personnel roles in the AAC assessment process.

Completing an augmentative and alternative communication (AAC) assessment is a complex process that involves many stakeholders and professionals. To help clarify professional roles and provide assessment guidelines, an AAC Assessment Personnel Framework was developed. This framework was adapted from the work of Beukelman, Ball, and Fager in 2008, which focused on general AAC needs (not just assessment) and concentrated specifically on adults. In contrast, the present model examines the assessment process for all individuals who require AAC. The following AAC assessment personnel are discussed: AAC finders, general practice SLPs, AAC clinical specialists, facilitators and communication partners, collaborating professionals, AAC research and policy specialists, manufacturers and vendors, funding agencies and personnel, and AAC/assistive technology agencies and personnel. Current barriers for successful assessment outcomes are discussed, and suggestions for addressing personnel-related barriers are explored.

Genius [corrected] without the "Great Man": new possibilities for the historian of psychology.

The Carlylian style of history, more commonly known as the "Great Man" approach, presented the "genius" as an individual worthy of celebration: history as hero worship. This style, which characterized the first wave of the history of psychology, has gone out of historiographic fashion. In its place is the "new history," which is marked by its external focus and privileging of social factors and cultural context in its explanations. This shift in historiographic sensibilities has also led to a revision in the appropriate subject matter for psychologist-historians. This article argues, in contrast, that it is possible to study eminent individuals without resorting to hagiography, and it presents various methods that could be used for this purpose. The aim of such an endeavor is to create a space for critically and historically informed perspectives on greatness and to suggest a reconsideration of the value of an "historical psychology".

Privacy and safety: Issues of dual compliance in high-secure and other forensic psychiatric hospitals.

Health care organizations are obligated to provide safe and effective treatment to their patients and also protect the safety of their workers. This paper analyzes the tensions arising from legislative regimes that, respectively, protect privacy and workplace safety, using a large, tertiary high-secure forensic psychiatric hospital in Ontario, Canada, as an example. In Ontario, the Personal Health Information Protection Act (PHIPA) prohibits personal health information (PHI) from being disclosed to individuals who fall outside the "circle of care," including nonclinical employees who have direct involvement with patients and may be at risk of violence. PHIPA permits the disclosure of information where there is a risk of violence, but the statute's scheme for privacy protection was not designed to address, and may not be compatible with, the operations and requirements of high-secure forensic and other psychiatric hospitals. At the same time, the Occupational Health and Safety Act (OHSA) creates a regulatory framework that sets health and safety standards, including an employer's duty to disclose the risk of violence. OHSA prosecutions and proceedings demonstrate how these duties have been enforced against psychiatric hospitals. We examine this regulatory backdrop, explaining that PHIPA provides little guidance to psychiatric hospitals, where the risk of violence is elevated. We also discuss issues of dual compliance that arise from a hospital's legal obligations under PHIPA and OHSA. Finally, we turn to the ongoing clinical and operational challenges, suggesting strategies for increasing staff safety. These include strengthening the therapeutic alliance and providing patients with the option of consenting to disclosure of PHI to those outside the circle of care.

Pulmonological issues.

Pediatric leukodystrophies are rare neurodegenerative diseases involving multiple systems. Each form has unique neurologic features but are characterized by encephalopathy with accompanying impairments evidenced in reflexes, muscle tone and movement control. Weakness of expiratory, inspiratory, and upper airway muscles may lead to impaired airway secretion clearance resulting in recurrent respiratory infections, dysphagia, sleep-disordered breathing, restrictive lung disease, and ultimately chronic respiratory insufficiency.

Communication skills among children with spinal muscular atrophy type 1: A parent survey.

Spinal muscular atrophy is one of the most common fatal autosomal recessive disorders. Children diagnosed with SMA Type 1 (SMAT1) demonstrate severe oral motor weakness and flaccid dysarthria progressing to complete anarthria. A review of literature illustrates that little has been described regarding augmentative and alternative communication (AAC) use among these children, although communication has a critical impact on quality of life and participation in daily activities. Responses to an investigator-developed parent survey were obtained to appraise communication skills and opportunities among children diagnosed with SMA1. Results illustrate parent perception of greater receptive than expressive language ability and highlight the benefits of implementing speech-generating devices (SGD). Barriers to SGD acquisition and implementation, including access and funding, are reported and described. Overall, families indicated that SGD increases quality of life and provides valued improvements through expanded functional communication.

A multi-disciplinary clinic for SCN8A-related epilepsy.

