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Accident; Analysis and Prevention Sep 2024Despite increased prevalence of methamphetamine in road trauma, it remains unclear how its use translates to an increased risk of traffic-related harm. Exploration of...
INTRODUCTION
Despite increased prevalence of methamphetamine in road trauma, it remains unclear how its use translates to an increased risk of traffic-related harm. Exploration of psychosocial factors may thus help identify relevant predictors of dangerous driving behaviour among people who regularly consume methamphetamine.
METHODS
Licenced individuals who report predominant and sustained methamphetamine use (at least 1-time/month for 6 months at heaviest use) were recruited from the Australian community and via targeted campaign (Eastern Health). Psychosocial, substance use and driving behaviour data (Dula Dangerous Driving Index, DDDI) were collected via a secure anonymous online forced-entry survey platform (Qualtrics).
RESULTS
Seventy-seven individuals (65.5 % male) aged between 20-50 years [mean = 29.7, ± Standard Deviation (SD) 6.1] were included. Most (90 %) respondents met criteria for problematic methamphetamine use [Severity of Dependency Scale (SDS) score ≥ 5], and 75 % were high-risk alcohol consumers [Alcohol Use Disorders Identification Test (AUDIT-C) score ≥ 4 for men and ≥ 3 for women]. On average, age of first methamphetamine use occurred at 23.3 years (±5.2). A best-possible subset's regression selection method with dangerous driving behaviour as the dependent variable determined the model with three predictors (alcohol use, substance dependence severity and trait anger) as most parsimonious. After controlling for substance use, trait anger strongly and positively predicted dangerous driving behaviour as measured by the DDDI ([F = 26.06, p < .001, adjusted R = 0.50, Cohens f = 0.42).
DISCUSSION AND CONCLUSIONS
Trait anger is a strong predictor of risky driving among road users who use methamphetamine. Interactions between stable negative-emotional and situational traffic and driving-related factors may increase risk of harm through greater engagement in risk-taking behaviour.
Topics: Humans; Male; Female; Adult; Methamphetamine; Middle Aged; Anger; Young Adult; Amphetamine-Related Disorders; Dangerous Behavior; Australia; Automobile Driving; Driving Under the Influence; Risk-Taking
PubMed: 38795421
DOI: 10.1016/j.aap.2024.107634 -
Medicina (Kaunas, Lithuania) Apr 2024The key objective in the hemodynamic treatment of septic shock is the optimization of tissue perfusion and oxygenation. This is usually achieved by the utilization of... (Review)
Review
The key objective in the hemodynamic treatment of septic shock is the optimization of tissue perfusion and oxygenation. This is usually achieved by the utilization of fluids, vasopressors, and inotropes. Dobutamine is the inotrope most commonly recommended and used for this purpose. Despite the fact that dobutamine was introduced almost half a century ago in the treatment of septic shock, and there is widespread use of the drug, several aspects of its pharmacodynamics remain poorly understood. In normal subjects, dobutamine increases contractility and lacks a direct effect on vascular tone. This results in augmented cardiac output and blood pressure, with reflex reduction in systemic vascular resistance. In septic shock, some experimental and clinical research suggest beneficial effects on systemic and regional perfusion. Nevertheless, other studies found heterogeneous and unpredictable effects with frequent side effects. In this narrative review, we discuss the pharmacodynamic characteristics of dobutamine and its physiologic actions in different settings, with special reference to septic shock. We discuss studies showing that dobutamine frequently induces tachycardia and vasodilation, without positive actions on contractility. Since untoward effects are often found and therapeutic benefits are occasional, its profile of efficacy and safety seems low. Therefore, we recommend that the use of dobutamine in septic shock should be cautious. Before a final decision about its prescription, efficacy, and tolerance should be evaluated throughout a short period with narrow monitoring of its wanted and side effects.
Topics: Humans; Cardiac Output; Cardiotonic Agents; Dobutamine; Hemodynamics; Shock, Septic; Animals
PubMed: 38792934
DOI: 10.3390/medicina60050751 -
International Journal of Molecular... May 2024Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to...
Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to treatment, falling into the category of treatment-resistant depression (TRD). This underscores the need for the exploration of novel therapeutic options. Our work aims to study the effect of chronic administration of the pyridoindole derivative SMe1EC2M3, a triple reuptake inhibitor, and the combination of zoletil and venlafaxine under conditions of stress induced by a 4-week chronic mild stress (CMS) procedure in Wistar-Kyoto male rats as an animal model of TRD. Therefore, we investigated the possible effect of the selected compounds in four experimental groups, i.e., stress + vehicle, stress + venlafaxine, stress + zoletil + venlafaxine and stress + SMe1EC2M3. The following variables were assessed: anhedonia in sucrose preference test (SPT), spontaneous locomotion and exploration in open field test (OF), anxiety-like behavior in elevated plus maze test (EPM), motivation and depressive-like behavior in forced swim test (FST) and nociception in tail flick test. We also evaluated cognition, particularly recognition memory, in the novel object recognition test (NOR). Sucrose preference was significantly increased in the SMe1EC2M3 group ( < 0.05) in comparison with the venlafaxine animals. In the OF, we observed a significantly higher number of entries into both the central and peripheral zones in the venlafaxine ( < 0.05 central zone; ≤ 0.05 periphery zone) and SMe1EC2M3 ( < 0.05 central zone; < 0.05 periphery zone) groups compared to the venlafaxine + zoletil group. SMe1EC2M3 was able to significantly increase the time of climbing in FST ( < 0.05) in comparison with the venlafaxine and control groups. The NOR test revealed a significantly higher discrimination ratio in the SMe1EC2M3 group ( < 0.05) compared to the control and venlafaxine groups. Analyses of the tail flick test showed a significant increase in reaction time to painful stimuli in the SMe1EC2M3 group ( < 0.05) in comparison to both the control and venlafaxine groups. Our findings suggest that SMe1EC2M3 has the potential to ameliorate some behavioral changes associated with TRD, and the venlafaxine + zoletil combination treatment was not a promising treatment alternative in the animal model of TRD.
Topics: Animals; Rats; Male; Disease Models, Animal; Antidepressive Agents; Venlafaxine Hydrochloride; Depression; Behavior, Animal; Depressive Disorder, Treatment-Resistant; Rats, Inbred WKY; Stress, Psychological; Anxiety; Indoles; Anhedonia
PubMed: 38791304
DOI: 10.3390/ijms25105265 -
CNS Neuroscience & Therapeutics May 2024Methamphetamine (METH) is a psychostimulant substance with highly addictive and neurotoxic effects, but no ideal treatment option exists to improve METH-induced...
BACKGROUND
Methamphetamine (METH) is a psychostimulant substance with highly addictive and neurotoxic effects, but no ideal treatment option exists to improve METH-induced neurocognitive deficits. Recently, mesenchymal stem cells (MSCs)-derived exosomes have raised many hopes for treating neurodegenerative sequela of brain disorders. This study aimed to determine the therapeutic potential of MSCs-derived exosomes on cognitive function and neurogenesis of METH-addicted rodents.
METHODS
Male BALB/c mice were subjected to chronic METH addiction, followed by intravenous administration of bone marrow MSCs-derived exosomes. Then, the spatial memory and recognition memory of animals were assessed by the Barnes maze and the novel object recognition test (NORT). The neurogenesis-related factors, including NeuN and DCX, and the expression of Iba-1, a microglial activation marker, were assessed in the hippocampus by immunofluorescence staining. Also, the expression of inflammatory cytokines, including TNF-α and NF-κB, were evaluated by western blotting.
RESULTS
The results showed that BMSCs-exosomes improved the time spent in the target quadrant and correct-to-wrong relative time in the Barnes maze. Also, NORT's discrimination index (DI) and recognition index (RI) were improved following exosome therapy. Additionally, exosome therapy significantly increased the expression of NeuN and DCX in the hippocampus while decreasing the expression of inflammatory cytokines, including TNF-α and NF-κB. Besides, BMSC-exosomes down-regulated the expression of Iba-1.
