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OBJECTIVE: Internally displaced persons (IDPs) can have limited access to HIV and hepatitis C Virus (HCV) treatment and prevention. IDPs comprise > 7% of Georgian population but prevalence and levels of HIV and HCV knowledge in this population remain unknown. We tested 100 IDPs in Georgia for HIV and HCV, many of whom had drug injecting experience, and interviewed them about their migration experience, sexual and drug injecting practices, and HIV/HCV transmission knowledge. RESULTS: The average age of participants was 37.5 years (range 18-63); 31% were women. Almost half (N = 48) of participants reported ever injecting drugs; 17% of those (N = 8) started injecting drugs within the last year. Anti-HCV and HIV prevalence was 11% and 0%, respectively. Fewer people without drug use experience compared to people who inject drugs correctly answered all questions on the HIV knowledge test (13% vs. 35%, p = 0.015) or knew where to get tested for HIV (67% vs 98%, p

Glucagon plays a central role in amino acid (AA) homeostasis. The dog is an established model of glucagon biology, and recently, metabolomic changes in people associated with glucagon infusions have been reported. Glucagon also has effects on the kidney; however, changes in urinary AA concentrations associated with glucagon remain under investigation. Therefore, we aimed to fill these gaps in the canine model by determining the effects of glucagon on the canine plasma metabolome and measuring urine AA concentrations. Employing two constant rate glucagon infusions (CRI) - low-dose (CRI-LO: 3 ng/kg/min) and high-dose (CRI-HI: 50 ng/kg/min) on five research beagles, we monitored interstitial glucose and conducted untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) on plasma samples and urine AA concentrations collected pre- and post-infusion. The CRI-HI induced a transient glucose peak (90-120 min), returning near baseline by infusion end, while only the CRI-LO resulted in 372 significantly altered plasma metabolites, primarily reductions (333). Similarly, CRI-HI affected 414 metabolites, with 369 reductions, evidenced by distinct clustering post-infusion via data reduction (PCA and sPLS-DA). CRI-HI notably decreased circulating AA levels, impacting various AA-related and energy-generating metabolic pathways. Urine analysis revealed increased 3-methyl-l-histidine and glutamine, and decreased alanine concentrations post-infusion. These findings demonstrate glucagons glucose-independent modulation of the canine plasma metabolome and highlight the dogs relevance as a translational model for glucagon biology. Understanding these effects contributes to managing dysregulated glucagon conditions and informs treatments impacting glucagon homeostasis.

OBJECTIVE: Multifocal motor neuropathy is a rare chronic immune-mediated neuropathy with impaired grip strength representing a common symptom. While intravenous immunoglobulin G is an effective treatment for the disease, significant variation in treatment response has been observed but not well understood. This analysis characterized dose-exposure-response relationships in multifocal motor neuropathy, using grip strength as a clinical efficacy measure. METHODS: Serum immunoglobulin G trough concentrations and grip strength data for the more affected hand from a Phase 3, randomized, double-blind, placebo-controlled, crossover trial of intravenous immunoglobulin 10% in 44 patients with multifocal motor neuropathy (NCT00666263) were used to develop a population pharmacokinetic-pharmacodynamic model. RESULTS: The model adequately described the observed pharmacokinetic and pharmacodynamic data and relationships between intravenous immunoglobulin 10% dose, serum immunoglobulin G trough levels, grip strength, and inter-patient variabilities in multifocal motor neuropathy. Model-based simulations for various dosing regimens (0.4-2.0 g/kg every 2-4 weeks) indicated that ≥1.6 g/kg/month would achieve clinically meaningful improvements in grip strength (≥4 kg) in ≥70% of patients. More frequent dosing at an equivalent monthly dose led to a more consistent response in grip strength. Furthermore, splitting the dose over multiple days for high doses (>1 g/kg) did not impact grip strength. INTERPRETATION: These findings suggest that the majority of patients with multifocal motor neuropathy would respond rapidly to intravenous immunoglobulin 10% with a range of dosing regimens. Shorter dosing intervals may avoid the diminishing response seen with longer dosing intervals. Dose-splitting provided similar outcomes while offering flexibility and convenience.

Background Intravenous prostate-specific membrane antigen (PSMA)-targeted radioligand therapy improves survival in men with metastatic castration-resistant prostate cancer. Yet, the impact of selective prostatic arterial administration on primary tumor uptake is unclear. Purpose To compare gallium 68 (68Ga)-PSMA-11 uptake using dynamic PET/CT in prostatic tumoral volumes of interest (VOIs) during intravenous and selective prostatic arterial infusions for individuals with untreated, high-risk prostate cancer. Materials and Methods In this prospective, intraindividual comparative study conducted at an academic medical center, five men aged 58, 61, 64, 66, and 68 years with treatment-naive prostate cancer were enrolled between January 2022 and February 2023 and underwent two dynamic 68Ga-PSMA-11 PET/CT examinations 1 week apart. During the first examination, the radiotracer was administered intravenously. During the second administration, the radiotracer was delivered into either the right or left prostatic artery through an angiographically placed microcatheter. The primary outcome was maximum standardized uptake value (SUVmax) in prostatic tumoral VOIs. The secondary outcomes included mean SUV (SUVmean) in prostatic tumoral VOIs and area under the SUVmean curves (AUC). Longitudinal mixed-effects models were used to compare dynamic SUVmax and SUVmean time-activity curves (TACs), and paired t tests were used for the remaining data. Results The mean SUVmax within tumoral VOIs was 14 (range, 3-43) for venous sessions and 938 (range, 460-1436) for arterial sessions (P = .008). The SUVmean within VOIs was greater during arterial sessions (P < .001) overall and 46-fold and 19-fold greater at peak uptake and final time points, respectively. The mean AUC was greater on arterial TACs than on venous TACs at 14600 SUV × min (range, 8353-20025 SUV × min) and 240 SUV × min (range, 69-622 SUV × min), respectively (P = .002). Conclusion Selective prostatic arterial infusion resulted in greater 68Ga-PSMA-11 tumoral SUV than intravenous infusion. Further study of local-regional, intra-arterial delivery of a PSMA-targeted theranostic agent is warranted in high-risk prostate cancer. ClinicalTrials.gov identifier: NCT04976257 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Civelek in this issue.

BACKGROUND: Despite its approval for acute ischemic stroke >25 years ago, intravenous thrombolysis (IVT) remains underused, with inequities by age, sex, race, ethnicity, and geography. Little is known about IVT rates by insurance status. METHODS AND RESULTS: We assessed temporal trends from 2002 to 2015 in IVT for acute ischemic stroke in the Nationwide Inpatient Sample using adjusted, survey-weighted logistic regression. We calculated odds ratios for IVT for each category in 2002 to 2008 (period 1) and 2009 to 2015 (period 2). IVT use for acute ischemic stroke increased from 1.0% in 2002 to 6.8% in 2015 (adjusted annual relative ratio, 1.15). Individuals aged ≥85 years had the most pronounced increase during 2002 to 2015 (adjusted annual relative ratio, 1.18) but were less likely to receive IVT compared with 18- to 44-year-olds in period 1 (adjusted odds ratio [aOR], 0.23) and period 2 (aOR, 0.36). Women were less likely than men to receive IVT, but the disparity narrowed over time (period 1: aOR, 0.81; period 2: aOR, 0.94). Inequities in IVT resolved for Hispanic individuals in period 2 (aOR, 0.96) but not for Black individuals (period 2: aOR, 0.81). The disparity in IVT for Medicare patients, compared with privately insured patients, lessened over time (period 1: aOR, 0.59; period 2: aOR, 0.75). Patients treated in rural hospitals remained less likely to receive IVT than in urban hospitals; a more dramatic increase in urbanity widened the inequity (period 2, urban nonteaching versus rural: aOR, 2.58, period 2, urban teaching versus rural: aOR, 3.90). CONCLUSIONS: IVT for acute ischemic stroke increased among adults. Despite some encouraging trends, the remaining disparities highlight the need for intensified efforts at addressing inequities.

Objectives. To describe the current financial health of syringe services programs (SSPs) in the United States and to assess the predictors of SSP budget levels and associations with delivery of public health interventions. Methods. We surveyed all known SSPs operating in the United States from February to June 2022 (n = 456), of which 68% responded (n = 311). We used general estimating equations to assess factors influencing SSP budget size and estimated the effects of budget size on multiple measures of SSP services. Results. The median SSP annual budget was $100 000 (interquartile range = $20 159‒$290 000). SSPs operating in urban counties and counties with higher levels of opioid overdose mortality had significantly higher budget levels, while SSPs located in counties with higher levels of Republican voting in 2020 had significantly lower budget levels. SSP budget levels were significantly and positively associated with syringe and naloxone distribution coverage. Conclusions. Current SSP funding levels do not meet minimum benchmarks. Increased funding would help SSPs meet community health needs. Public Health Implications. Federal, state, and local initiatives should prioritize sustained SSP funding to optimize their potential in addressing multiple public health crises. (Am J Public Health. 2024;114(4):435-443. https://doi.org/10.2105/AJPH.2024.307583).

