Recognition and management of clozapine adverse effects: A systematic review and qualitative synthesis.

OBJECTIVE: Clozapine is substantially underutilized in most countries and clinician factors including lack of knowledge and concerns about adverse drug effects (ADEs) contribute strongly to treatment reluctance. The aim of this systematic review was to provide clinicians with a comprehensive information source regarding clozapine ADEs. METHODS: PubMed and Embase databases were searched for English language reviews concerned with clozapine ADEs; publications identified by the automated search were manually searched for additional relevant citations. Following exclusion of redundant and irrelevant reports, pertinent information was summarized in evidence tables corresponding to each of six major ADE domains; two authors reviewed all citations for each ADE domain and summarized their content by consensus in the corresponding evidence table. This study was conducted in accordance with PRISMA principles. RESULTS: Primary and secondary searches identified a total of 305 unique reports, of which 152 were included in the qualitative synthesis. Most clozapine ADEs emerge within 3 months, and almost all appear within 6 months, after initiation. Notable exceptions are weight gain, diabetic ketoacidosis (DKA), severe clozapine-induced gastrointestinal hypomotility (CIGH), clozapine-induced cardiomyopathy (CICM), seizures, and clozapine-induced neutropenia (CIN). Most clozapine ADEs subside gradually or respond to dose reduction; those that prompt discontinuation generally do not preclude rechallenge. Rechallenge is generally inadvisable for clozapine-induced myocarditis (CIM), CICM, and clozapine-induced agranulocytosis (CIA). Clozapine plasma levels >600-1000 µg/L appear more likely to cause certain ADEs (e.g., seizures) and, although there is no clear toxicity threshold, risk/benefit ratios are generally unfavorable above 1000 µg/L. CONCLUSION: Clozapine ADEs rarely require discontinuation.

Probing the Neurophysiology of Temporal Sensitivity in the Somatosensory System Using the Mismatch Negativity (MMN) Sensory Memory Paradigm.

Duration is an amodal feature common to all sensory experiences, but low-level processing of the temporal qualities of somatosensation remains poorly understood. The goal of the present study was to evaluate electrophysiological discrimination of parametric somatosensory stimuli to better understand how the brain processes the duration of tactile information. This research used a somatosensory mismatch negativity (sMMN) paradigm to evaluate electrophysiological sensitivity to differences in the duration of vibrotactile stimuli in healthy young adults. Specifically, a 100 ms standard vibration was presented 80% of the time while the remaining 20% of presentations were made up of deviant stimuli with one of the following durations: 115, 130, 145, or 160 ms. When a deviation from the anticipated tactile input is detected, the distinct electrophysiological signature of the sMMN is present. A companion behavioral task assessed individual thresholds for cognizant awareness of the standard and deviant vibrotactile stimuli. The results of the present study demonstrated a sMMN response when deviant stimuli were 130, 145, and 160 ms, but not when they were 115 ms. This suggests that on average the participants did not electrophysiologically discriminate between the 100 and 115 ms. Future work may apply this paradigm to better understand atypical tactile sensitivity in various clinical conditions.

Integrating community voices in the research continuum: Perspectives on a consultation service.

The Community Research Advisory Council (C-RAC) of the Johns Hopkins Institute for Clinical and Translational Research was established in 2009 to provide community-engaged research consultation services. In 2016-2017, C-RAC members and researchers were surveyed on their consultation experiences. Survey results and a 2019 stakeholder meeting proceeding helped redesign the consultation services. Transitioning to virtual consultations during COVID-19, the redesigning involved increasing visibility, providing consultation materials in advance, expanding member training, and effective communications. An increase in consultations from 28 (2009-2017) to 114 (2020-2022) was observed. Implementing stakeholder-researcher inputs is critical to holistic and sustained community-engaged research.

Current status of immunotherapies for addiction.

The treatment of substance use disorders has always been challenging because multiple neurotransmitters mediate addiction. However, with smoking being the leading cause of preventable death and the recent opioid epidemic in the United States, the search for novel solutions becomes more imperative. In this review, we discuss the use of antibodies to treat addictions and highlight areas of success and areas that require improvement, using examples from cocaine, nicotine, and opioid vaccines. Through each example, we examine creative problem-solving strategies for developing future vaccines, such as using an adenovirus vector as a carrier, designing bivalent vaccines, stimulating Toll-like receptors for adjuvant effects, and altering the route of administration. Our review also covers passive immunization alone to override or prevent drug toxicity as well as in combination with vaccines for more rapid and potentially greater efficacy.

Exploring community engaged research experiences and preferences: a multi-level qualitative investigation.

BACKGROUND: Community engagement may make research more relevant, translatable, and sustainable, hence improving the possibility of reducing health disparities. The purpose of this study was to explore strategies for community engagement adopted by research teams and identify areas for enhancing engagement in future community engaged research. METHODS: The Community Engagement Program of the Johns Hopkins Institute for Clinical and Translational Research hosted a forum to engage researchers and community partners in group discussion to reflect on their diverse past and current experiences in planning, implementing, and evaluating community engagement in health research. A total of 50 researchers, research staff, and community partners participated in five concurrent semi-structured group interviews and a whole group wrap-up session. Group interviews were audiotaped, transcribed verbatim, and analyzed using content analysis. RESULTS: Four themes with eight subthemes were identified. Main themes included: Community engagement is an ongoing and iterative process; Community partner roles must be well-defined and clearly communicated; Mutual trust and transparency are central to community engagement; and Measuring community outcomes is an evolving area. Relevant subthemes were: engaging community partners in various stages of research; mission-driven vs. "checking the box"; breadth and depth of engagement; roles of community partner; recruitment and selection of community partners; building trust; clear communication for transparency; and conflict in community engaged research. CONCLUSION: The findings highlight the benefits and challenges of community engaged research. Enhanced capacity building for community engagement, including training and communication tools for both community and researcher partners, are needed.

Solid-phase synthesis of azidomethylene inhibitors targeting cysteine proteases.

An efficient strategy for the solid-phase synthesis of azidomethylene inhibitors targeting cysteine proteases is described. The method is highlighted by its compatibility with readily available building blocks, as well as its ability to accommodate different functional groups. A 249-member library has thus far been successfully synthesized, characterized, and screened against Caspase-1, -3 and -7.

Small molecule microarray-facilitated screening of affinity-based probes (AfBPs) for gamma-secretase.

A small molecule microarray (SMM) platform is developed herein, which enables high-throughput discovery of affinity-based probes (AfBPs) against gamma-secretase.