CONCLUSION
Our findings indicate that BMSC-exosomes mitigated METH-caused cognitive dysfunction by improving neurogenesis and inhibiting neuroinflammation in the hippocampus.
Topics: Animals; Exosomes; Male; Neurogenesis; Doublecortin Protein; Mice; Methamphetamine; Mesenchymal Stem Cells; Mice, Inbred BALB C; Amphetamine-Related Disorders; Hippocampus; Cognition; Maze Learning; Recognition, Psychology; Nerve Tissue Proteins; Central Nervous System Stimulants; Spatial Memory; Microfilament Proteins; Mesenchymal Stem Cell Transplantation; Calcium-Binding Proteins; DNA-Binding Proteins
PubMed: 38783536
DOI: 10.1111/cns.14719 -
Harm Reduction Journal May 2024Methylenedioxymethamphetamine (MDMA) is a popular drug worldwide and use is prevalent in Aotearoa New Zealand. Although associated with some significant harms, including...
BACKGROUND
Methylenedioxymethamphetamine (MDMA) is a popular drug worldwide and use is prevalent in Aotearoa New Zealand. Although associated with some significant harms, including fatalities, MDMA is ultimately less harmful than other commonly consumed drugs. We aimed to expand the understanding of MDMA harm and harm reduction strategies from a consumer perspective so that national harm reduction efforts can be better informed.
METHODS
We conducted 14 semi-structured focus group discussions including 60 people (aged 18-67, median = 21) who use MDMA in the Southern region of Aotearoa New Zealand to explore their thoughts and experiences regarding MDMA associated harm and harm reduction. Reflexive thematic analysis was conducted from a critical realist perspective.
RESULTS
Five themes were generated; (1) Mindset and setting matters; (2) Looking after your body and mind, not overdoing it; (3) Other substances increase risk and harm; (4) Trusted friends and peers are protective; and (5) Valid information is key for healthy self-determination; and one subtheme 5.1) Drug checking is essential harm reduction.
CONCLUSIONS
We discuss the implications for MDMA consumers and aim to inform national drug policy and the harm reduction practices of consumers and organisations, for the ultimate purpose of reducing MDMA-related harm in Aotearoa New Zealand.
Topics: Humans; New Zealand; N-Methyl-3,4-methylenedioxyamphetamine; Harm Reduction; Male; Adult; Female; Young Adult; Middle Aged; Adolescent; Aged; Focus Groups; Health Knowledge, Attitudes, Practice; Hallucinogens
PubMed: 38783300
DOI: 10.1186/s12954-024-01024-8 -
Scientific Reports May 2024We studied the inhibitory actions of docosahexaenoic acid (DHA) on the contractions induced by carbachol (CCh), angiotensin II (Ang II), and bradykinin (BK) in guinea...
We studied the inhibitory actions of docosahexaenoic acid (DHA) on the contractions induced by carbachol (CCh), angiotensin II (Ang II), and bradykinin (BK) in guinea pig (GP) gastric fundus smooth muscle (GFSM), particularly focusing on the possible inhibition of store-operated Ca channels (SOCCs). DHA significantly suppressed the contractions induced by CCh, Ang II, and BK; the inhibition of BK-induced contractions was the strongest. Although all contractions were greatly dependent on external Ca, more than 80% of BK-induced contractions remained even in the presence of verapamil, a voltage-dependent Ca channel inhibitor. BK-induced contractions in the presence of verapamil were not suppressed by LOE-908 (a receptor-operated Ca channel (ROCC) inhibitor) but were suppressed by SKF-96365 (an SOCC and ROCC inhibitor). BK-induced contractions in the presence of verapamil plus LOE-908 were strongly inhibited by DHA. Furthermore, DHA inhibited GFSM contractions induced by cyclopiazonic acid (CPA) in the presence of verapamil plus LOE-908 and inhibited the intracellular Ca increase due to Ca addition in CPA-treated 293T cells. These findings indicate that Ca influx through SOCCs plays a crucial role in BK-induced contraction in GP GFSM and that this inhibition by DHA is a new mechanism by which this fatty acid inhibits GFSM contractions.