BackgroundAbout 10-20% of Kawasaki disease (KD) patients are resistant to the initial infusion of intravenous immunoglobin (IVIG). The aim of this study was to assess whether IVIG resistance in KD patients could be predicted using standard clinical and laboratory features.MethodsData were from two cohorts: a Korean cohort of 7101 KD patients from 2015 to 2017 and a cohort of 649 KD patients from San Diego enrolled from 1998 to 2021. Features included laboratory values, the worst Z-score from the initial echocardiogram or during hospitalization, and the five clinical KD signs at presentation.ResultsFive machine learning models achieved a maximum median AUC of 0.711 [IQR: 0.706-0.72] in the Korean cohort and 0.696 [IQR: 0.609-0.722] in the San Diego cohort during stratified 10-fold cross-validation using significant laboratory features identified from univariate analysis. Adding the Z-score, KD clinical signs, or both did not considerably improve the median AUC in either cohort.ConclusionsUsing commonly measured clinical laboratory data alone or in conjunction with echocardiographic findings and clinical features is not sufficient to predict IVIG resistance. Further attempts to predict IVIG resistance will need to incorporate additional data such as transcriptomics, proteomics, and genetics to achieve meaningful predictive utility.ImpactWe demonstrated that laboratory, echocardiographic, and clinical findings cannot predict intravenous immunoglobin (IVIG) resistance to a clinically meaningful extent using machine learning in a homogenous Asian or ethnically diverse population of patients with Kawasaki disease (KD). Visualizing these features using uniform manifold approximation and projection (UMAP) is an important step to evaluate predictive utility in a qualitative manner. Further attempts to predict IVIG resistance in KD patients will need to incorporate novel biomarkers or other specialized features such as genetic differences or transcriptomics to be clinically useful.

BACKGROUND: As many as 2.4 million Americans are affected by chronic Hepatitis C Virus (HCV) in the United States.In 2018, the estimated number of adults with a history of HCV infection in San Diego County was 55,354 (95% CI: 25,411-93,329). This corresponded to a seroprevalence of 2.1% (95% CI: 2.1-3.4%). One-third of infections were among PWID. Published research has demonstrated that direct-acting antivirals (DAAs) have high efficacy and can now be used by primary care providers to treat HCV. In addition, limited evidence exists to support the effectiveness of simplified algorithms in clinical trial and real-world settings. Even with expanded access to HCV treatment in primary care settings, there are still groups, especially people who inject drugs (PWID) and people experiencing homelessness, who experience treatment disparities due to access and treatment barriers. The current study extends the simplified algorithm with a streetside one-stop-shop approach with integrated care (including the offer of buprenorphine prescriptions and abscess care) using a mobile clinic situated adjacent to a syringe service program serving many homeless populations. Rates of HCV treatment initiation and retention will be compared between patients offered HCV care in a mobile clinic adjacent to a syringe services program (SSP) and homeless encampment versus those who are linked to a community clinics current practice of usual care, which includes comprehensive patient navigation. METHODS: A quasi-experimental, prospective, interventional, comparative effectiveness trial with allocation of approximately 200 patients who inject drugs and have chronic HCV to the simplified care pathway (intervention group) or the usual care pathway (control group). Block randomization will be performed with a 1:1 randomization. DISCUSSION: Previous research has demonstrated acceptable outcomes for patients treated using simplified algorithms for DAAs and point-of-care testing in mobile medical clinics; however, there are opportunities to explore how these new, innovative systems of care impact treatment initiation rates or other HCV care cascade outcomes among PWID. TRIAL REGISTRATION: We have registered our study with ClinicalTrials.gov, a resource of the United States National Library of Medicine. This database contains research studies from United States and other countries around the world. Our study has not been previously published. The ClinicalTrials.gov registration identifier is NCT04741750.

IntroductionKawasaki disease (KD) is a pediatric vasculitis that can result in coronary artery aneurysm (CAA) formation, which is a dangerous complication. Treatment with intravenous immunoglobulin (IVIg) significantly decreases the risk of CAA, possibly through competitive binding to Fc-gamma receptors (FcγRs), which reduces the binding of pathological immune complexes. However, ~20% of children have recrudescence of fever and have an increased risk of CAA. Therefore, we aimed to identify genetic markers at the FCGR2/3 locus associated with susceptibility to KD, IVIg resistance, or CAA.Materials and methodsWe investigated the association of single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs) at the FCGR2/3 locus with KD susceptibility, IVIg resistance, and CAA risk using a family-based test (KD susceptibility) and case-control analyses (IVIg resistance and CAA risk) in different cohorts, adding up to a total of 1,167 KD cases. We performed a meta-analysis on IVIg resistance and CAA risk including all cohorts supplemented by previous studies identified through a systematic search.ResultsFCGR2A-p.166His was confirmed to be strongly associated with KD susceptibility (Z = 3.17, p = 0.0015). In case-control analyses, all of the investigated genetic variations at the FCGR2/3 locus were generally not associated with IVIg resistance or with CAA risk, apart from a possible association in a Polish cohort for the FCGR3B-NA2 haplotype (OR = 2.15, 95% CI = 1.15-4.01, p = 0.02). Meta-analyses of all available cohorts revealed no significant associations of the FCGR2/3 locus with IVIg resistance or CAA risk.DiscussionFCGR2/3 polymorphisms are associated with susceptibility to KD but not with IVIg resistance and CAA formation. Currently known genetic variations at the FCGR2/3 locus are not useful in prediction models for IVIg resistance or CAA risk.

BackgroundXylazine is an increasingly common adulterant in the North American unregulated drug supply that is associated with adverse health outcomes (e.g., skin infections, overdose). However, there are significant knowledge gaps regarding how xylazine was initially identified and how syringe services program (SSP) staff and clients (people who use drugs) responded to its emergence.MethodsFrom June-July 2023, we conducted qualitative interviews with medical (e.g., clinicians) and frontline SSP staff (e.g., outreach workers) and adult clients with a history of injection drug use at a Miami-based SSP. Inductive memos identified emergent codes; thematic analysis involving team consensus established final themes.ResultsFrom interviews with SSP staff (n = 8) and clients (n = 17), xylazine emergence was identified at different times, in various ways. Initially, during summer 2022, clients identified a "tranquilizer-like substance" that worsened sedation and withdrawal and caused wounds. SSP medical staff later identified this adulterant as xylazine by treating new medical cases and through diverse information-sharing networks that included professional societies and news sources; however, frontline SSP staff and clients needed additional educational resources about xylazine and its side effects. With limited guidance on how to reduce harm from xylazine, SSP clients altered their drug consumption routes, reduced drug use, and relied on peers' experiences with the drug supply to protect themselves. Some individuals also reported preferring xylazine-adulterated opioids and increasing their drug use, including the use of stimulants to avoid over sedation.ConclusionsXylazine's emergence characterizes the current era of unprecedented shifts in the unregulated drug supply. We found that xylazine spurred important behavioral changes among people who use drugs (e.g., transitioning from injecting to smoking). Incorporating these experiences into early drug warning surveillance systems and scaling up drug-checking services and safer smoking supply distribution could help mitigate significant health harms caused by xylazine and other emergent adulterants.

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 recipients 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.

BackgroundDomains of adequate menstrual health (MH) include access to water, sanitation, and hygiene (WASH). People who menstruate with social disadvantages-such as homelessness or drug injection practices-often face barriers to WASH access. However, validated instruments to measure MH are limited among marginalized populations, and available instruments involve lengthy surveys. We developed and evaluated psychometric properties of a novel 'MH WASH Domain Scale-12' among people who menstruate and who inject drugs in the Tijuana-San Diego region and identified correlates of MH access using this scale.MethodsWe constructed a MH-scale based on access to twelve WASH-related items: (1) menstrual products, (2) body hygiene (bathing per week), (3) water sources for bathing, (4) improved, (5) non-shared, (6) available, (7) private, (8) nearby, (9) and safe sanitation facilities, (10) availability of soap, (11) water source for handwashing, and (12) handwashing facilities with soap/water. Variables were dichotomized and summed, with scores ranging from 0-12 points and higher scores indicating better MH access. We assessed the scale's reliability and construct and content validity using data from a binational cross-sectional study. The sample included people who inject drugs (PWID) who had ever menstruated in their lifetime and were 18+ during 2020-2021. MH-WASH items were described, and the scale was further used as an outcome variable to identify correlates.ResultsAmong 125 (124 cis-female and 1 trans-male) PWID that reported menstruating, our 'MH WASH Domain Scale-12' was reliable (Cronbach's alpha = 0.81, McDonald's Omega total = 0.83) and valid. We identified two sub-domains: Factor-1 included items describing 'WASH availability' and Factor-2 contained items related to 'WASH security'-encompassing physical and biological safety. Scale scores were significantly lower among participants experiencing unsheltered homelessness compared to participants experiencing sheltered homelessness or living in permanent housing.ConclusionWe constructed and validated a novel and reliable scale to measure MH-related WASH access that can be used to assess MH among marginalized populations in English- and Spanish-speaking contexts. Using this scale we identified disparities in MH-WASH access among PWID and who menstruate in the US-Mexico border region.

