Serotonin Signaling in Hippocampus during Initial Cocaine Abstinence Drives Persistent Drug Seeking.

The initiation of abstinence after chronic drug self-administration is stressful. Cocaine-seeking behavior on the first day of the absence of the expected drug (Extinction Day 1, ED1) is reduced by blocking 5-HT signaling in dorsal hippocampal cornu ammonis 1 (CA1) in both male and female rats. We hypothesized that the experience of ED1 can substantially influence later relapse behavior and that dorsal raphe (DR) serotonin (5-HT) input to CA1 may be involved. We inhibited 5-HT1A/1B receptors (WAY-100635 plus GR-127935), or DR input (chemogenetics), in CA1 on ED1 to test the role of this pathway on cocaine-seeking persistence 2 weeks later. We also inhibited 5-HT1A or 5-HT1B receptors in CA1 during conditioned place preference (CPP) for cocaine, to examine mechanisms involved in the persistent effects of ED1 manipulations. Inhibition of DR inputs, or 5-HT1A/1B signaling, in CA1 decreased drug seeking on ED1 and decreased cocaine seeking 2 weeks later revealing that 5-HT signaling in CA1 during ED1 contributes to persistent drug seeking during abstinence. In addition, 5-HT1B antagonism alone transiently decreased drug-associated memory performance when given prior to a CPP test, whereas similar antagonism of 5-HT1A alone had no such effect but blocked CPP retrieval on a test 24 h later. These CPP findings are consistent with prior work showing that DR inputs to CA1 augment recall of the drug-associated context and drug seeking via 5-HT1B receptors and prevent consolidation of the updated nondrug context via 5-HT1A receptors. Thus, treatments that modulate 5-HT-dependent memory mechanisms in CA1 during initial abstinence may facilitate later maintenance of abstinence.

HIV Testing Disruptions and Service Adaptations During the COVID-19 Pandemic: A Systematic Literature Review.

Access to treatment and care in safe clinical settings improves people's lives with HIV. The COVID-19 pandemic disrupted vital HIV programs and services, increasing the risk of adverse health outcomes for people with HIV and HIV transmission rates in the community. This systematic literature review provides a meta-analysis of HIV testing disruptions and a synthesis of HIV/AIDS services adapted during COVID-19. We searched scholarly databases from 01 January 2020 to 30 June 2022 using key terms on HIV testing rates and services during the COVID-19 pandemic. The process of how the included articles were identified, selected, appraised, and synthesised was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included 17 articles that reported changes in HIV testing during the COVID-19 pandemic and 22 that reported adaptations in HIV/AIDS services. We found that HIV testing decreased by 37% during the search period because of the COVID-19 pandemic. Service providers adopted novel strategies to support remote service delivery by expanding community antiretroviral therapy dispensing, setting up primary care outreach points, and instituting multi-month dispensing services to sustain client care. Therefore, service providers and policymakers should explore alternative strategies to increase HIV testing rates impacted by COVID-19 and leverage funding to continue providing the identified adapted services.

Gliotoxin-mediated bacterial growth inhibition is caused by specific metal ion depletion.

Overcoming antimicrobial resistance represents a formidable challenge and investigating bacterial growth inhibition by fungal metabolites may yield new strategies. Although the fungal non-ribosomal peptide gliotoxin (GT) is known to exhibit antibacterial activity, the mechanism(s) of action are unknown, although reduced gliotoxin (dithiol gliotoxin; DTG) is a zinc chelator. Furthermore, it has been demonstrated that GT synergises with vancomycin to inhibit growth of Staphylococcus aureus. Here we demonstrate, without precedent, that GT-mediated growth inhibition of both Gram positive and negative bacterial species is reversed by Zn2+ or Cu2+ addition. Both GT, and the known zinc chelator TPEN, mediate growth inhibition of Enterococcus faecalis which is reversed by zinc addition. Moreover, zinc also reverses the synergistic growth inhibition of E. faecalis observed in the presence of both GT and vancomycin (4 µg/ml). As well as zinc chelation, DTG also appears to chelate Cu2+, but not Mn2+ using a 4-(2-pyridylazo)resorcinol assay system and Zn2+ as a positive control. DTG also specifically reacts in Fe3+-containing Siderotec™ assays, most likely by Fe3+ chelation from test reagents. GSH or DTT show no activity in these assays. Confirmatory high resolution mass spectrometry, in negative ion mode, confirmed, for the first time, the presence of both Cu[DTG] and Fe[DTG]2 chelates. Label free quantitative proteomic analysis further revealed major intracellular proteomic remodelling within E. faecalis in response to GT exposure for 30-180 min. Globally, 4.2-7.2% of detectable proteins exhibited evidence of either unique presence/increased abundance or unique absence/decreased abundance (n = 994-1160 total proteins detected), which is the first demonstration that GT affects the bacterial proteome in general, and E. faecalis, specifically. Unique detection of components of the AdcABC and AdcA-II zinc uptake systems was observed, along with apparent ribosomal reprofiling to zinc-free paralogs in the presence of GT. Overall, we hypothesise that GT-mediated bacterial growth inhibition appears to involve intracellular zinc depletion or reduced bioavailability, and based on in vitro chelate formation, may also involve dysregulation of Cu2+ homeostasis.

