BACKGROUND: Overdose deaths continue to reach new records in New York City and nationwide, largely driven by adulterants such as fentanyl and xylazine in the illicit drug supply. Unknowingly consuming adulterated substances dramatically increases risks of overdose and other health problems, especially when individuals consume multiple adulterants and are exposed to a combination of drugs they did not intend to take. Although test strips and more sophisticated devices enable people to check drugs for adulterants including fentanyl and xylazine prior to consumption and are often available free of charge, many people who use drugs decline to use them.
OBJECTIVE: We sought to better understand why people in the New York City area do or do not check drugs before use. We plan to use study findings to inform the development of technology-based interventions to encourage consistent drug checking.
METHODS: In summer 2023, team members who have experience working with people who use drugs conducted 22 semistructured qualitative interviews with a convenience sample of people who reported illicit drug use within the past 90 days. An interview guide examined participants\' knowledge of and experience with adulterants including fentanyl, xylazine, and benzodiazepines; using drug testing strips; and whether they had ever received harm reduction services. All interviews were audio recorded, transcribed, and analyzed for emerging themes.
RESULTS: Most participants lacked knowledge of adulterants, and only a few reported regularly checking drugs. Reasons for not checking included lacking convenient access to test supplies, or a place to check samples out of the public\'s view, as well as time considerations. Some participants also reported a strong belief that they were not at risk from fentanyl, xylazine, or other adulterants because they exclusively used cocaine or crack, or that they were confident the people they bought drugs from would not sell them adulterated substances. Those who did report testing their drugs described positive interactions with harm reduction agency staff.
CONCLUSIONS: New forms of outreach are needed not only to increase people\'s knowledge of adulterated substances and awareness of the increasing risks they pose but also to encourage people who use drugs to regularly check their substances prior to use. This includes new intervention messages that highlight the importance of drug checking in the context of a rapidly changing and volatile drug supply. This messaging can potentially help normalize drug checking as an easily enacted behavior that benefits public health. To increase effectiveness, messages can be developed with, and outreach can be conducted by, trusted community members including people who use drugs and, potentially, people who sell drugs. Pairing this messaging with access to no-cost drug-checking supplies and equipment may help address the ongoing spiral of increased overdose deaths nationwide.

BACKGROUND: Interventions are required that address delays in treatment-seeking and low treatment coverage among people consuming methamphetamine.
OBJECTIVE: We aim to determine whether a self-administered smartphone-based intervention, the \"S-Check app\" can increase help-seeking and motivation to change methamphetamine use, and determine factors associated with app engagement.
METHODS: This study is a randomized, 28-day waitlist-controlled trial. Consenting adults residing in Australia who reported using methamphetamine at least once in the last month were eligible to download the app for free from Android or iOS app stores. Those randomized to the intervention group had immediate access to the S-Check app, the control group was wait-listed for 28 days before gaining access, and then all had access until day 56. Actual help-seeking and intention to seek help were assessed by the modified Actual Help Seeking Questionnaire (mAHSQ), modified General Help Seeking Questionnaire, and motivation to change methamphetamine use by the modified readiness ruler. χ2 comparisons of the proportion of positive responses to the mAHSQ, modified General Help Seeking Questionnaire, and modified readiness ruler were conducted between the 2 groups. Logistic regression models compared the odds of actual help-seeking, intention to seek help, and motivation to change at day 28 between the 2 groups. Secondary outcomes were the most commonly accessed features of the app, methamphetamine use, feasibility and acceptability of the app, and associations between S-Check app engagement and participant demographic and methamphetamine use characteristics.
RESULTS: In total, 560 participants downloaded the app; 259 (46.3%) completed eConsent and baseline; and 84 (32.4%) provided data on day 28. Participants in the immediate access group were more likely to seek professional help (mAHSQ) at day 28 than those in the control group (n=15, 45.5% vs n=12, 23.5%; χ21=4.42, P=.04). There was no significant difference in the odds of actual help-seeking, intention to seek help, or motivation to change methamphetamine use between the 2 groups on the primary logistic regression analyses, while in the ancillary analyses, the imputed data set showed a significant difference in the odds of seeking professional help between participants in the immediate access group compared to the waitlist control group (adjusted odds ratio 2.64, 95% CI 1.19-5.83, P=.02). For participants not seeking help at baseline, each minute in the app increased the likelihood of seeking professional help by day 28 by 8% (ratio 1.08, 95% CI 1.02-1.22, P=.04). Among the intervention group, a 10-minute increase in app engagement time was associated with a decrease in days of methamphetamine use by 0.4 days (regression coefficient [β] -0.04, P=.02).
CONCLUSIONS: The S-Check app is a feasible low-resource self-administered intervention for adults in Australia who consume methamphetamine. Study attrition was high and, while common in mobile health interventions, warrants larger studies of the S-Check app.
BACKGROUND: Australian New Zealand Clinical Trials Registry ACTRN12619000534189; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377288&isReview=true.