BackgroundWater, sanitation, and hygiene (WASH) access is critical to public health and human dignity. People who inject drugs (PWID) experience stigma and structural violence that may limit WASH access. Few studies have assessed WASH access, insecurity, and inequities among PWID. We describe WASH access, social and geographic inequalities, and factors associated with WASH insecurity among PWID in the Tijuana-San Diego metropolitan area.MethodsIn this cross-sectional binational study, we interviewed PWID (age 18+) in 2020-2021 about WASH access and insecurity. City of residence (Tijuana/San Diego) and housing status were considered as independent variables to describe key WASH access outcomes and to assess as factors associated with WASH insecurity outcomes. Measures of association between outcomes and independent variables were assessed using log modified-Poisson regression models adjusting for covariates.ResultsOf 586 PWID (202 Tijuana; 384 San Diego), 89% reported basic access to drinking water, 38% had basic hand hygiene, 28% basic sanitation, and 46% access to bathing, and 38% reported recent open defecation. Participants residing in Tijuana reported significantly higher insecurity in accessing basic drinking water (aRR: 1.68, 95%CI: 1.02-2.76), basic hygiene (aRR: 1.45, 95%CI: 1.28-1.64), and bathing (aRR: 1.21, 95%CI: 1.06-1.39) than those living in San Diego. Participants experiencing unsheltered homelessness experienced significantly higher insecurity in accessing basic drinking water (aRR: 2.03, 95%CI: 1.07-3.86), basic sanitation (aRR: 1.68, 95%CI: 1.48, 1.92), bathing (aRR: 1.84, 95%CI: 1.52-2.22), and improved water sources for cleaning wounds (aRR: 3.12, 95%CI: 1.55-6.29) and for preparing drugs (aRR: 2.58, 95%CI: 1.36-4.89) than participants living in permanent housing.ConclusionWASH access among PWID in the Tijuana-San Diego metropolitan area was low by international standards and lower than the national averages in both countries. Homelessness was significantly associated with WASH insecurity in this population. Concentrated efforts are needed to guarantee continuously available WASH services for PWID-especially those who are unsheltered.

INTRODUCTION: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT. METHODS: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment. RESULTS: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week. DISCUSSION: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic that induces a rapid and transient altered state of consciousness when inhaled or injected via bolus administration. Its marked and novel subjective effects make DMT a powerful tool for the neuroscientific study of consciousness and preliminary results show its potential role in treating mental health conditions. In a within-subjects, placebo-controlled study, we investigated a novel method of DMT administration involving a bolus injection paired with a constant-rate infusion, with the goal of extending the DMT experience. Pharmacokinetic parameters of DMT estimated from plasma data of a previous study of bolus intravenous DMT were used to derive dose regimens necessary to keep subjects in steady levels of immersion into the DMT experience over an extended period of 30 min, and four dose regimens consisting of a bolus loading dose and a slow-rate infusion were tested in eleven healthy volunteers (seven male, four female, mean age ± SD = 37.09 ± 8.93 years). The present method is effective for extending the DMT experience in a stable and tolerable fashion. While subjective effects were maintained over the period of active infusion, anxiety ratings remained low and heart rate habituated within 15 min, indicating psychological and physiological safety of extended DMT. Plasma DMT concentrations increased consistently starting 10 min into DMT administration, whereas psychological effects plateaued into the desired steady state, suggesting the development of acute psychological tolerance to DMT. Taken together, these findings demonstrate the safety and effectiveness of continuous IV DMT administration, laying the groundwork for the further development of this method of administration for basic and clinical research.

BackgroundPersons with opioid use disorders who inject drugs (PWID) in the United States (US) face multiple and intertwining health risks. These include interference with consistent access, linkage, and retention to health care including medication for opioid use disorder (MOUD), HIV prevention using pre-exposure prophylaxis (PrEP), and testing and treatment for sexually transmitted infections (STIs). Most services, when available, including those that address substance misuse, HIV prevention, and STIs, are often provided in multiple locations that may be difficult to access, which further challenges sustained health for PWID. HPTN 094 (INTEGRA) is a study designed to test the efficacy of an integrated, "whole-person" strategy that provides integrated HIV prevention including antiretroviral therapy (ART), PrEP, MOUD, and STI testing and treatment from a mobile health delivery unit ("mobile unit") with peer navigation compared to peer navigation alone to access these services at brick and mortar locations.MethodsHPTN 094 (INTEGRA) is a two-arm, randomized controlled trial in 5 US cities where approximately 400 PWID without HIV are assigned either to an experimental condition that delivers 26 weeks of "one-stop" integrated health services combined with peer navigation and delivered in a mobile unit or to an active control condition using peer navigation only for 26 weeks to the same set of services delivered in community settings. The primary outcomes include being alive and retained in MOUD and PrEP at 26 weeks post-randomization. Secondary outcomes measure the durability of intervention effects at 52 weeks following randomization.DiscussionThis trial responds to a need for evidence on using a "whole-person" strategy for delivering integrated HIV prevention and substance use treatment, while testing the use of a mobile unit that meets out-of-treatment PWID wherever they might be and links them to care systems and/or harm reduction services. Findings will be important in guiding policy for engaging PWID in HIV prevention or care, substance use treatment, and STI testing and treatment by addressing the intertwined epidemics of addiction and HIV among those who have many physical and geographic barriers to access care.Trial registrationClinicalTrials.gov NCT04804072 . Registered on 18 March 2021.

It is generally believed that bioavailability (F) calculated based on systemic concentration area under the curve (AUC) measurements cannot exceed 1.0, yet some published studies report this inconsistency. We teach and believe, based on differential equation derivations, that rate of absorption has no influence on measured systemic clearance following an oral dose, i.e., determined as available dose divided by AUC. Previously, it was thought that any difference in calculating F from urine data versus that from systemic concentration AUC data was due to the inability to accurately measure urine data. A PubMed literature search for drugs exhibiting F > 1.0 and studies for which F was measured using both AUC and urinary excretion dose-corrected analyses yielded data for 35 drugs. We show and explain, using Kirchhoff's Laws, that these universally held concepts concerning bioavailability may not be valid in all situations. Bioavailability, determined using systemic concentration measurements, for many drugs may be overestimated since AUC reflects not only systemic elimination but also absorption rate characteristics, which is most easily seen for renal clearance measures. Clearance of drug from the absorption site must be significantly greater than clearance following an iv bolus dose for F(AUC) to correctly correspond with F(urine). The primary purpose of this paper is to demonstrate that studies resulting in F > 1.0 and/or greater systemic vs urine bioavailability predictions may be accurate. Importantly, these explications have no significant impact on current regulatory guidance for bioequivalence testing, nor on the use of exposure (AUC) measures in making drug dosing decisions.

BackgroundHIV self-testing (HIVST) could increase HIV testing access among people who inject drugs (PWID), and secondary distribution (i.e., peer-delivery) of HIVST kits in PWID social networks could further expand coverage. We assessed willingness to use and distribute HIVST kits among PWID in the San Diego-Tijuana border region.MethodsFrom 2020 to 2021, HIV-negative PWID in San Diego, USA, and Tijuana, Mexico, completed surveys and provided data on individual (N = 539) and social network (N = 366) characteristics. We used modified Poisson regression to examine the effects of individual and social network characteristics on willingness to use and distribute HIVST kits.ResultsMost participants were willing to use (81%) and distribute (81%) HIVST kits. At the individual level, prior HIV testing was positively associated with willingness to use (adjusted prevalence ratio [aPR] = 1.24, 95% confidence interval [CI] 1.10-1.40) and distribute (aPR = 1.27, 95% CI 1.12-1.43) HIVST kits, while perceiving oneself to be at higher HIV risk than others was negatively associated with willingness to use HIVST kits (aPR = 0.83, 95% CI 0.74-0.93). At the network level, willingness to distribute HIVST kits was positively associated with network size (aPR = 1.04 per member, 95% CI 1.01-1.08) and greater proportions of one's network encouraging them to use drugs (aPR = 1.29, 95% CI 1.16-1.44) and having a history of homelessness (aPR = 1.51, 95% CI 1.31-1.74) or detention/arrest (aPR = 1.57, 95% CI 1.36-1.82), and negatively associated with a greater proportion of one's network including "very close" persons (aPR = 0.80, 95% CI 0.69-0.94).ConclusionsWe found high potential for HIVST kits and their secondary distribution to increase HIV testing among PWID who face the greatest barriers to facility-based testing.

BackgroundWater, sanitation, and hygiene (WaSH) insecurity increases the risk of water-related diseases. However, limited research has been conducted on psychosocial distress as it relates to WaSH insecurity, especially among people who inject drugs (PWID). We examined the relationship between WaSH insecurity and related anxiety among PWID living in different housing conditions along the US-Mexico border region.MethodsFrom 2020-2021, a cross-sectional study was conducted among 585 people who injected drugs within the last month in Tijuana (N = 202), San Diego (N = 182), and in both Tijuana and San Diego (N = 201). Participants underwent interviewer-administered surveys related to WaSH access, substance use, and generalized anxiety disorder (GAD-7). Quasi-Poisson regressions were used to assess associations between WaSH insecurity and anxiety in the prior 6-months.ResultsParticipants were 75% male, 42% were unhoused and 91% experienced WaSH insecurity in the prior 6-months. After adjusting for housing status, gender, and age, lack of access to basic drinking water (Adj RR: 1.28; 95% CI: 1.02-1.58), sanitation (Adj RR:1.28; 95% CI: 1.07-1.55), and a daily bath/shower (Adj RR: 1.38; 95% CI: 1.15-1.66) were associated with mild-severe anxiety. The number of WaSH insecurities was independently associated with a 20% increased risk of experiencing anxiety per every additional insecurity experienced (Adj RR: 1.20; CI: 1.12-1.27). We also found a significant interaction between gender and housing status (p = 0.003), indicating that among people experiencing sheltered/unsheltered homelessness, women had a higher risk of mild-severe anxiety compared to men (Adj RR: 1.55; 95% CI: 1.27-1.89). At the same time, among women, those who are unhoused have 37% increased risk of anxiety than those who live in stable housing conditions (Adj RR: 1.37; 95% CI: 1.01-1.89).ConclusionThe lack of specific WaSH services, particularly lack of drinking water, toilets, and daily showers were associated with higher levels of anxiety among PWID in the Tijuana-San Diego border region. Women experiencing homelessness were especially vulnerable. WaSH interventions that provide safe, 24-h access may help to reduce anxiety and health risks associated with WaSH insecurity.