Topics: Animals; Guinea Pigs; Docosahexaenoic Acids; Bradykinin; Muscle, Smooth; Carbachol; Muscle Contraction; Angiotensin II; Gastric Fundus; Verapamil; Calcium; Male; Humans; Calcium Channels; HEK293 Cells; Calcium Channel Blockers; Imidazoles
PubMed: 38778154
DOI: 10.1038/s41598-024-62578-y -
PloS One 2024Illicitly manufactured fentanyls and stimulants are implicated in the escalating US mortality from drug overdose. San Francisco, California (SF) has seen declining...
BACKGROUND
Illicitly manufactured fentanyls and stimulants are implicated in the escalating US mortality from drug overdose. San Francisco, California (SF) has seen declining fentanyl injection while smoking has increased. Beliefs and behaviors surrounding this development are not well understood.
METHODS
The study used rapid ethnography to explore fentanyl and methamphetamine use in SF. The team conducted semi-structured interviews (n = 34) with participants recruited from syringe service programs. Video-recorded smoking sequences (n = 12), photography and daily field notes supplemented interview data.
RESULTS
Difficulty injecting and fear of overdose motivated transitions from injecting to smoking. Fentanyl was extremely cheap-$10/gram-with variability in quality. Foil was the most commonly used smoking material but glass bubbles, bongs and dabbing devices were also popular. No reliable visible methods for determining fentanyl quality existed, however, participants could gauge potency upon inhalation, and developed techniques to regulate dosage. Several participants reported at least hourly use, some reporting one or more grams of daily fentanyl consumption. Smoking was also very social, with people sharing equipment, drugs and information. Participants raised concerns about hygiene and overdose risk to others arising from shared equipment. Reportedly potent fentanyl 'residue' accumulated on smoking materials and was commonly shared/traded/stolen or consumed accidentally with diverse preferences for its use.
CONCLUSION
Our data highlight fentanyl residue as a new overdose risk with potential mismatch between the potency of the residual drug and the recipient's tolerance. Further, large doses of fentanyl are being consumed (estimated at approximately 50 mg of pure fentanyl/day). Smoking fentanyl has potential health benefits over injecting and may be protective against overdose, but substantial uncertainty exists. However, SF overdose mortality hit a record high in 2023. Recommendations to reduce fentanyl smoking overdose risks through pacing, greater awareness of dosages consumed and checking tolerance of residue recipients are potentially viable interventions deserving further exploration.
Topics: Fentanyl; Humans; San Francisco; Male; Female; Adult; Smoking; Drug Overdose; Middle Aged; Substance Abuse, Intravenous; Methamphetamine
PubMed: 38776268
DOI: 10.1371/journal.pone.0303403 -
Theranostics 2024Methamphetamine (METH) withdrawal anxiety symptom and relapse have been significant challenges for clinical practice, however, the underlying neuronal basis remains...
Methamphetamine (METH) withdrawal anxiety symptom and relapse have been significant challenges for clinical practice, however, the underlying neuronal basis remains unclear. Our recent research has identified a specific subpopulation of choline acetyltransferase (ChAT) neurons localized in the external lateral portion of parabrachial nucleus (eLPB), which modulates METH primed-reinstatement of conditioned place preference (CPP). Here, the anatomical structures and functional roles of eLPB projections in METH withdrawal anxiety and primed reinstatement were further explored. In the present study, a multifaceted approach was employed to dissect the LPB projections in male mice, including anterograde and retrograde tracing, acetylcholine (Ach) indicator combined with fiber photometry recording, photogenetic and chemogenetic regulation, as well as electrophysiological recording. METH withdrawal anxiety-like behaviors and METH-primed reinstatement of conditioned place preference (CPP) were assessed in male mice. We identified that eLPB send projections to PKCδ-positive (PKCδ) neurons in lateral portion of central nucleus of amygdala (lCeA) and oval portion of bed nucleus of the stria terminalis (ovBNST), forming eLPB-lCeA and eLPB-ovBNST pathways. At least in part, the eLPB neurons positively innervate lCeA neurons and ovBNST neurons through regulating synaptic elements of presynaptic Ach release and postsynaptic nicotinic acetylcholine receptors (nAChRs). METH withdrawal anxiety and METH-primed reinstatement of CPP respectively recruit eLPB-lCeA pathway and eLPB-ovBNST pathway in male mice. Our findings put new insights into the complex neural networks, especially focusing on the eLPB projections. The eLPB is a critical node in the neural networks governing METH withdrawal anxiety and primed-reinstatement of CPP through its projections to the lCeA and ovBNST, respectively.