P26-A125†Donation medicine: a change of paradigm in procuring ocular tissues for transplantation.

PURPOSE: To reflect on the implementation of the concept of 'Donation Medicine' as a substitute for 'Procurement' to describe the Foundation's activities in the procurement of ocular tissue and donor selection, considering that the prevailing connotation of procurement (the action of obtaining materials, goods and services necessary to the functioning of a productive activity) did not express satisfactorily all the social, human and medical implications of a programme aimed at promoting ocular tissue donation and recovery. Moreover, in medicine the term 'Procurement' is generally associated with the worst therapeutic outcome, which is the end of a human life. METHODS: A retrospective evaluation of the main indicators pertaining to activities in 2021 was performed, with particular regard to donor screening ,tissue recovery, and the human and professional relations with donor families and hospital staff. The results were assessed by an interdisciplinary team, composed of eye bank and healthcare personnel, regulators and experts in medical humanities. RESULTS: In 2021, in light of 2944 non-oppositions to donation (opting out system), 891 consultations of the national SIT donor registry were performed (Sistema Informativo Trapianti), with 2551 clinical charts reviewed, 4332 related phone consultations performed, and 2032 nasopharyngeal swabs for SARS-CoV-2 nucleic acid tested; as a consequence, 2213 condolence and gratitude letters were sent to donor families, of which 57%(1269) conveyed the outcome of donation, along with 115 gratitude letters sent in instances of the non-recovery. 24 families requested, and were granted, the opportunity to visit the eye bank. CONCLUSION: A consensus was reached on the evidence that the term 'Procurement' has obvious limitations in the long term nurturing and maintenance of the motivation of the eye bank and healthcare personnel. As a consequence, the concept of 'Donation Medicine' was implemented to define and develop the activities related to the promotion of donation, the recovery of ocular tissues for transplantation, and internal/external relations with healthcare personnel, thus changing the meaning of 'Procurement', from a process at the end of a life to the realization of a new pathway of care that takes into account both donor families and recipients. Donation medicine begins with the re-opening of the donor clinical chart, the interaction with donor relatives and the recovery of a precious gift for use in the restoration of sight of patients.

A Phase I Trial of the ABCB1 Inhibitor, Oral Valspodar, in Combination With Paclitaxel in Patients With Advanced Solid Tumors.