Study Design. Retrospective cohort. Objective. The purpose of this study was to compare the efficacy of cefazolin versus vancomycin for perioperative infection prophylaxis. Summary of Background Data. The relative efficacy of cefazolin alternatives for perioperative infection prophylaxis is poorly understood. Materials and Methods. This study was a single-center multisurgeon retrospective review of all patients undergoing primary spine surgery from an institutional registry. Postoperative infection was defined by the combination of three criteria: irrigation and debridement within 3 months of the index procedure, clinical suspicion for infection, and positive intraoperative cultures. Microbiology records for all infections were reviewed to assess the infectious organism and organism susceptibilities. Univariate and multivariate analyses were performed. Results. A total of 10, 122 patients met inclusion criteria. The overall incidence of infection was 0.78%, with an incidence of 0.73% in patients who received cefazolin and 2.03% in patients who received vancomycin (OR: 2.83, 95% CI: 1.35-5.91, P = 0.004). Use of IV vancomycin (OR: 2.83, 95% CI: 1.35-5.91, P = 0.006), BMI (MD: 1.56, 95% CI: 0.32-2.79, P = 0.014), presence of a fusion (OR: 1.62, 95% CI: 1.04-2.52, P = 0.033), and operative time (MD: 42.04, 95% CI: 16.88-67.21, P = 0.001) were significant risk factors in the univariate analysis. In the multivariate analysis, only noncefazolin antibiotics (OR: 2.48, 95% CI: 1.18-5.22, P = 0.017) and BMI (MD: 1.56, 95% CI: 0.32-2.79, P = 0.026) remained significant independent risk factors. Neither IV antibiotic regimen nor topical vancomycin significantly impacted Gram type, organism type, or antibiotic resistance (P> 0.05). The most common reason for antibiosis with vancomycin was a penicillin allergy (75.0%). Conclusions. Prophylactic antibiosis with IV vancomycin leads to a 2.5 times higher risk of infection compared with IV cefazolin in primary spine surgery. We recommend the routine use of IV cefazolin for infection prophylaxis, and caution against the elective use of alternative regimens like IV vancomycin unless clinically warranted. [ABSTRACT FROM AUTHOR]

Background: Pre-exposure prophylaxis (PrEP) holds promise for decreasing new HIV infections among people who inject drugs (PWID), yet daily oral PrEP use is low, and PrEP modality and delivery strategy preferences in this population remain understudied. Methods: From May 2022-June 2023, we conducted a discrete choice experiment (DCE) with PWID in San Diego, California. Participants viewed 18 PrEP program scenarios in sets of three and chose their preferred scenario within each set. Scenarios consisted of various combinations of five characteristics: PrEP modality (injectable, implantable, oral), frequency of use (annual, bi-monthly, daily), service location (community-based organization, clinic, telemedicine), prescription access location (on-site, street outreach, mail), and adherence supports (social support, outreach worker, phone/text reminder). Multinomial logit regression estimated probabilities of choosing PrEP program scenarios as a function of the five characteristics to estimate part-worth utility scores (PWUS; reflecting relative preferences for specific characteristic values) and relative importance scores (RIS; reflecting the relative influence of each characteristic on program choice). We also explored differences by hypothesized modifiers of preferences (i.e., sex assigned at birth, housing status, injection frequency, prior PrEP awareness). Results: Among 262 participants, mean age was 43.1 years, and most reported male sex assigned at birth (69.5%), identified as non-Hispanic (60.3%), and were previously unaware of PrEP (75.2%). Frequency of use (RIS: 51.5) and PrEP modality (RIS: 35.3) had the greatest influence on PrEP program choice. Within these characteristics, participants had relative preferences for annual use (PWUS: 0.83) and oral PrEP (PWUS: 0.57), and relative aversions to daily use (PWUS: -0.76) and implantable PrEP (PWUS: -0.53). Generally, participants did not indicate preferences for specific service or prescription access locations, or adherence supports; however, among those with prior PrEP awareness, prescription access location and adherence supports had a slightly greater influence on PrEP program choices. Conclusion: Our study considered diverse PrEP scenarios and highlighted potential preferences for long-acting oral modalities. Although not currently available, renewed investment in long-acting oral PrEP formulations may facilitate PrEP care engagement among PWID. Additional delivery and implementation strategy research is needed to support PrEP uptake and persistence in this population. [ABSTRACT FROM AUTHOR]

Objectives: Optimal imaging of ischemic or inflammed myocardium via 18F-FDG PET imaging requires suppression of background carbohydrate metabolism in normal myocardium. Sole administration of intravenous lipid emulsion has not previously been used to rapidly prepare unfasted patients, such as in emergent clinical situations. In this proof-of-concept pilot, we posited that intravenous fat emulsion suppresses physiological metabolic uptake of in non-ischemic, non-inflammatory myocardium in unprepared and unfasted setting for enhanced cardiac positron emission tomography (PET) imaging. Methods: We conducted an ethics-approved, single-blind, prospective randomized crossover trial of 10 healthy volunteers from January 2020 to June 2021. Participants were unfasted and rendered hyperglycemic before being administered either high dose intravenous lipid emulsion—1.5 ml kg of 20% lipid emulsion, followed by 15 ml/kg/hr for 30mins—or saline prior to 18F-FDG injection and subsequent cardiac PET imaging. Assessors undertook image analysis for maximum standard uptake value (SUVmax), minimum standard uptake value (SUVmin) and qualitative assessment, and groups were compared using univariate analysis. Results: The study population age was 44.5 years [IQR 32.5–56.5], with 50% male and a median BMI of 22.75 [IQR 25.0–28.5] kg/m2. The study was feasible and there were no adverse side effects from the interventions. In these participants with normal myocardium, 18F-FDG uptake was reduced by intravenous lipid emulsion as assessed by SUVmax and qualitative assessment (p = 0.042, r = 0.454 and p = 0.009, r = –0.581, respectively). Conclusions: Intravenous lipid emulsion suppresses background metabolic uptake of 18F-FDG even in unprepared and unfasted patients. Our findings prove and expand the possible applications for cardiac 18F-FDG PET in various settings, including in emergent settings as a means of rapid preparation in place of current more time-consuming standard protocols, allowing time-critical management to be effected. [ABSTRACT FROM AUTHOR]

Breast cancer is a public health concern worldwide, characterized by increasing incidence and mortality rates, requiring novel and effective therapeutic strategies. Curcumin is a bioactive compound extracted from turmeric with several pharmacological activities. Curcumin is a multifaceted anticancer agent through mechanisms including the modulation of signaling pathways, inhibition of cell proliferation, induction of apoptosis, and production of reactive oxygen species. However, the poor water solubility and bioavailability of curcumin create important barriers in its clinical application. This review elaborates on the therapeutic potential of curcumin in breast cancer treatment, focusing on the efficacy of different administration routes and synergistic effects with other therapeutic agents. The intravenous administration of curcumin-loaded nanoparticles significantly improves bioavailability and therapeutic outcomes compared to oral routes. Innovative formulations, such as nano-emulsifying drug delivery systems, have shown promise in enhancing oral bioavailability. While intravenous delivery ensures higher bioavailability and direct action on tumor cells, it is more invasive and expensive than oral administration. Advancing research on curcumin in breast cancer treatment is essential for improving therapeutic outcomes and enhancing the quality of life of patients. [ABSTRACT FROM AUTHOR]

This meta-analysis aimed to evaluate the effects of intracoronary (IC) low-dose tirofiban versus intravenous (IV) administration on clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). All published randomised controlled trials (RCTs) comparing the effects of IC low-dose tirofiban (a bolus of ≤10 ug/kg) versus IV administration in patients with STEMI were identified by searching PubMed, EMBASE, Cochrane Library, and ISI Web of Science from inception to June 2023, with no language restriction. The risk ratio (RR) with 95% confidence intervals (CI) and the weighted mean difference (WMD) with 95% CI were calculated. Eleven RCTs involving 1,802 patients were included. Compared with the IV group, IC low-dose tirofiban was associated with improved major adverse cardiac events rate (RR 0.595, 95% CI 0.442–0.802; p=0.001), left ventricular ejection fraction (WMD 1.982, 95% CI 0.565–3.398; p=0.006), thrombolysis in myocardial infarction (TIMI) flow grade (RR 1.065, 95% CI 1.004–1.131; p=0.037), and TIMI myocardial perfusion grade (RR 1.194, 95% CI 1.001–1.425; p=0.049). The two groups had no significant difference in bleeding events (RR 0.952, 95% CI 0.709–1.279; p=0.745). Intracoronary low-dose tirofiban administration may be a safe and effective alternative to IV administration in STEMI patients. [ABSTRACT FROM AUTHOR]