Topics: Animals; Methamphetamine; Male; Mice; Substance Withdrawal Syndrome; Anxiety; Mice, Inbred C57BL; Neurons; Choline O-Acetyltransferase; Septal Nuclei; Behavior, Animal
PubMed: 38773977
DOI: 10.7150/thno.95383 -
Trials May 2024Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several...
BACKGROUND
Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer.
METHODS
Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first.
DISCUSSION
This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness.
TRIAL REGISTRATION
Trial registered on Australian New Zealand Clinical Trials Registry.
REGISTRATION NUMBER
ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.
Topics: Humans; N-Methyl-3,4-methylenedioxyamphetamine; Neoplasms; Anxiety; Double-Blind Method; Randomized Controlled Trials as Topic; Affect; Hallucinogens; Treatment Outcome; Depression; Quality of Life; Methylphenidate; Time Factors; Male; Neoplasm Staging
PubMed: 38773523
DOI: 10.1186/s13063-024-08174-x -
BMJ Paediatrics Open May 2024There exists limited agreement on the recommendations for the treatment of transitional circulatory instability (TCI) in preterm neonates OBJECTIVE: To compare the... (Meta-Analysis)
Meta-Analysis Comparative Study
Comparative efficacy of volume expansion, inotropes and vasopressors in preterm neonates with probable transitional circulatory instability in the first week of life: a systematic review and network meta-analysis.
BACKGROUND
There exists limited agreement on the recommendations for the treatment of transitional circulatory instability (TCI) in preterm neonates OBJECTIVE: To compare the efficacy of various interventions used to treat TCI METHODS: Medline and Embase were searched from inception to 21 July 2023. Two authors extracted the data independently. A Bayesian random effects network meta-analysis was used. Recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework.
INTERVENTIONS
Dopamine, dobutamine, epinephrine, hydrocortisone, vasopressin, milrinone, volume and placebo.
MAIN OUTCOME MEASURES
Mortality, major brain injury (MBI) (intraventricular haemorrhage > grade 2 or cystic periventricular leukomalacia), necrotising enterocolitis (NEC) ≥stage 2 and treatment response (as defined by the author).
RESULTS
15 Randomized Controlled Trials (RCTs) were included from the 1365 titles and abstracts screened. Clinical benefit or harm could not be ruled out for the critical outcome of mortality. For the outcome of MBI, epinephrine possibly decreased the risk when compared to dobutamine and milrinone (very low certainty). Epinephrine was possibly associated with a lesser risk of NEC when compared with dopamine, dobutamine, hydrocortisone and milrinone (very low certainty). Dopamine was possibly associated with a lesser risk of NEC when compared with dobutamine (very low certainty). Vasopressin possibly decreased the risk of NEC compared with dopamine, dobutamine, hydrocortisone and milrinone (very low certainty). Clinical benefit or harm could not be ruled out for the outcome response to treatment.
CONCLUSIONS
Epinephrine may be used as the first-line drug in preterm neonates with TCI, the evidence certainty being very low. We suggest future trials evaluating the management of TCI with an emphasis on objective criteria to define it.
Topics: Humans; Infant, Newborn; Cardiotonic Agents; Vasoconstrictor Agents; Infant, Premature; Network Meta-Analysis; Infant, Premature, Diseases; Randomized Controlled Trials as Topic; Dobutamine
PubMed: 38769048
DOI: 10.1136/bmjpo-2024-002500