OBJECTIVES: Multidrug resistance mediated by P-glycoprotein is a potential obstacle to cancer treatment. This phase 1 trial determined the safety of paclitaxel with valspodar, a P-glycoprotein inhibitor, in patients with advanced solid tumors. METHODS: Patients were treated with single-agent paclitaxel Q3W 175 mg/m 2 (or 135 mg/m 2 if heavily pretreated) as a 3-hour infusion. If their disease was stable (SD) or progressive (PD), paclitaxel at 30% (52.5 mg/m 2 ), 40% (70 mg/m 2 ), or 50% (87.5 mg/m 2 ) of 175 mg/m 2 (full dose) was administered with valspodar 5 mg/kg orally 4 times daily for 12 doses. Pharmacokinetic sampling (PK) for paclitaxel and valspodar was performed during single-agent and combination therapy. RESULTS: Sixteen patients had SD/PD after one cycle of paclitaxel and then received paclitaxel at 30% (n=3), 40% (n=3), and 50% (n=10) with valspodar. Hematologic adverse events (AEs) including myelosuppression at paclitaxel 40% were comparable to those of full-dose paclitaxel. Non-hematologic AEs consisted of reversible hepatic (hyperbilirubinemia and transaminitis) and neurologic AEs (ataxia and paresthesias). Eleven patients experienced SD with a median of 12.7 weeks (range, 5.4 to 36.0), 4 patients progressed, and 1 was inevaluable. Reduced dose paclitaxel with valspodar resulted in lower plasma peak concentrations of paclitaxel; otherwise, concentrations were similar to single-agent paclitaxel. CONCLUSION: Paclitaxel at 70 mg/m 2 was administered safely with valspodar. Limited efficacy in hematologic and solid tumors resulted in discontinuation of its clinical development and other transporter inhibitors. Recently, the development of ATP-binding cassette transporter inhibitors has been reconsidered to mitigate resistance to antibody-drug conjugates.

Advances in Genetics and Epigenetics of Developmental Coordination Disorder in Children.

Developmental coordination disorder (DCD) is a developmental disorder characterized by impaired motor coordination, often co-occurring with attention deficit disorder, autism spectrum disorders, and other psychological and behavioural conditions. The aetiology of DCD is believed to involve brain changes and environmental factors, with genetics also playing a role in its pathogenesis. Recent research has identified several candidate genes and genetic factors associated with motor impairment, including deletions, copy number variations, single nucleotide polymorphisms, and epigenetic modifications. This review provides an overview of the current knowledge in genetic research on DCD, highlighting the importance of continued research into the underlying genetic mechanisms. While evidence suggests a genetic contribution to DCD, the evidence is still in its early stages, and much of the current evidence is based on studies of co-occurring conditions. Further research to better understand the genetic basis of DCD could have important implications for diagnosis, treatment, and our understanding of the condition's aetiology.

Gliotoxin and related metabolites as zinc chelators: implications and exploitation to overcome antimicrobial resistance.

Antimicrobial resistance (AMR) is a major global problem and threat to humanity. The search for new antibiotics is directed towards targeting of novel microbial systems and enzymes, as well as augmenting the activity of pre-existing antimicrobials. Sulphur-containing metabolites (e.g., auranofin and bacterial dithiolopyrrolones [e.g., holomycin]) and Zn2+-chelating ionophores (PBT2) have emerged as important antimicrobial classes. The sulphur-containing, non-ribosomal peptide gliotoxin, biosynthesised by Aspergillus fumigatus and other fungi exhibits potent antimicrobial activity, especially in the dithiol form (dithiol gliotoxin; DTG). Specifically, it has been revealed that deletion of the enzymes gliotoxin oxidoreductase GliT, bis-thiomethyltransferase GtmA or the transporter GliA dramatically sensitise A. fumigatus to gliotoxin presence. Indeed, the double deletion strain A. fumigatus ΔgliTΔgtmA is especially sensitive to gliotoxin-mediated growth inhibition, which can be reversed by Zn2+ presence. Moreover, DTG is a Zn2+ chelator which can eject zinc from enzymes and inhibit activity. Although multiple studies have demonstrated the potent antibacterial effect of gliotoxin, no mechanistic details are available. Interestingly, reduced holomycin can inhibit metallo-ß-lactamases. Since holomycin and gliotoxin can chelate Zn2+, resulting in metalloenzyme inhibition, we propose that this metal-chelating characteristic of these metabolites requires immediate investigation to identify new antibacterial drug targets or to augment the activity of existing antimicrobials. Given that (i) gliotoxin has been shown in vitro to significantly enhance vancomycin activity against Staphylococcus aureus, and (ii) that it has been independently proposed as an ideal probe to dissect the central 'Integrator' role of Zn2+ in bacteria - we contend such studies are immediately undertaken to help address AMR.

Locus coeruleus and dorsal cingulate morphology contributions to slowed processing speed.