Objective: The safety, feasibility, and potential functional improvement following the intravenous infusion of mesenchymal stem cells (MSCs) were investigated in patients with chronic severe spinal cord injury (SCI). Methods: The intravenous infusion of autologous MSCs cultured in auto-serum under Good Manufacturing Practices (GMP) was administered to seven patients with chronic SCI (ranging from 1.3 years to 27 years after the onset of SCI). In addition to evaluating feasibility and safety, neurological function was evaluated using the American Spinal Injury Association Impairment Scale (AIS), International Standards for Neurological Classification of Spinal Cord Injury (ISCSCI-92), and Spinal Cord Independence Measure III (SCIM-III). Results: No serious adverse events occurred. Neither CNS tumors, abnormal cell growth, nor neurological deterioration occurred in any patients. While this initial case series was not blinded, significant functional improvements and increased quality of life (QOL) were observed at 90 and 180 days post-MSC infusion compared to pre-infusion status. One patient who had an AIS grade C improved to grade D within six months after MSC infusion. Conclusions: This case series suggests that the intravenous infusion of autologous MSCs is a safe and feasible therapeutic approach for chronic SCI patients. Furthermore, our data showed significant functional improvements and better QOL after MSC infusion in patients with chronic SCI. A blind large-scale study will be necessary to fully evaluate this possibility. [ABSTRACT FROM AUTHOR]

Background Antibiotic overuse leads to the emergence of antibiotic resistance that threatens immunocompromised cancer patients. Infections caused by MDR Gram-negative pathogens are difficult to treat and associated with high mortality. Hence, empirical therapy with standard-of-care (SOC) antibiotics could be suboptimal in these vulnerable patients. New antibiotics covering potential resistant pathogens may be considered. Methods We conducted a randomized non-inferiority study comparing safety and efficacy of imipenem/cilastatin/relebactam (IPM/REL), a β-lactam/β-lactamase inhibitor combination, with SOC antibiotics (cefepime, piperacillin/tazobactam or meropenem) in cancer patients with febrile neutropenia. Patients received at least 48 h of IV antibiotics and were assessed at end-of-IV (EOIV) therapy, test of cure (TOC; Days 21–28), and late follow-up (LFU; Days 35–42). Results A total of 100 patients were enrolled (49 IPM/REL and 50 SOC). Demographics and rates of documented microbiological infections were similar in both groups. In the SOC arm, 86% of antibiotics consisted of cefepime. Patients on IPM/REL had a higher favourable clinical response at EOIV than those on SOC (90% versus 74%; P  = 0.042); however, responses were similar at TOC and LFU. Microbiological eradication was comparable at all three timepoints. Study drug-related adverse events and adverse events leading to drug discontinuation were similar in both groups, with no study drug-related mortality. Conclusions Our results suggest that compared with SOC antibiotics, predominantly cefepime, IPM/REL for empirical coverage of febrile neutropenia in cancer patients is generally safe and could be associated with a better clinical outcome at EOIV. The current SOC consisting mainly of agents that do not cover for ESBL-producing and carbapenem-resistant Enterobacterales bacteria should be reconsidered. [ABSTRACT FROM AUTHOR]

Simple Summary: There is no literature that compares the clinical outcomes between intraperitoneal chemotherapy without bevacizumab and triweekly intravenous chemotherapy plus bevacizumab. The aim of this study was to elucidate whether, in the frontline treatment of advanced ovarian, fallopian tube and primary peritoneal cancer, intraperitoneal cisplatin/paclitaxel chemotherapy without bevacizumab will confer an improved survival benefit when compared with the combination of triweekly intravenous carboplatin/paclitaxel chemotherapy and bevacizumab. We found that intraperitoneal chemotherapy without bevacizumab is associated with better survival when compared with intravenous chemotherapy with bevacizumab. Objectives: To compare the clinical outcomes of intravenous carboplatin/paclitaxel chemotherapy plus bevacizumab versus intraperitoneal cisplatin/paclitaxel chemotherapy without bevacizumab as the frontline treatment in women with advanced ovarian, fallopian tube and primary peritoneal cancer. Methods: Between November 2012 and January 2024, medical records of all consecutive women with stage II~IV cancer treated with either frontline adjuvant intraperitoneal cisplatin/paclitaxel without bevacizumab (IP group), intravenous carboplatin/paclitaxel without bevacizumab (IV group) or intravenous carboplatin/paclitaxel with bevacizumab (IVB group) at a tertiary referral center were reviewed. Results: A total of 143 women (IP group, n = 57; IVB group, n = 23; IV group, n = 63) were reviewed. The IP group had greater progression-free survival compared to the IVB group (49.1 months, 95% confidence interval [CI] = 27.8 months to infinity, versus 11.9 months, 95% CI = 11.2 to 16.2 months; adjusted hazard ratio [HR] = 0.45, 95% CI = 0.24 to 0.87, p = 0.017). Additionally, the IP group also had a higher overall survival compared to the IVB group (not reached, 95% CI = 55.6 months to infinity, versus 38.9 months, 95% CI = 21.9 months to infinity; adjusted HR = 0.34, 95% CI = 0.15 to 0.79, p = 0.012). Conclusions: Intraperitoneal cisplatin/paclitaxel chemotherapy without bevacizumab seems to offer a survival advantage when compared with intravenous carboplatin/paclitaxel with bevacizumab in the frontline treatment of women with advanced ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Parenteral artesunate is the first-line therapy for severe malaria. Artesunate, in its current formulation, must be prepared immediately before administration by first dissolving in sodium bicarbonate solution and then diluting in saline. A novel solvent for rapid and stable single step reconstitution of artesunate was recently developed showing improved solubility and stability. This study aimed to compare the safety and pharmacokinetic properties of the currently available and newly developed parenteral formulation of artesunate in healthy Thai volunteers. Methods: This was an open-label, randomized, 4 periods, 4-treatments, 24-sequence, single-dose, cross-over study in 72 male and female healthy Thai volunteers. Frequent pharmacokinetic samples were collected in all volunteers at each dose occasion. Observed concentration–time profiles were analysed with a non-compartmental approach followed by a bioequivalence evaluation. Results: Both intramuscular and intravenous administrations of the new parenteral formulation of artesunate were safe and well-tolerated, with no additional safety signals compared to the currently used formulation. The pharmacokinetic properties of artesunate and its active metabolite, dihydroartemisinin, were well-characterized, and showed rapid conversion of artesunate into dihydroartemisinin. Intramuscular administration of the newly formulated artesunate resulted in almost complete bioavailability of dihydroartemisinin. The pharmacokinetic properties were similar between the old and new formulation. Conclusions: The new and more easily prepared formulation of artesunate was safe and well-tolerated, with similar pharmacokinetic properties compared to the currently used formulation. Dihydroartemisinin, the active metabolite responsible for the majority of the anti-malarial effect, showed equivalent exposure after both intravenous and intramuscular administration of artesunate, suggesting that both routes of administration should generate comparable therapeutic effects. Trial registration: The study was registered to clinicaltrials.gov (#TCTR20170907002). [ABSTRACT FROM AUTHOR]

Introduction: Following NOVA (part 1) and the approval of the subcutaneous (SC) route of administration of natalizumab by the European Medicines Agency, an extension phase of the NOVA phase IIIb study (part 2) was initiated to collect patient preference data for SC versus intravenous (IV) dosing in patients receiving every-6-week (Q6W) dosing of natalizumab. This study was performed to evaluate patient preference for SC versus IV natalizumab administration and explore the efficacy, safety, and pharmacology characteristics of both routes of administration. Methods: In part 2, participants received natalizumab (Tysabri®) 300 mg via IV infusion Q6W for 36 weeks and then were randomized to 48 weeks of crossover treatment (24 weeks SC Q6W and 24 weeks IV Q6W, or vice versa). The primary endpoint was the proportion of participants who indicated a preference for natalizumab SC administration on the Patient Preference Questionnaire. Results: A total of 153 participants were randomized in NOVA part 2. Of 123 with patient preference data, 108 (87.8%) preferred the SC route of administration for natalizumab over the IV route; 102 (82.9%) specified "requires less time in the clinic" as the reason for the SC preference. Conclusion: In NOVA (part 2), most participants on Q6W dosing of natalizumab preferred SC administration versus IV administration. ClinicalTrials.gov: NCT03689972. Infographic: [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is a global concern, with Peru experiencing a high incidence and mortality. Trastuzumab, a crucial treatment for human epidermal growth factor receptor 2-positive BC, is administered intravenously or subcutaneously (SC). This study evaluates the costs associated with both methods at Peru's Instituto Nacional de Enfermedades Neoplásicas. Real data indicate that SC administration reduces treatment costs by approximately S/15,049.09. Cross-continental comparisons highlight a global trend favouring SC administration for efficiency and cost-effectiveness. The analysis provides insights for informed decision-making in resource-constrained healthcare settings like Peru, emphasising the need to consider local contexts in optimising oncology care. [ABSTRACT FROM AUTHOR]