OBJECTIVE: We endeavored to evaluate a cohort of patients diagnosed with SCN8A-related epilepsy in a multi-disciplinary clinic and to create a bio-repository. METHODS: We recruited patients with epilepsy due to SCN8A variants at Children's National Medical Center, through family organizations, or SCN8A.net. Study procedures included medical record review, review of EEG and MRI data, clinical evaluation, the Vineland Adaptive Behavior Scales, Third Edition (VABS-3), DNA extraction, and preparation of peripheral blood mononuclear cells. RESULTS: Seventeen patients (9 months - 19 years) completed the study. Age at seizure onset was 1 day to 4 years old (median age 4 months). Epilepsy phenotype ranged from mild epilepsy to severe developmental and epileptic encephalopathy. Medications targeting the voltage-gated sodium channel were most often effective, while levetiracetam resulted in worsening seizures and/or developmental regression in 7/16 (p < 0.05). VABS-3 scores were below age expectations for most children; older children had lower scores. Neurological examination revealed hypotonia (13), spastic quadriparesis (1), ataxia (9), dyskinesia (2)/ dystonia (7), and four non-ambulatory. CONCLUSIONS: This is the first report of a large series of patients with epilepsy due to SCN8A variants evaluated in a single multi-disciplinary clinic. By utilizing a more comprehensive and consistent evaluation, we clarify specific seizure and epilepsy types, describe a distinct epilepsy phenotype in a patient with a nonsense variant, delineate patterns of developmental delay, language, and swallow function (specifically anomic aphasia and flaccid dysarthria), identify and characterize movement disorders, report common findings on physical exam, and demonstrate clinical worsening with levetiracetam.

Twin research, revisionism and metahistory.

We understand metahistory as an approach that studies how histories within a particular discipline have been written and focus on insider scientists' reconstructions of twin research. Using the concept of ethical-political affordances we suggest that such histories are based on a management of resources that prove to be beneficial for representing one's own research traditions in a positive light. Instead of discussing information on the context and intellectual life of pioneers of the twin method, which include high-caliber eugenicists and Nazi ideologues, and on how the twin method has been used and abused, insider scientists' accounts present twin research as neutral, objective and void of any kind of political connotations. We show how important leaders of German twin research have been historically managed, and how their contributions have been distorted and omitted. Reasons for historical revisionism by omission and for selectively revised accounts of the past are discussed. Suggestions for writing accounts of the twin method are included and focus on the necessity of self-reflection, considerations regarding one's own ethical-political inclinations, and review of the existing historical literature. In analyzing these connections, we attempt to understand how science, politics and history interact.

Sharing of Injection Drug Preparation Equipment Is Associated With HIV Infection: A Cross-sectional Study.

BACKGROUND: Sharing needles/syringes and sexual transmission are widely appreciated as means of HIV transmission among persons who inject drugs (PWIDs). London, Canada, is experiencing an outbreak of HIV among PWIDs, despite a large needle/syringe distribution program and low rates of needle/syringe sharing. OBJECTIVE: To determine whether sharing of injection drug preparation equipment (IDPE) is associated with HIV infection. METHODS: Between August 2016 and June 2017, individuals with a history of injection drug use and residence in London were recruited to complete a comprehensive questionnaire and HIV testing. RESULTS: A total of 127 participants were recruited; 8 were excluded because of failure to complete HIV testing. The remaining 35 HIV-infected (cases) and 84 HIV-uninfected (controls) participants were assessed. Regression analysis found that sharing IDPE, without sharing needles/syringes, was strongly associated with HIV infection (adjusted odds ratio: 22.1, 95% confidence interval: 4.51 to 108.6, P < 0.001). CONCLUSIONS: Sharing of IDPE is a risk factor for HIV infection among PWIDs, even in the absence of needle/syringe sharing. Harm reduction interventions to reduce HIV transmission associated with this practice are urgently needed.

Heating Injection Drug Preparation Equipment Used for Opioid Injection May Reduce HIV Transmission Associated With Sharing Equipment.

BACKGROUND: London, Canada, experienced an HIV outbreak among persons who inject drugs despite widespread distribution of harm reduction equipment. Hydromorphone controlled-release (HMC) is the local opioid of choice. Injection drug preparation equipment (IDPE; ie, cookers and filters) is often shared and reused because of the perception that there is residual HMC in the IDPE after use. The purpose of this study was to investigate the mechanisms of HIV transmission in this context. METHODS: Residual hydromorphone, (controlled-release or immediate-release), remaining in the IDPE, was measured with liquid chromatography-tandem mass spectrometry, in conditions replicating persons who inject drug use. HIV was added to IDPE in the presence HMC, hydromorphone immediate-release, or microcrystalline cellulose (an HMC drug excipient). HIV viral persistence was measured by reverse transcriptase activity and infectivity of indicator Tzm-bl cells. RESULTS: Forty-five percent of HMC remained in the IDPE after the first aspiration of solution, with no change after heating. HIV persistence and infectivity were preserved in the presence of HMC, and less so with microcrystalline cellulose. Heating the IDPE rapidly inactivated HIV. CONCLUSIONS: Sharing of IDPE is a potential means of HIV transmission. HMC encourages IDPE sharing because of the residual drug in the IDPE, and the HMC excipients preserve HIV viability. Heating IDPE before aspiration of the opioid may be a harm reduction strategy.

An AAC personnel framework: adults with acquired complex communication needs.

A personnel framework designed to support people who rely on augmentative and alternative communication (AAC) because of acquired medical conditions and those who assist them is described. The roles of AAC finders, general practice clinicians, AAC intervention specialists, AAC facilitators, and AAC experts are summarized. These roles are described in detail for people with amyotrophic lateral sclerosis, brainstem impairment, and severe chronic aphasia. The personnel preparation needs for each of these support personnel groups are identified.