Slowed information processing speed is a defining feature of cognitive aging. Nucleus locus coeruleus (LC) and medial prefrontal regions are targets for understanding slowed processing speed because these brain regions influence neural and behavioral response latencies through their roles in optimizing task performance. Although structural measures of medial prefrontal cortex have been consistently related to processing speed, it is unclear if 1) declines in LC structure underlie this association because of reciprocal connections between LC and medial prefrontal cortex, or 2) if LC declines provide a separate explanation for age-related changes in processing speed. LC and medial prefrontal structural measures were predicted to explain age-dependent individual differences in processing speed in a cross-sectional sample of 43 adults (19-79 years; 63% female). Higher turbo-spin echo LC contrast, based on a persistent homology measure, and greater dorsal cingulate cortical thickness were significantly and each uniquely related to faster processing speed. However, only dorsal cingulate cortical thickness appeared to statistically mediate age-related differences in processing speed. The results suggest that individual differences in cognitive processing speed can be attributed, in part, to structural variation in nucleus LC and medial prefrontal cortex, with the latter key to understanding why older adults exhibit slowed processing speed.

Prelimbic and infralimbic medial prefrontal cortex neuron activity signals cocaine seeking variables across multiple timescales.

RATIONALE AND OBJECTIVES: The prefrontal cortex is critical for execution and inhibition of reward seeking. Neural manipulation of rodent medial prefrontal cortex (mPFC) subregions differentially impacts execution and inhibition of cocaine seeking. Dorsal, or prelimbic (PL), and ventral, or infralimbic (IL) mPFC are implicated in cocaine seeking or extinction of cocaine seeking, respectively. This differentiation is not seen across all studies, indicating that further research is needed to understand specific mPFC contributions to drug seeking. METHODS: We recorded neuronal activity in mPFC subregions during cocaine self-administration, extinction, and cue- and cocaine-induced reinstatement of cocaine seeking. RESULTS: Both PL and IL neurons were phasically responsive around lever presses during cocaine self-administration, and activity in both areas was reduced during extinction. During both cue- and, to a greater extent, cocaine-induced reinstatement, PL neurons exhibited significantly elevated responses, in line with previous studies demonstrating a role for the region in relapse. The enhanced PL signaling in cocaine-induced reinstatement was driven by strong excitation and inhibition in different groups of neurons. Both of these response types were stronger in PL vs. IL neurons. Finally, we observed tonic changes in activity in all tasks phases, reflecting both session-long contextual modulation as well as minute-to-minute activity changes that were highly correlated with brain cocaine levels and motivation associated with cocaine seeking. CONCLUSIONS: Although some differences were observed between PL and IL neuron activity across sessions, we found no evidence of a go/stop dichotomy in PL/IL function. Instead, our results demonstrate temporally heterogeneous prefrontal signaling during cocaine seeking and extinction in both PL and IL, revealing novel and complex functions for both regions during these behaviors. This combination of findings argues that mPFC neurons, in both PL and IL, provide multifaceted contributions to the regulation of drug seeking and addiction.

Association of developmental coordination disorder with early-life exposure to fine particulate matter in Chinese preschoolers.

Although fine particulate matter (PM2.5) is a neurotoxicant, little is known about whether early-life PM2.5 exposure is associated with an increased risk of developmental coordination disorder (DCD). We conducted a cohort study of 109 731 children aged 3-5 years from 551 county-level cities in China between April 2018 and December 2019. Residential PM2.5 exposure was estimated using a hybrid satellite-based exposure model. Children's motor performance was assessed using the Little DCD Questionnaire (LDCDQ). Linear mixed-effect models and generalized linear mixed models with a binomial distribution were used to examine the associations of PM2.5 exposure with LDCDQ scores and risk of DCD, respectively. Both prenatal and postnatal exposure to a higher level of PM2.5 was significantly associated with reduced total LDCDQ score, and the impacts were evident on subscales of control during movement and general coordination function but not fine motor function. For example, an interquartile range increase in PM2.5 exposure in ages 0-3 was associated with a 0.19 (95% confidence interval [CI]: 0.05, 0.33) decrement in the total score. Additionally, higher PM2.5 exposure was associated with increased risk of DCD, and the adjusted odds ratios were 1.06 (95% CI: 1.01, 1.10) and 1.06 (95% CI: 1.01, 1.13) for each interquartile range increase in PM2.5 exposure during the first trimester and the first 3 years, respectively. Children who were from rural areas, had neonatal intensive care unit admission, or were exclusively breastfed for less than 6 months appeared to be more susceptible to PM2.5 exposure than their counterparts. Our findings provide robust evidence that early-life PM2.5 exposure contributes to an elevated risk of DCD.