Background/Objective: Intravenous fluid shortages have led to fluid-sparing measures such as intravenous push (IVP) administration of antibiotics. This study aimed to compare the safety and efficacy of IVP and intravenous piggyback (IVPB) ceftriaxone in critically ill patients. Results: Demographics were similar in IVP (n = 201) and IVPB (n = 200) groups. Sequential Organ Failure Assessment (SOFA) score was higher, and sepsis and septic shock were more common in the IVP group. Treatment failure occurred in 37.8% of IVP and 19.5% of IVPB groups (p < 0.001). Hospital mortality was more common with IVP (21.4% vs. 9.5%, p < 0.001). Hospital LOS was longer with IVP while intensive care unit (ICU) LOS was similar between the groups. IVP ceftriaxone (OR 2.33, 95% CI 1.43–3.79) and the SOFA score (OR 1.18, 95% CI 1.1–1.27) were associated with treatment failure. Methods: A single-center, retrospective cohort study included adults admitted to an ICU from 2016 to 2021 who received empiric ceftriaxone for ≥72 h. The primary outcome was treatment failure, defined as a composite of inpatient mortality or escalation of antibiotics. Secondary outcomes included length of stay (LOS) and mortality. Chi-squared and independent-sample t-tests were used. Treatment failure was evaluated using multivariate logistic regression. Conclusions: Compared to IVPB, IVP ceftriaxone was associated with higher treatment failure in critically ill patients. Both safety and efficacy should be considered before implementing novel antibiotic administration strategies in practice based primarily on convenience. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the impact of acute intravenous beta-blocker administration on myocardial blood flow (MBF) during same-day hybrid coronary computed tomography angiography (CCTA) and 13N-ammonia positron emission tomography (PET) myocardial perfusion imaging (MPI). Previous research on the discontinuation of oral beta-blockers before MPI has shown mixed results, with no studies yet exploring the acute intravenous administration in the context of same-day hybrid imaging. This retrospective study included patients with suspected chronic coronary syndromes undergoing same-day hybrid CCTA/13N-ammonia PET MPI. Exclusion criteria comprised coronary artery stenosis ≥ 50% or regional perfusion abnormalities on PET, and baseline oral beta-blocker medication. Intravenous metoprolol (up to 30 mg) was administered as needed for heart rate control before CCTA. MBF measurements were obtained at rest (rMBF) and during stress (sMBF), and myocardial flow reserve (MFR) was calculated. After excluding 281 patients, 154 were eligible for propensity-score matching, resulting in 108 patients divided into two equal groups based on beta-blocker administration. The groups showed no significant differences in baseline characteristics. Among those who received beta-blockers, there was a significant decrease in sMBF (2.21 [IQR 1.72–2.78] versus 2.46 [2.08–2.99] ml∙min−1∙g−1, p = 0.027) and MFR (3.46 [2.70–4.05] versus 3.79 [3.22–4.46], p = 0.030), respectively, compared to those who did not receive beta-blockers. In contrast, rMBF remained unaffected (0.65 [0.54–0.78] versus 0.64 [0.55–0.76] ml∙min−1∙g−1, p = 0.931). Acute intravenous beta-blocker administration significantly impacts MBF, leading to a slight reduction in sMBF and MFR. In contrast, rMBF appears unaffected, suggesting that beta-blockers primarily affect the coronary capacity to respond to vasodilators. [ABSTRACT FROM AUTHOR]

Highly efficient adeno associated viruses (AAVs) targeting the central nervous system (CNS) are needed to deliver safe and effective therapies for inherited neurological disorders. The goal of this study was to compare the organ-specific transduction efficiencies of two AAV capsids across three different delivery routes. We compared AAV9-CBA-fLucYFP to AAV-DJ-CBA-fLucYFP using the following delivery routes in mice: intracerebroventricular (ICV) 1 × 1012 vg/kg, intrathecal (IT) 1 × 1012 vg/kg, and intravenous (IV) 1 × 1013 vg/kg body weight. Our evaluations revealed that following ICV and IT administrations, AAV-DJ demonstrated significantly increased vector genome (vg) uptake throughout the CNS as compared to AAV9. Through the IV route, AAV9 demonstrated significantly increased vg uptake in the CNS. However, significantly fewer vgs were detected in the off-target organs (kidney and liver) following administration of AAV-DJ using the IT and IV delivery routes as compared to AAV9. Distributions of vgs correlate well with transgene transcript levels, luciferase enzyme activities, and immunofluorescence detection of YFP. Overall, between the two vectors, AAV-DJ resulted in better targeting and expression in CNS tissues paired with de-targeting and reduced expression in liver and kidneys. Our findings support further examination of AAV-DJ as a gene therapy capsid for the treatment of neurological disorders. [ABSTRACT FROM AUTHOR]

Introduction: Globally, there have been significant declines in HIV incidence over the past two decades, but this decline is slowing, and in some settings, declines have stalled or are growing—particularly where epidemics are concentrated in key populations (KPs). Understanding temporal changes in HIV incidence among KP is critical yet, due to logistical constraints, there are few sources of longitudinal incidence data, particularly among KP. Methods: We present HIV incidence rates from June 2014 to December 2022 among cisgender men who have sex with men (MSM) and people who inject drugs (PWID) attending community‐based integrated care centres (ICCs) in 15 Indian cities. ICCs, established between 2014 and 2017, provide HIV testing and other services to MSM (eight sites) or PWID (eight sites). Client HIV testing data were included in the analysis if they had ≥2 tests and were not positive on the first test. We calculated incidence rates per 100 person‐years (PY), stratified by KP, city/site and year. Poisson regression explored associations of incidence with time, age, gender (PWID only) and ICC use. Results: From June 2014 to December 2022, 13,501 clients (5722 MSM, 7779 PWID) had ≥2 HIV tests over a median of 1.8 years. There were a total of 1093 incident HIV acquisitions. Overall incidence rates for MSM and PWID were 1.9/100 PY (95% CI: 1.7−2.2) and 4.1 (3.9−4.4), respectively. Among MSM sites, incidence ranged from 0.4 to 3.5 and in PWID sites from 0.6 to 17.9. From adjusted models, incidence increased by 17% annually among MSM. Among PWID, incidence increased by 11% annually up until 2020 and then decreased by 29% after 2020; when excluding the outlier of New Delhi, incidence was stable among PWID. MSM and PWID 21−25 years old had the highest risk of HIV and among PWID, those more consistently engaged in medication for opioid use disorder were at the lowest risk. Conclusions: While there was substantial geographic variability, MSM and PWID engaged in a free community‐based clinic experienced persistently high HIV incidence (>2/100 PY). KP in low‐ and middle‐income countries should be a focus when considering novel strategies such as long‐acting pre‐exposure prophylaxis to curtail incidence. [ABSTRACT FROM AUTHOR]

These toxicity studies aimed to assess the safety and tolerability of a novel intravenous diclofenac sodium (37.5 mg/mL) formulation containing povidone K12 (80 mg/mL) as the key excipient in Wistar rats. This formulation was tested at doses of 3, 7, and 15 mg/kg/day and was administered daily for 28 days by intravenous route. Toxicokinetic estimation revealed a dose-proportional increase in plasma exposure to diclofenac. The formulation was well tolerated in males; however, mortality was observed in females (2/15) at the highest dose (15 mg/kg/day). Adverse gastrointestinal events related to NSAIDS and a few other treatment-related effects on clinical and anatomic pathology were noted at the 15 mg/kg/day dose, which normalized at the end of the 2-week recovery period. In addition, the excipient povidone K12 was present in a higher amount than the approved Inactive Ingredient Database (IID) limit in the proposed novel formulation. It was qualified through a separate 28-day repeated dose toxicity study by intravenous route in Wistar rats. Povidone K12 was found to be well tolerated and safe up to a dose of 165 mg/kg/day. No treatment-related adverse effects were observed in this study. In conclusion, repeated administration of a novel intravenous formulation containing diclofenac sodium was found to be safe up to the dose of 7 mg/kg/day in female rats and 15 mg/kg/day in male rats. [ABSTRACT FROM AUTHOR]

Simple Summary: Menbutone is a drug that increases hepato-digestive secretions and has been used for more than 50 years in Europe to treat a wide number of digestive disorders in livestock and dogs. However, despite this use, little is known about its pharmacokinetics, more specifically in cattle. This work contributes to a better knowledge of the pharmacokinetics of menbutone when administered intravenously and intramuscularly to cattle (12 Holstein calves), being the first study to describe it in this animal species. After intravenous administration, the drug showed a moderate volume of distribution and a fast elimination from the body. After intramuscular administration, menbutone exhibited quick and high absorption. Menbutone is a choleretic agent currently used in Europe to treat digestive disorders in livestock and dogs. Pharmacokinetic parameters were established in 4-month Holstein calves after intravenous (IV) and intramuscular (IM) administration. The drug was administered to 12 animals (10 mg/kg) for both IV and IM routes following a crossover design. Plasma samples were collected at various time points over 24 h and analyzed by reverse-phase high-performance liquid chromatography with a photodiode-array detector, following a method validated according to European Medicines Agency guidelines. Pharmacokinetic parameters were calculated using compartmental and non-compartmental methods. Menbutone followed a two-compartment open model after IV injection, with a total clearance (Cl) of 71.9 ± 13.5 mL/h/kg, an elimination half-life (t½β) of 4.53 ± 2.45 h, and a volume of distribution at steady-state (Vss) of 310.4 ± 106.4 mL/kg. Non-compartmental elimination half-life (t½λ) was 4.2 ± 1.1 h. After IM administration, drug pharmacokinetics was best described by a one-compartment open model. The peak plasma concentration (Cmax) was 15.1 ± 4.3 µg/mL; the time to reach Cmax (tmax), 1.66 ± 0.55 h; and the mean absorption time (MAT), 2.50 ± 1.42 h. Absorption was high, with a fraction of the dose absorbed (F) of 83.5 ± 22.4%. Menbutone was rapidly eliminated from plasma for both routes of administration, with a fast and high IM bioavailability. [ABSTRACT FROM AUTHOR]

