Faculty Bibliography

Psychosocial interventions remain the primary strategy for addressing cocaine use disorder (CUD), although many individuals do not benefit from these approaches. Amphetamine-based interventions have shown significant promise and may improve outcomes among individuals continuing to use cocaine in the context of behavioral interventions. One hundred forty-five adults (122 males) who used cocaine a minimum of 4 days in the prior month and met the criteria for a CUD enrolled in a two-stage intervention. All participants received a computer-delivered skills intervention and contingency management for reinforcing abstinence for a 1-month period. Participants demonstrating less than 3 weeks of abstinence in the first month were randomized to receive mixed amphetamine salts-extended release (MAS-ER) or placebo (80 mg/day) for 10 weeks under double-blind conditions. All participants continued with the behavioral intervention. The primary outcome was the proportion of individuals who achieved 3 consecutive weeks of abstinence as measured by urine toxicology confirmed self-report at the study end. The proportion of participants demonstrating 3 consecutive weeks of abstinence at study end did not differ between the medication groups: MAS-ER = 15.6% (7/45) and placebo = 12.2% (5/41). Participants who received MAS-ER reported greater reductions in the magnitude of wanting cocaine, although no group differences were noted in either the perceived improvement or the frequency of wanting cocaine. Retention rates were greater for both medication groups compared to behavioral responders. Overall, augmenting a behavioral intervention with MAS-ER did not significantly increase the abstinence rate among individuals continuing to use cocaine following a month of behavioral therapy alone. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The HEALing (Helping to End Addiction Long-term) Communities Study (HCS) aims to test the effectiveness of the Communities That HEAL intervention in decreasing opioid overdose deaths in 67 communities across four U.S. states. This intervention enlists a collaborative team of researchers, academic experts, and community coalitions to select and implement interventions from a menu of evidence-based practices, including medications for opioid use disorder (MOUD). The HCS's New York team developed an integrated network systems (INS) approach with a mapping tool to coach coalitions in the selection of strategies to enhance medication treatment. With the INS approach, community coalitions develop a map of service delivery venues in their local county to better engage people with medication treatment wherever this need arises. The map is structured around core services that can provide maintenance MOUD and satellite services, which include all settings where people with opioid use disorder are encountered and can be identified, possibly given medication, and referred to core programs for ongoing MOUD care. This article describes the rationale for the INS mapping tool, with a discussion framed by the consolidated framework for implementation research, and provides a case example of its application.

Contingency Management (CM) is a psychological treatment that aims to change behavior with financial incentives. In substance use disorders (SUDs), deployment of CM has been enriched by longstanding discussions around the cost-effectiveness of prized-based and voucher-based approaches. In prize-based CM, participants earn draws to win prizes, including small incentives to reduce costs, and the number of draws escalates depending on the duration of maintenance of abstinence. In voucher-based CM, participants receive a predetermined voucher amount based on specific substance test results. While both types have enhanced treatment outcomes, there is room for improvement in their cost-effectiveness: the voucher-based system requires enduring financial investment; the prize-based system might sacrifice efficacy. Previous work in computational psychiatry of SUDs typically employs frameworks wherein participants make decisions to maximize their expected compensation. In contrast, we developed new frameworks that clinical decision-makers choose actions, CM structures, to reinforce the substance abstinence behavior of participants. We consider the choice of the voucher or prize to be a sequential decision, where there are two pivotal parameters: the prize probability for each draw and the escalation rule determining the number of draws. Recent advancements in Reinforcement Learning, more specifically, in off-policy evaluation, afforded techniques to estimate outcomes for different CM decision scenarios from observed clinical trial data. We searched CM schemas that maximized treatment outcomes with budget constraints. Using this framework, we analyzed data from the Clinical Trials Network to construct unbiased estimators on the effects of new CM schemas. Our results indicated that the optimal CM schema would be to strengthen reinforcement rapidly in the middle of the treatment course. Our estimated optimal CM policy improved treatment outcomes by 32% while maintaining costs. Our methods and results have broad applications in future clinical trial planning and translational investigations on the neurobiological basis of SUDs.

Heyde syndrome is characterized by the association between aortic stenosis and gastrointestinal bleeding. This report examines two cases of Heyde syndrome in elderly females who experience bleeding recurrence within months following aortic valve replacement (AVR). The discussion highlights the controversies surrounding the optimal management of Heyde syndrome, particularly in the context of AVR type (surgical vs. transcatheter) and postoperative complications. The report underscores the need for a multidisciplinary approach to Heyde syndrome management and the importance of individualized treatment strategies considering patient-specific factors such as lesion location and postoperative complications.

Cotranslational protein folding depends on general chaperones that engage highly diverse nascent chains at the ribosomes. Here we discover a dedicated ribosome-associated chaperone, Chp1, that rewires the cotranslational folding machinery to assist in the challenging biogenesis of abundantly expressed eukaryotic translation elongation factor 1A (eEF1A). Our results indicate that during eEF1A synthesis, Chp1 is recruited to the ribosome with the help of the nascent polypeptide-associated complex (NAC), where it safeguards eEF1A biogenesis. Aberrant eEF1A production in the absence of Chp1 triggers instant proteolysis, widespread protein aggregation, activation of Hsf1 stress transcription and compromises cellular fitness. The expression of pathogenic eEF1A2 variants linked to epileptic-dyskinetic encephalopathy is protected by Chp1. Thus, eEF1A is a difficult-to-fold protein that necessitates a biogenesis pathway starting with dedicated folding factor Chp1 at the ribosome to protect the eukaryotic cell from proteostasis collapse.