Orexin Reserve: A Mechanistic Framework for the Role of Orexins (Hypocretins) in Addiction.

In 2014, we proposed that orexin signaling transformed motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a threat, a process we referred to as motivational activation. Advancements in animal models since then have permitted higher-resolution measurements of motivational states; in particular, the behavioral economics approach for studying drug demand characterizes conditions that lead to the enhanced motivation that underlies addiction. This motivational plasticity is paralleled by persistently increased orexin expression in a topographically specific manner-a finding confirmed across species, including in humans. Normalization of orexin levels also reduces drug motivation in addiction models. These new advancements lead us to update our proposed framework for the orexin function. We now propose that the capacity of orexin neurons to exhibit dynamic shifts in peptide production contributes to their role in adaptive motivational regulation and that this is achieved via a pool of reserve orexin neurons. This reserve is normally bidirectionally recruited to permit motivational plasticity that promotes flexible, adaptive behavior. In pathological states such as addiction, however, we propose that the orexin system loses capacity to adaptively adjust peptide production, resulting in focused hypermotivation for drug, driven by aberrantly and persistently high expression in the orexin reserve pool. This mechanistic framework has implications for the understanding and treatment of several psychiatric disorders beyond addiction, particularly those characterized by motivational dysfunction.

A Single Aspergillus fumigatus Gene Enables Ergothioneine Biosynthesis and Secretion by Saccharomyces cerevisiae.

The naturally occurring sulphur-containing histidine derivative, ergothioneine (EGT), exhibits potent antioxidant properties and has been proposed to confer human health benefits. Although it is only produced by select fungi and prokaryotes, likely to protect against environmental stress, the GRAS organism Saccharomyces cerevisiae does not produce EGT naturally. Herein, it is demonstrated that the recombinant expression of a single gene, Aspergillus fumigatus egtA, in S. cerevisiae results in EgtA protein presence which unexpectedly confers complete EGT biosynthetic capacity. Both High Performance Liquid Chromatography (HPLC) and LC−mass spectrometry (MS) analysis were deployed to detect and confirm EGT production in S. cerevisiae. The localisation and quantification of the resultant EGT revealed a significantly (p < 0.0001) larger quantity of EGT was extracellularly present in culture supernatants than intracellularly accumulated in 96 h yeast cultures. Methionine addition to cultures improved EGT production. The additional expression of two candidate cysteine desulfurases from A. fumigatus was thought to be required to complete EGT biosynthesis, namely AFUA_2G13295 and AFUA_3G14240, termed egt2a and egt2b in this study. However, the co-expression of egtA and egt2a in S. cerevisiae resulted in a significant decrease in the observed EGT levels (p < 0.05). The AlphaFold prediction of A. fumigatus EgtA 3-Dimensional structure illuminates the bidomain structure of the enzyme and the opposing locations of both active sites. Overall, we clearly show that recombinant S. cerevisiae can biosynthesise and secrete EGT in an EgtA-dependent manner which presents a facile means of producing EGT for biotechnological and biomedical use.

Mediating role for metacognitive processes in the relationship between schizotypy and anxiety and depression symptoms.

