Does Treatment Readiness Shape Service-Design Preferences of Gay, Bisexual, and Other Men Who Have Sex with Men Who Use Crystal Methamphetamine? A Cross Sectional Study.

Crystal methamphetamine (CM) disproportionately impacts gay, bisexual, and other men who have sex with men (gbMSM). However, not all gbMSM are interested in changing their substance use. The present study aimed to examine whether participant-preferred service characteristics were associated with their readiness to change. We surveyed gbMSM who used CM in the past six months, aged 18 plus years, on dating platforms. Participants rated service-design characteristics from "very unimportant" to "very important". Multivariable regression tested service preference ratings across levels of the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES-8D). Among 291 participants, 38.7% reported their CM use was not problematic, 19.5% were not ready to take any action to reduce or stop using CM, and 41.7% were ready to take action. On average, participants rated inclusive, culturally-appropriate, out-patient counselling-based interventions as most important. Participants with greater readiness-to-change scores rated characteristics higher than gbMSM with lesser readiness. Contingency management and non-abstinence programming were identified as characteristics that might engage those with lesser readiness. Services should account for differences in readiness-to-change. Programs that provide incentives and employ harm reduction principles are needed for individuals who may not be seeking to reduce or change their CM use.

Perceived difficulty of getting help to reduce or abstain from substances among sexual and gender minority men who have sex with men (SGMSM) and use methamphetamine during the early period of the COVID-19 pandemic.

BACKGROUND: This study examined the perceived difficulty of getting help with substance use among sexual and gender minorities who have sex with men (SGMSM) who use methamphetamine during the early COVID-19 period. METHODS: SGMSM, aged 18+, who reported sex with a man and methamphetamine use in the past 6 months were recruited to complete an online survey using online advertisements. Ordinal regression models examined predictors of greater perceived difficulty of getting help. Explanatory variables included participant characteristics (i.e., age, HIV status, ethnicity, sexuality, gender, region, income) and variables assessing patterns of methamphetamine use (i.e., frequency, % time methamphetamine is used alone and during sex; perceived need for help) and patterns of healthcare access (i.e., regular provider, past substance use service utilization). RESULTS: Of 376 participants, most were gay-identified (76.6%), white (72.3%), cisgender (93.6%), and had annual incomes of less than $60,000 CAD (68.9%). Greater perceived difficulty of getting help was associated with having lower income, sometimes using methamphetamine prior to or during sex, and greater perceived need for help. CONCLUSION: Based on these results, we urge greater investments in one-stop, low-barrier, culturally-appropriate care for SGMSM who use methamphetamine. This is especially important given that participants who perceive themselves as needing help to reduce or abstain from substance use perceive the greatest difficulty of getting such help.

The ART of conversation: feasibility and acceptability of a pilot peer intervention to help transition complex HIV-positive people from hospital to community.

OBJECTIVES: To pilot a peer-based intervention for people living with HIV who used substances, had challenges with antiretroviral adherence and would be discharged from hospital to community. STUDY DESIGN: A community-based, quasi-experimental pilot intervention study designed to assess feasibility, acceptability and connection to a community-based HIV organisation. SETTING: This study was conducted in Toronto, Canada, at Casey House (CH; hospital for people living with HIV) in collaboration with the AIDS Committee of Toronto (ACT; community-based HIV organisation). PARTICIPANTS: People living with HIV who were CH inpatient between 1 April 2017 and 31 March 2018, struggled with antiretroviral adherence, actively used substances and would be discharged to community were eligible. Forty people met criteria, 19 were approached by an inpatient nurse and 17 consented. Average age was 48.8 years (SD=11.4), 58.8% were male and participants averaged 7.8 physical and mental health comorbidities (SD=3.1). INTERVENTION: Titled 'The ART of Conversation', the three-pronged personalised intervention was developed through input from CH clients and ACT volunteers, all living with HIV. Intervention components were (a) predischarge goal-setting (adherence, substance use and self-identified goal) with the study nurse; (b) predischarge meeting with an HIV+ peer volunteer (PV) and (c) nine postdischarge phone calls between PV and participant, once per day for 3 days, then once per week for 6 weeks. PRIMARY OUTCOMES: Feasibility was measured through proportion of eligible participants recruited and PV availability. Acceptability was assessed through participant interviews at three times (preintervention, post-intervention and 6 weeks follow-up) and through PV call logs. Client records determined connection to ACT within the study timeframe. RESULTS: Twelve participants completed the intervention and nine connected with ACT. Predischarge goal-setting and PV meeting were both feasible and acceptable. Postdischarge phone calls were a challenge as half of completers missed at least one call. CONCLUSIONS: Although predischarge goal-setting and PV meeting were feasible, methods to maintain connection following discharge require further investigation.

Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity.

The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith-Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.

The activity of Plasmodium falciparum arginase is mediated by a novel inter-monomer salt-bridge between Glu295-Arg404.