To determine the pharmacokinetics and physiological effects following oral and intravenous (IV) administration of gabapentin in goats. Prospective, crossover study with a 3 week washout period between treatments. A total of eight healthy, client-owned, female goats. Gabapentin (10 mg kg–1) was administered to goats either orally or IV. Gabapentin concentrations were measured in serum samples collected 0–96 hours post-administration using liquid chromatography–quadrupole time-of-flight mass spectrometry. Heart rate, respiratory rate, blood pressure and temperature were recorded before and throughout the study. Correlations of the mean serum concentrations of gabapentin to those of each physiological parameter were determined using the Pearson method. The mean and standard deviation of oral bioavailability for gabapentin was 60.9 ± 11.2%. Maximum serum concentration of gabapentin was lower following oral (1.19 ± 0.29 μg mL–1) than after IV administration (59.76 ± 14.38 μg mL–1, p < 0.0001). Half-lives were longer following PO (8.18 ± 0.57 hours) than after IV administration (1.79 ± 0.06 hours, p < 0.0001). Time to maximum concentration was 6.86 ± 2.27 hours following oral administration. Heart rate was inversely correlated with serum gabapentin concentrations. Slight ataxia was observed in three animals, and one became recumbent following IV gabapentin. Gabapentin is well-absorbed following oral administration to goats but yielded significantly lower serum concentrations than the IV route. The longer half-life of gabapentin following oral than after IV administration may result from prolonged absorption throughout the caprine gastrointestinal tract. IV gabapentin may cause slight ataxia in some goats. [ABSTRACT FROM AUTHOR]

Intravenous fluids are commonly prescribed to children in hospitals. However, there are risks associated with their use. In order to safely prescribe these clinicians should understand the indications for their use, the principles underpinning their use and know the likely complications associated with intravenous fluid administration in children. Intravenous fluids should be prescribed depending on individual needs of each child and with careful monitoring and re-assessment. This review aims to provide a general approach to fluid prescription in children, providing some background of different physiological principles, different fluid composition, and the role of anti-diuretic hormone in fluid homeostasis. Fluid prescription is discussed, with an approach taking into consideration resuscitation boluses, dehydration, replacing ongoing losses and maintenance requirements. Case examples are provided to further facilitate readers' comprehension. Electrolyte abnormalities and an approach to the management of deranged electrolytes is addressed. Complications associated with fluid administration are highlighted, in particular, emphasizing the assessment and emergency management of the child with suspected cerebral oedema or hyponatraemic encephalopathy. Special consideration and discussion is given to the differing approach to fluid management of children in the setting of burns or diabetic ketoacidosis. [ABSTRACT FROM AUTHOR]

BackgroundNeedle and syringe programs (NSPs) are effective at preventing HIV and hepatitis C virus (HCV) among people who inject drugs (PWID), yet global coverage is low, partly because governments lack data on the cost and cost-effectiveness of NSP in their countries to plan and fund their responses. We conducted a global systematic review of unit costs of NSP provision to inform estimation of cost drivers and extrapolated costs to other countries.MethodsWe conducted a systematic review to extract data on the cost per syringe distributed and its cost drivers. We estimated the impact of country-level and program-level variables on the cost per syringe distributed using linear mixed-effects models. These models were used to predict unit costs of NSP provision, with the best performing model used to extrapolate the cost per syringe distributed for 137 countries. The total cost for a comprehensive NSP (200 syringes per PWID/year) was also estimated for 68 countries with PWID population size estimates.ResultsWe identified 55 estimates of the unit cost per syringe distributed from 14 countries. Unit costs were extrapolated for 137 countries, ranging from $0.08 to $20.77 (2020 USD) per syringe distributed. The total estimated spend for a high-coverage, comprehensive NSP across 68 countries with PWID size estimates is $5 035 902 000 for 10 887 500 PWID, 2.1-times higher than current spend.ConclusionOur review identified cost estimates from high-income, upper-middle-income, and lower-middle-income countries. Regression models may be useful for estimating NSP costs in countries without data to inform HIV/HCV prevention programming and policy.

Abstract Background Parenteral artesunate is the first-line therapy for severe malaria. Artesunate, in its current formulation, must be prepared immediately before administration by first dissolving in sodium bicarbonate solution and then diluting in saline. A novel solvent for rapid and stable single step reconstitution of artesunate was recently developed showing improved solubility and stability. This study aimed to compare the safety and pharmacokinetic properties of the currently available and newly developed parenteral formulation of artesunate in healthy Thai volunteers. Methods This was an open-label, randomized, 4 periods, 4-treatments, 24-sequence, single-dose, cross-over study in 72 male and female healthy Thai volunteers. Frequent pharmacokinetic samples were collected in all volunteers at each dose occasion. Observed concentration–time profiles were analysed with a non-compartmental approach followed by a bioequivalence evaluation. Results Both intramuscular and intravenous administrations of the new parenteral formulation of artesunate were safe and well-tolerated, with no additional safety signals compared to the currently used formulation. The pharmacokinetic properties of artesunate and its active metabolite, dihydroartemisinin, were well-characterized, and showed rapid conversion of artesunate into dihydroartemisinin. Intramuscular administration of the newly formulated artesunate resulted in almost complete bioavailability of dihydroartemisinin. The pharmacokinetic properties were similar between the old and new formulation. Conclusions The new and more easily prepared formulation of artesunate was safe and well-tolerated, with similar pharmacokinetic properties compared to the currently used formulation. Dihydroartemisinin, the active metabolite responsible for the majority of the anti-malarial effect, showed equivalent exposure after both intravenous and intramuscular administration of artesunate, suggesting that both routes of administration should generate comparable therapeutic effects. Trial registration: The study was registered to clinicaltrials.gov (#TCTR20170907002).

Abstract Highly efficient adeno associated viruses (AAVs) targeting the central nervous system (CNS) are needed to deliver safe and effective therapies for inherited neurological disorders. The goal of this study was to compare the organ-specific transduction efficiencies of two AAV capsids across three different delivery routes. We compared AAV9-CBA-fLucYFP to AAV-DJ-CBA-fLucYFP using the following delivery routes in mice: intracerebroventricular (ICV) 1 × 1012 vg/kg, intrathecal (IT) 1 × 1012 vg/kg, and intravenous (IV) 1 × 1013 vg/kg body weight. Our evaluations revealed that following ICV and IT administrations, AAV-DJ demonstrated significantly increased vector genome (vg) uptake throughout the CNS as compared to AAV9. Through the IV route, AAV9 demonstrated significantly increased vg uptake in the CNS. However, significantly fewer vgs were detected in the off-target organs (kidney and liver) following administration of AAV-DJ using the IT and IV delivery routes as compared to AAV9. Distributions of vgs correlate well with transgene transcript levels, luciferase enzyme activities, and immunofluorescence detection of YFP. Overall, between the two vectors, AAV-DJ resulted in better targeting and expression in CNS tissues paired with de-targeting and reduced expression in liver and kidneys. Our findings support further examination of AAV-DJ as a gene therapy capsid for the treatment of neurological disorders.

Purpose: Corticosteroids are widely used in total knee arthroplasty (TKA) to ameliorate post-operative pain. This study compared the effects of intravenous administration (IVA) and periarticular injection (PAI) of dexamethasone on pain, nausea, and blood glucose levels following TKA. Methods: An institutional database was used to retrospectively examine two cohorts of patients who had undergone unilateral TKA from August 2018 to September 2020. The IVA group (n ​= ​50) received 10 ​mg dexamethasone 1 ​h before surgery and 24 ​h after surgery. The PAI group (n ​= ​50) received 10 ​mg dexamethasone during surgery. Pain scores at rest and during walking as well as nausea scores were recorded using the 0–10 numerical rating scale after surgery. Fasting blood glucose (FBG) levels were measured post-operatively. Results: A total of 100 patients were enrolled (mean age, 71 years; 86% female). The rest pain score 24 ​h post-operatively was significantly lower in the PAI group than in the IVA group (3.3 vs. 4.3; absolute difference 1.0, 95% confidence interval, 0.4–1.3; P ​= ​0.007). The nausea score did not differ markedly between groups. FBG was significantly higher in the PAI group than in the IVA group in the morning of post-operative Day 1. Conclusion: PAI with dexamethasone was found to control pain more effectively at 24 ​h than IVA. FBG on the morning of post-operative Day 1 was significantly higher in the PAI group. Level of evidence, III; retrospective cohort.

BACKGROUND: Drug injection is a major health-related problem worldwide. Injection cessation and relapse to injection could significantly alter the risk of HIV and hepatitis C virus (HCV) among people who inject drugs (PWID). This study aimed to estimate the rate of injection cessation and relapse to injection among PWID in Iran. METHODS: This cohort study was conducted from 2018 to 2021 in the cities of Kerman and Tehran. Using a respondent-driven sampling (RDS) approach, 118 PWID with a history of injection in the last six months and negative HIV and HCV tests were recruited. Follow-up visits occurred every three months over a period of one year. Participants were interviewed and tested for HIV and HCV using rapid tests. Injection cessation was defined as the no injection of any type of drugs in the last three months. Relapse to injection was defined as re-initiating drug injection among those who had ceased injection. Two separate Cox regression models were applied, and an adjusted hazard ratio (aHR) with a 95% confidence interval (CI) were measured to assess the factors associated with each outcome. RESULTS: The rate of injection cessation was 26.1 (95% CI: 21.3, 32.0) per 100 person-years, and the rate of relapse to injection was 32.7 (95% CI: 24.7, 43.2) per 100 person-years. At the baseline interview, 39.8% (n = 47) of participants reported injection cessation in the past three months before the interview. In the multivariable Cox regression analysis, the rate of relapse to injection was greater among women (aHR = 1.58; 95% CI: 1.01, 2.52), and those with higher monthly income (aHR = 1.63; 95% CI: 1.03, 2.59). However, there was no significant variable that predicted injection cessation. CONCLUSION: Injection cessation was common among PWID in Iran, however, one-third relapsed to injection shortly after cessation. Harm reduction programs should include comprehensive strategies to reduce the probability of relapse among PWID who achieve injection cessation.