Introduction: Depression and anxiety symptoms are highly prevalent in schizophrenia-spectrum disorders and are commonly associated with schizotypy in non-clinical samples. However, it remains unclear what factors could be contributing to the relationships between schizotypy and anxiety and depression symptoms. Using path analysis, we explored the complex interplay between schizotypy, metacognitive beliefs, cognitive insight, and symptoms of emotional distress.Methods: Self-report data of schizotypy, metacognitive beliefs, cognitive insight, depression, and anxiety symptoms were collected from 344 participants from a predominantly student sample.Results: Path analysis confirmed unique associations between schizotypy dimensions, metacognitive beliefs, and cognitive insight. Furthermore, negative beliefs about worry mediated the link between the schizotypy dimensions, unusual experiences, cognitive disorganisation, and introvertive anhedonia and both depression and anxiety symptoms. Lack of cognitive confidence also mediated the relationship between cognitive disorganisation and depression symptoms. Finally, the cognitive insight subcomponent self-reflectiveness mediated the relationship between unusual experiences and cognitive disorganisation and anxiety.Conclusions: This study significantly furthers our understanding of the complex relationship between schizotypy, metacognitive processes, and emotional distress. Our findings also provide support for interventions which modify metacognitive beliefs and self-reflectiveness, which may prove beneficial for treatment in clinical settings.

A Phase I Study of Apolizumab, an Anti-HLA-DR ß-chain Monoclonal Antibody, in Patients With Solid Tumor Malignancies.

BACKGROUND: Human leukocyte antigen (HLA)-DR, a member of the major histocompatibility complex class II antigen family, is a target for antibody-based therapeutics. Apolizumab (Hu1D10, Remitogen), a humanized IgG1 monoclonal anti-HLA-DR ß-chain antibody targets the antigen, 1D10, expressed on a wide variety of hematologic and solid tumor malignancies. In this Phase 1 trial, the maximum tolerated dose and dose-limiting toxicity of weekly apolizumab in patients with advanced solid tumor malignancies were determined. PATIENTS AND METHODS: Eligible patients with refractory solid tumors were initially screened for ID10 Ag on their tumor. Patients whose tumors expressed 1D10 were administered apolizumab 0.5, 1.0, 1.5, or 3.0 mg/kg intravenously over 90 minutes weekly for 4 consecutive weeks, followed by a 4-week break, and assessment of response. Patients whose disease had not progressed were offered additional treatment. RESULTS: Tumors from 75 patients were screened for 1D10 Ag of which 17 patients were positive and underwent treatment. The first 3 dose levels were well-tolerated. Dose-limiting toxicities of grade 3 infusion-related hypersensitivity reactions and grade 3 headache and hypertension occurred in 2 patients, respectively, at apolizumab 3.0 mg/kg. Four patients, 1 each with breast carcinoma, melanoma, renal cell carcinoma, and sarcoma had stable disease for a median of 15 weeks (range: 12 to 19 wk). CONCLUSION: Apolizumab can be administered safely at a maximum tolerated dose of 1.5 mg/kg for 4 consecutive weeks. Adverse events and limited clinical data in both hematologic and solid tumor malignancies resulted in discontinuation of clinical development of apolizumab. HLA-DR remains an interesting immunotherapeutic target.

Rat Anterior Cingulate Cortex Continuously Signals Decision Variables in a Patch Foraging Task.

In patch foraging tasks, animals must decide whether to remain with a depleting resource or to leave it in search of a potentially better source of reward. In such tasks, animals consistently follow the general predictions of optimal foraging theory (the marginal value theorem; MVT): to leave a patch when the reward rate in the current patch depletes to the average reward rate across patches. Prior studies implicate an important role for the anterior cingulate cortex (ACC) in foraging decisions based on MVT: within single trials, ACC activity increases immediately preceding foraging decisions, and across trials, these dynamics are modulated as the value of staying in the patch depletes to the average reward rate. Here, we test whether these activity patterns reflect dynamic encoding of decision-variables and whether these signals are directly involved in decision-making. We developed a leaky accumulator model based on the MVT that generates estimates of decision variables within and across trials, and tested model predictions against ACC activity recorded from male rats performing a patch foraging task. Model predicted changes in MVT decision variables closely matched rat ACC activity. Next, we pharmacologically inactivated ACC in male rats to test the contribution of these signals to decision-making. ACC inactivation had a profound effect on rats' foraging decisions and response times (RTs) yet rats still followed the MVT decision rule. These findings indicate that the ACC encodes foraging-related variables for reasons unrelated to patch-leaving decisions.SIGNIFICANCE STATEMENT The ability to make adaptive patch-foraging decisions, to remain with a depleting resource or search for better alternatives, is critical to animal well-being. Previous studies have found that anterior cingulate cortex (ACC) activity is modulated at different points in the foraging decision process, raising questions about whether the ACC guides ongoing decisions or serves a more general purpose of regulating cognitive control. To investigate the function of the ACC in foraging, the present study developed a dynamic model of behavior and neural activity, and tested model predictions using recordings and inactivation of ACC. Findings revealed that ACC continuously signals decision variables but that these signals are more likely used to monitor and regulate ongoing processes than to guide foraging decisions.