The Amyloid precursor protein (APP) is a transmembrane glycoprotein from which amyloid-β (Aβ) peptides are generated after proteolytic cleavage. Aβ peptides are the main constituent of amyloid plaques in Alzheimer\'s Disease (AD). The physiological functions of APP in the human adult brain are very diverse including intracellular signaling, synaptic and neuronal plasticity, and cell adhesion, among others. There is growing evidence that APP becomes dysfunctional in AD and that this dyshomeostasis may impact several APP functions beyond Aβ generation. The vast majority of current anti-amyloid approaches in AD have focused on reducing the synthesis of Aβ or increasing the clearance of brain Aβ aggregates following a paradigm in which Aβ plays a solo in APP dyshomeostasis. A wider view places APP at the center stage in which Aβ is an important, but not the only, factor involved in APP dyshomeostasis. Under this paradigm, APP dysfunction is universal in AD, but with some differences across different subtypes. Little is known about how to approach APP dysfunction therapeutically beyond anti-Aβ strategies. In this review, we will describe the role of APP dyshomeostasis in AD beyond Aβ and the potential therapeutic strategies targeting APP.

This paper is the forty-sixth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2023 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug and alcohol abuse (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).

Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.

UNASSIGNED: Osteoarthritis (OA) related pain has affected millions of people worldwide. However, the current pharmacological options for managing OA-related pain have not achieved a satisfactory effect.
UNASSIGNED: This narrative review provides an overview of the current and emerging drugs for OA-related pain. It covers the drugs\' mechanism of action, safety, efficacy, and limitations. The National Library of Medicine (PubMed) database was primarily searched from 2000 to 2024.
UNASSIGNED: Current treatment options are limited and suboptimal for OA pain management. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are the recognized and first-line treatment in the management of OA-related pain, and other drugs are inconsistent recommendations by guidelines. Emerging treatment options are promising for OA-related pain, including nerve growth factor (NGF) inhibitors, ion channel inhibitors, and calcitonin gene-related peptide (CGRP) antagonists. Besides, drugs repurposing from antidepressants and antiepileptic analgesics are shedding light on the management of OA-related pain. The management of OA-related pain is challenging as pain is heterogeneous and subjective. A more comprehensive strategy combined with non-pharmacological therapy needs to be considered, and tailored management options to individualized patients.

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BACKGROUND: Outcomes from cardiopulmonary resuscitation (CPR) following sudden cardiac arrest are suboptimal. Postresuscitation targeted temperature management has been shown to have benefit in subjects with sudden cardiac arrest due to ventricular fibrillation, but there are few data for outcomes from sudden cardiac arrest due to pulseless electrical activity. In addition, intra-CPR cooling is more effective than postresuscitation cooling. Physical cooling is associated with increased protein kinase B activity. Therefore, our group developed a novel peptide, TAT-PHLPP9c, which regulates protein kinase B. We hypothesized that when given during CPR, TAT-PHLPP9c would improve survival and neurologic outcomes following pulseless electrical activity arrest.
RESULTS: In 24 female pigs, pulseless electrical activity was induced by inflating balloon catheters in the right coronary and left anterior descending arteries for ≈7 minutes. Advanced life support was initiated. In 12 control animals, epinephrine was given after 1 and 3 minutes. In 12 peptide-treated animals, 7.5 mg/kg TAT-PHLPP9c was also administered at 1 and 3 minutes of CPR. The balloons were removed after 2 minutes of support. Animals were recovered and neurologically scored 24 hours after return of spontaneous circulation. Return of spontaneous circulation was more common in the peptide group, but this difference was not significant (8/12 control versus 12/12 peptide; P=0.093), while fully intact neurologic survival was significantly more common in the peptide group (0/12 control versus 11/12 peptide; P<0.00001). TAT-PHLPP9c significantly increased myocardial nicotinamide adenine dinucleotide levels.
CONCLUSIONS: TAT-PHLPP9c resulted in improved survival with full neurologic function after sudden cardiac arrest in a swine model of pulseless electrical activity, and the peptide shows potential as an intra-CPR pharmacologic agent.

Microbes constitute the most prevalent life form on Earth, yet their remarkable diversity remains mostly unrecognized. Microbial diversity in vertebrate models presents a significant challenge for investigating host-microbiome interactions. The model organism Caenorhabditis elegans has many advantages for delineating the effects of host genetics on microbial composition. In the wild, the C. elegans gut contains various microbial species, while in the laboratory it is usually a host for a single bacterial species. There is a potential host-microbe interaction between microbial metabolites, drugs, and C. elegans phenotypes. This mini-review aims to summarize the current understanding regarding the microbiome in C. elegans. Examples using C. elegans to study host-microbe-metabolite interactions are discussed.

Collagen, a versatile family of proteins with 28 members and 44 genes, is pivotal in maintaining tissue integrity and function. It plays a crucial role in physiological processes like wound healing, hemostasis, and pathological conditions such as fibrosis and cancer. Collagen is a target in these processes. Direct methods for collagen modulation include enzymatic breakdown and molecular binding approaches. For instance, Clostridium histolyticum collagenase is effective in treating localized fibrosis. Polypeptides like collagen-binding domains offer promising avenues for tumor-specific immunotherapy and drug delivery. Indirect targeting of collagen involves regulating cellular processes essential for its synthesis and maturation, such as translation regulation and microRNA activity. Enzymes involved in collagen modification, such as prolyl-hydroxylases or lysyl-oxidases, are also indirect therapeutic targets. From another perspective, collagen is also a natural source of drugs. Enzymatic degradation of collagen generates bioactive fragments known as matrikines and matricryptins, which exhibit diverse pharmacological activities. Overall, collagen-derived peptides present significant therapeutic potential beyond tissue repair, offering various strategies for treating fibrosis, cancer, and genetic disorders. Continued research into specific collagen targeting and the application of collagen and its derivatives may lead to the development of novel treatments for a range of pathological conditions.