The severity of aortic stenosis (AS) is associated with acquired von Willebrand syndrome (AVWS) and gastrointestinal bleeding, leading to anemia (Heyde's syndrome). We investigated how anemia is linked with AS and AVWS using the LA100 mouse model and patients with AS. Induction of anemia in LA100 mice increased transforming growth factor (TGF)-β1 activation, AVWS, and AS progression. Patients age >75 years with severe AS had higher plasma TGF-β1 levels and more severe anemia than AS patients age <75 years, and there was a correlation between TGF-β1 and anemia. These data are compatible with the hypothesis that the blood loss anemia of Heyde's syndrome contributes to AS progression via WSS-induced activation of platelet TGF-β1 and additional gastrointestinal bleeding via WSS-induced AVWS.

Hematology is a clinical specialty with strong roots in the laboratory; accordingly, the lab can help solve perplexing clinical problems. This review highlights clinical-pathological conundrums addressed during my 35-year hematology career at McMaster University. Heyde syndrome is the association between aortic stenosis and bleeding gastrointestinal (GI) angiodysplasia where the bleeding is usually cured by aortic valve replacement; the chance reading of a neonatal study showing reversible deficiency of high-molecular-weight (HMW) multimers of von Willebrand factor (vWF) following surgical correction of congenital heart disease provided the key insight that a subtle deficiency of HMW multimers of vWF explains Heyde syndrome. The unusual immunobiology of heparin-induced thrombocytopenia (HIT)-a highly prothrombotic, antibody-mediated, anti-platelet factor 4 (PF4) disorder featuring rapid appearance and then disappearance (seroreversion) of the pathological heparin-dependent platelet-activating antibodies-permitted identification of key clinical features that informed development of a scoring system (4Ts) to aid in HIT diagnosis. Atypical clinical presentations of HIT prompted identification of heparin-independent anti-PF4 antibodies, now recognized as the explanation for vaccine-induced immune thrombotic thrombocytopenia (VITT), as well as VITT-like disorders triggered by adenovirus infection. Another unusual feature of HIT is its strong association with limb ischemia, including limb necrosis secondary to deep-vein/microvascular thrombosis (venous limb gangrene). The remarkable observation that supratherapeutic warfarin anticoagulation predisposes to HIT- and cancer-associated venous limb gangrene provided insight into disturbed procoagulant/anticoagulant balance; these concepts are relevant to microvascular thrombosis in critical illness (symmetrical peripheral gangrene), including a pathophysiological role for proximate "shock liver" (impaired hepatic synthesis of natural anticoagulants).

UNLABELLED:Heyde's syndrome is described as angio-dysplastic gastrointestinal (GI) bleeding in elderly patients with degenerative severe calcific aortic stenosis (AS), resulting in anaemia. It was first reported by Edward C. Heyde in 1958 and thus carried his name. Although this condition is considered to develop in 10-20% of severe AS, it is a less familiar entity in clinical practice. With the rising geriatric population in the communities, there is a proportionate increase in the incidence of AS and accompanying Heyde's syndrome. Heyde's syndrome has also been associated with hypertrophic cardiomyopathy, left ventricular assist device, ventricular septal defect, and patent ductus arteriosus. This article reports a case of Heyde's syndrome associated with congenital annular AS, successfully treated by aortic root enlargement and valve replacement. SUPPLEMENTARY INFORMATION/UNASSIGNED:The online version contains supplementary material available at 10.1007/s12055-023-01636-y.

Primary gastric leiomyosarcoma is an exceptionally rare disease. This review covers 41 post-gastrointestinal stromal tumor (GIST) era gastric leiomyosarcoma cases that are supported by immunohistochemistry markers. Other spindle cell lesions are also excluded through histological and immunohistochemistry evaluations. The patients range from 3 to 82 years old, with an average age of 54.6 years. The male-to-female ratio is 1.4:1, from diverse geographic areas. Patients may experience abdominal symptoms, and tumor sizes vary between 1 cm and 22 cm. Morphologically, tumors originate from the muscularis propria or the muscularis mucosae, well-circumscribed with spindle cells arranged in fascicule. Tumoral cells exhibit positivity for smooth muscle markers while being negative for GIST markers and others. The mitotic index ranges from 2 to 500/50 high power field. Ki-67 index varies from 15% to 70%. Management typically involves gastrectomy and other appropriate treatments, with tumor recurrence being uncommon. 56% of patients are alive, with 5 patients dying from this disease. Statistical analyses conducted on post-GIST era cases reveal that a mitotic index of ≥100/50 high power field, tumor recurrence, metastasis, or positive lymph nodes significantly correlate with prognosis.

We present the case of an elderly man with a history of diastolic congestive heart failure, severe aortic stenosis and atrial fibrillation, who presented with fatigue, weakness, coffee ground emesis and black tarry stool. Haemoglobin was 68 g/L. Lactate dehydrogenase was elevated at 1038. Evaluation by cardiology and gastroenterology specialists revealed reflux oesophagitis and a mild hiatal hernia on oesophagogastroduodenoscopy, normal colonoscopy and small bowel series without obstruction. Capsule endoscopy identified angiodysplasia in the small intestine.The patient was diagnosed with Heyde's syndrome based on the triad of severe aortic stenosis, gastrointestinal bleeding from angiodysplasia and acquired von Willebrand syndrome. The patient underwent transcatheter aortic valve replacement, resulting in the resolution of symptoms.Heyde's syndrome represents a challenging clinical entity requiring a multidisciplinary approach for accurate diagnosis and management. Early recognition, prompt intervention and interdisciplinary collaboration are crucial in optimising patient outcomes.