UNLABELLED: BCMA-targeted bispecific antibodies (BiAb) are efficacious in relapsed/refractory multiple myeloma; however, serious infections have emerged as important toxicities. In this retrospective study, we characterized all infections and their risk factors, and evaluated the impact of infection prophylaxis in patients treated with BCMA-targeted BiAbs. Among 37 patients, 15 (41%) experienced a grade 3-5 infection, with two infection-related deaths during deep remissions. Most (84%) infections occurred during disease remissions. The cumulative probability of grade 3-5 infection increased over time with no plateau. Among responders (n = 26), profound hypogammaglobulinemia occurred in 100% and continued throughout the entire duration of treatment. During periods when patients were receiving intravenous immunoglobulin (IVIg), the rate of grade 3-5 infections was 90% lower than during observation (incidence rate ratio, 0.10; 95% confidence interval, 0.01-0.80; P = 0.0307). No other risk factors for infection were identified. This study demonstrates that profound hypogammaglobulinemia is universal with BCMA-targeted BiAbs, with intravenous immunoglobulin potentially abrogating most of the infection risk. SIGNIFICANCE: To the best of our knowledge, this is the first study to comprehensively analyze risk factors and mitigation strategies to prevent infections in myeloma patients receiving anti-BCMA bispecific antibodies. Profound and prolonged hypogammaglobulinemia was universal among responders, while immunoglobulin replacement was associated with 90% lower rates of grade 3-5 infections. See related commentary by Garfall and Stadtmauer, p. 427 . This article is featured in Selected Articles from This Issue, p. 419.

PURPOSE: To assess the pharmacokinetics (PK) of subcutaneous immunoglobulin (SCIG) and hyaluronidase-facilitated SCIG (fSCIG) therapy across body mass index (BMI) and age categories in patients with primary immunodeficiency diseases (PIDD) previously treated with intravenous immunoglobulin (IVIG). METHODS: Using our previously published integrated population PK model based on data from eight clinical trials, simulations were conducted to examine the effects of BMI and age on serum immunoglobulin G (IgG) PK after administration of SCIG 0.15 g/kg weekly or fSCIG 0.6 g/kg every 4 weeks in patients switching from stable IVIG. Patients were assumed to have baseline IgG trough concentrations of 7 g/L (hypothetical protective threshold). RESULTS: Mean steady-state serum IgG trough values (Cmin,ss or trough) increased with BMI and age. Mean Cmin,ss was 18% (SCIG) and 16% (fSCIG) higher in the obese than the healthy BMI group. Pediatric patients aged

BACKGROUND: Most people who inject drugs (PWID) in Iran have not undergone recent HIV testing. While PWID face barriers when seeking HIV testing at health facilities, HIV self-testing (HIVST) could be a promising approach to improve HIV testing uptake. We examined the awareness and willingness to use HIVST among PWID in Iran. We also identified participants characteristics associated with a higher willingness to use HIVST. METHODS: PWID were recruited in 11 cities using a respondent-driven sampling method. Willingness to use HIVST was defined as a binary variable (very low/low willingness vs. high/very high willingness). We performed multivariable modified Poisson regression to examine associated factors and report adjusted prevalence ratios (aPR) and 95% confidence intervals (CI). RESULTS: Of 2,252 PWID, 362 (16.2%; 95% CI 14.7, 17.8) had ever heard of HIVST; however, 1,658 (73.6%; 95% CI 71.7, 75.4) reported high/very high willingness to use HIVST. Willingness to use HIVST was higher among PWID who reported having a high/moderate HIV risk perception (aPR 1.22; 95% CI 1.09, 1.37), ever experiencing homelessness (aPR 1.15; 95% CI 1.03, 1.28), > 10 years of injecting history (aPR 1.16; 95% CI 1.00, 1.34), and high injection frequency in the last three months (aPR 1.18; 95% CI 1.05, 1.32). CONCLUSION: Most PWID in Iran, particularly those experiencing homelessness, have a longer injecting history, engage in more frequent injection practices, and possess a heightened perception of HIV risk would be willing to adopt HIVST. Enhancing HIVST awareness through increased access to HIVST and health education programs are needed. Additionally, conducting implementation science studies to effectively design and run HIVST programs in Iran can also increase PWIDs access to HIV testing.

BACKGROUND: Although Kawasaki disease is commonly regarded as a single disease entity, variability in clinical manifestations and disease outcome has been recognised. We aimed to use a data-driven approach to identify clinical subgroups. METHODS: We analysed clinical data from patients with Kawasaki disease diagnosed at Rady Childrens Hospital (San Diego, CA, USA) between Jan 1, 2002, and June 30, 2022. Patients were grouped by hierarchical clustering on principal components with k-means parcellation based on 14 variables, including age at onset, ten laboratory test results, day of illness at the first intravenous immunoglobulin infusion, and normalised echocardiographic measures of coronary artery diameters at diagnosis. We also analysed the seasonality and Kawasaki disease incidence from 2002 to 2019 by subgroup. To explore the biological underpinnings of identified subgroups, we did differential abundance analysis on proteomic data of 6481 proteins from 32 patients with Kawasaki disease and 24 healthy children, using linear regression models that controlled for age and sex. FINDINGS: Among 1016 patients with complete data in the final analysis, four subgroups were identified with distinct clinical features: (1) hepatobiliary involvement with elevated alanine transaminase, gamma-glutamyl transferase, and total bilirubin levels, lowest coronary artery aneurysm but highest intravenous immunoglobulin resistance rates (n=157); (2) highest band neutrophil count and Kawasaki disease shock rate (n=231); (3) cervical lymphadenopathy with high markers of inflammation (erythrocyte sedimentation rate, C-reactive protein, white blood cell, and platelet counts) and lowest age-adjusted haemoglobin Z scores (n=315); and (4) young age at onset with highest coronary artery aneurysm but lowest intravenous immunoglobulin resistance rates (n=313). The subgroups had distinct seasonal and incidence trajectories. In addition, the subgroups shared 211 differential abundance proteins while many proteins were unique to a subgroup. INTERPRETATION: Our data-driven analysis provides insight into the heterogeneity of Kawasaki disease, and supports the existence of distinct subgroups with important implications for clinical management and research design and interpretation. FUNDING: US National Institutes of Health and the Irving and Francine Suknow Foundation.

N,N-dimethyltryptamine (DMT) is a psychedelic compound that is being studied as a therapeutic option in various psychiatric disorders. Due to its short half-life, continuous infusion of DMT has been proposed to extend the psychedelic experience and potential therapeutic effects. The primary aim of this work was to design an infusion protocol for DMT based on a desired level of psychedelic intensity using population pharmacokinetic/pharmacodynamic modeling. As a secondary aim, the impact of choosing a continuous variable or a bounded integer pharmacokinetic/pharmacodynamic model to inform such an infusion protocol was investigated. A previously published continuous variable model and two newly developed bounded integer models were used to assess optimal doses for achieving a target response. Simulations were performed to identify an optimal combination of a bolus dose and an infusion rate. Based on the simulations, optimal doses to achieve intensity ratings between 7 and 9 (possible range = 0-10) were a bolus dose of 16 mg DMT fumarate followed by an infusion rate of 1.4 mg/min based on the continuous variable model and 14 mg with 1.2 mg/min for the two bounded integer models. However, the proportion within target was low (

BackgroundMultiple HIV outbreaks among people who inject drugs (PWIDs) have occurred in the USA since 2015, highlighting the need for additional HIV prevention tools. Despite high levels of need, pre-exposure prophylaxis (PrEP) is drastically underutilized among PWIDs. Implicit bias toward PWID held by clinicians may impede PrEP scale-up among these underserved patients. This study examined how primary care providers' (PCPs) clinical decisions related to PrEP can be impacted by biases when the patient has a history of substance use.MethodsWe conducted an online survey of PCPs (n = 208). The survey included the implicit association test (IAT) to assess unconscious attitudes toward PWIDs, direct questions regarding clinicians' explicit PWID attitudes, and an embedded experiment in which we systematically varied the risk behavior of a hypothetical patient and asked PCPs to make clinical judgments.ResultsA minority (32%) of PCPs reported explicit PWID bias. The IAT indicated strong implicit PWID bias (meant IAT score = 0.59, p

ObjectiveChildren with Kawasaki disease (KD) and an initial echocardiogram that demonstrates coronary artery aneurysms (CAAs, Z score ≥2.5) are at high risk for severe cardiovascular complications. We sought to determine if primary adjunctive infliximab treatment at a dose of either 5 or 10 mg/kg, compared with intravenous immunoglobulin (IVIG) alone, is associated with a greater likelihood of CAA regression in patients with KD with CAA at the time of diagnosis.Design and settingSingle-centre observational study.PatientsChildren with acute KD and Z score ≥2.5 at baseline.InterventionsPrimary adjunctive infliximab (5 or 10 mg/kg) within 48 hours of initiating IVIG 2 g/kg.Main outcome measuresIncidence of CAA regression to Zmax