HIV among migrants in precarious circumstances in the EU and European Economic Area.

HIV epidemics in the EU and European Economic Area are increasingly diverse in transmission modes and groups affected. Substantial gaps in data exist on HIV burden and access to the HIV continuum of care among migrants living in this region, particularly individuals in precarious circumstances such as migrants with irregular status. Migrants have a higher HIV burden compared with the general population, and high rates of post-migration HIV acquisition. Migrants also face challenges in access to health and HIV services, with irregular migrants, foreign-born key populations such as men who have sex with men, sex workers, and people who inject drugs, and migrants from sub-Saharan Africa being most affected. Intersecting factors negatively affect their access to services along the full continuum of care, including prevention and psychosocial services. Ensuring equitable access to general health and HIV services, regardless of immigration status, and implementing interventions to reduce stigma and discrimination are crucial to ending AIDS by 2030.

Novelty preference does not predict trait cocaine behaviors in male rats.

Heightened novelty seeking is a risk factor for the initiation of drug use and development of substance use disorders. In rats, novelty seeking can be examined by assessing preference for a novel environment. Some evidence indicates that high novelty preferring (HNP) rats have higher drug intake compared to low novelty preferring (LNP) rats, although these data are mixed. Moreover, the extent to which the HNP phenotype can predict other initial drug behaviors, including economic demand for cocaine, has not been tested. Here, we screened a cohort (n=60) of male rats for novelty preference and several subsequent cocaine behaviors, including locomotor reactivity to a cocaine priming injection, acquisition of cocaine self-administration, as well as cocaine demand using a within-session behavioral economics procedure. Novelty preference did not correlate with cocaine behaviors, nor were there any differences between HNP and LNP rats identified using a median split strategy. Moreover, regression analyses indicated that novelty preference did not have predictive utility for any of the cocaine behaviors tested. Thus, the extent to which the novelty preference trait can predict initial cocaine-related behaviors in male rats may be limited. This is in contrast to the novel locomotor reactivity phenotype, which is strongly linked with initial cocaine intake, indicating that these traits are distinct and differentially predict cocaine behaviors in rats.

Hormonal milieu drives economic demand for cocaine in female rats.

There are substantial sex differences in drug abuse, and a key feature of cocaine addiction is pathologically high motivation for drug. We investigated the role of ovarian hormones on cocaine demand in female rats using a within-session threshold behavioral economics (BE) procedure, which allows us to compare motivation for drug across hormonal states and sex while controlling for differences in dose and intake. This approach quantifies demand elasticity (α) and free consumption (Q0, consumption at null effort) to determine motivation for cocaine. Overall, female rats showed greater motivation for cocaine compared to males. However, this difference was cycle phase-dependent - motivation for cocaine when females were in proestrus was lower compared to the same animals across cycle phases, and overall similar to that of males. Hormonal cycle phase accounted for 70% of the within-subject variance in demand elasticity, obscuring other individual differences in female demand. High serum progesterone (P4; e.g., in proestrus) predicted decreased cocaine motivation (high demand elasticity), whereas serum estradiol (E2) correlated to greater intake at null effort (Q0). However, individual differences were revealed across OVX females, who displayed a range of demand elasticity, as seen in males. E2 replacement in OVX females increased motivation for cocaine, whereas P4 replacement decreased motivation. We also found that as few as 4 weeks of cocaine self-administration accelerated estropause in female rats as young as 12 weeks old. By 13 weeks of self-administration, proestrus epochs were no longer observed, and cocaine demand was potentiated by persistent estrus in all females. Thus, P4 signaling is a key modulator of cocaine demand in females that may underlie previously observed sex differences in addiction phenotypes.

Veterinary history and the development of human relationships with animals.

Reviewed by the chair of the Veterinary History Society Gary Clayton Jones.