A recent study implicated a role for Plasmodium falciparum arginase in the systemic depletion of arginine levels, which in turn has been associated with human cerebral malaria pathogenesis. Arginase (EC 3.5.3.1) is a multimeric metallo-protein that catalyses the hydrolysis of arginine to ornithine and urea by means of a binuclear spin-coupled Mn(2+) cluster in the active site. A previous report indicated that P. falciparum arginase has a strong dependency between trimer formation, enzyme activity and metal co-ordination. Mutations that abolished Mn(2+) binding also caused dissociation of the trimer; conversely, mutations that abolished trimer formation resulted in inactive monomers. By contrast, the monomers of mammalian (and therefore host) arginase are also active. P. falciparum arginase thus appears to be an obligate trimer and interfering with trimer formation may therefore serve as an alternative route to enzyme inhibition. In the present study, the mechanism of the metal dependency was explored by means of homology modelling and molecular dynamics. When the active site metals are removed, loss of structural integrity is observed. This is reflected by a larger equilibration rmsd for the protein when the active site metal is removed and some loss of secondary structure. Furthermore, modelling revealed the existence of a novel inter-monomer salt-bridge between Glu295 and Arg404, which was shown to be associated with the metal dependency. Mutational studies not only confirmed the importance of this salt-bridge in trimer formation, but also provided evidence for the independence of P. falciparum arginase activity on trimer formation.

Novel properties of malarial S-adenosylmethionine decarboxylase as revealed by structural modelling.

In the malaria parasite, the two main regulatory activities of polyamine biosynthesis, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) occur in a single bifunctional protein. The AdoMetDC domain was modeled using the human and potato X-ray crystal structures as templates. Three parasite-specific inserts and the core active site region was identified using a structure-based alignment approach. The domain was modeled without the two largest inserts, to give a root mean square deviation of 1.85 angstroms from the human template. Contact with the rest of the bifunctional complex is predicted to occur on one face of the Plasmodium falciparum AdoMetDC (PfAdoMetDC) domain. In the active site there are four substitutions compared to the human template. One of these substitutions may be responsible for the lack of inhibition by Tris, compared to mammalian AdoMetDC. The model also provides an explanation for the lack of putrescine stimulation in PfAdoMetDC compared to mammalian AdoMetDC. A network of residues that connects the putrescine-binding site with the active site in human AdoMetDC is conserved in the malarial and plant cognates. Internal basic residues are found to assume the role of putrescine, based on the model and site-directed mutagenesis: Arg11 is absolutely required for normal activity, while disrupting Lys15 and Lys215 each cause 50% inhibition of AdoMetDC activity. These novel features of malarial AdoMetDC suggest possibilities for the discovery of parasite-specific inhibitors.

Parasite-specific inserts in the bifunctional S-adenosylmethionine decarboxylase/ornithine decarboxylase of Plasmodium falciparum modulate catalytic activities and domain interactions.

Polyamine biosynthesis of the malaria parasite, Plasmodium falciparum, is regulated by a single, hinge-linked bifunctional PfAdoMetDC/ODC [ P. falciparum AdoMetDC (S-adenosylmethionine decarboxylase)/ODC (ornithine decarboxylase)] with a molecular mass of 330 kDa. The bifunctional nature of AdoMetDC/ODC is unique to Plasmodia and is shared by at least three species. The PfAdoMetDC/ODC contains four parasite-specific regions ranging in size from 39 to 274 residues. The significance of the parasite-specific inserts for activity and protein-protein interactions of the bifunctional protein was investigated by a single- and multiple-deletion strategy. Deletion of these inserts in the bifunctional protein diminished the corresponding enzyme activity and in some instances also decreased the activity of the neighbouring, non-mutated domain. Intermolecular interactions between AdoMetDC and ODC appear to be vital for optimal ODC activity. Similar results have been reported for the bifunctional P. falciparum dihydrofolate reductase-thymidylate synthase [Yuvaniyama, Chitnumsub, Kamchonwongpaisan, Vanichtanankul, Sirawaraporn, Taylor, Walkinshaw and Yuthavong (2003) Nat. Struct. Biol. 10, 357-365]. Co-incubation of the monofunctional, heterotetrameric approximately 150 kDa AdoMetDC domain with the monofunctional, homodimeric ODC domain (approximately 180 kDa) produced an active hybrid complex of 330 kDa. The hinge region is required for bifunctional complex formation and only indirectly for enzyme activities. Deletion of the smallest, most structured and conserved insert in the ODC domain had the biggest impact on the activities of both decarboxylases, homodimeric ODC arrangement and hybrid complex formation. The remaining large inserts are predicted to be non-globular regions located on the surface of these proteins. The large insert in AdoMetDC in contrast is not implicated in hybrid complex formation even though distinct interactions between this insert and the two domains are inferred from the effect of its removal on both catalytic activities. Interference with essential protein-protein interactions mediated by parasite-specific regions therefore appears to be a viable strategy to aid the design of selective inhibitors of polyamine metabolism of P. falciparum.