Preventive Regimens Research Articles

Preferences of people living with HIV for features of tuberculosis preventive treatment regimens in Uganda: a discrete choice experiment.

Tuberculosis (TB) preventive treatment (TPT) is recommended for people living with HIV (PLHIV) in high TB burden settings. While 6 months of daily isoniazid remains widely used, shorter regimens are now available. However, little is known about preferences of PLHIV for key features of TPT regimens. From July to November 2022, we conducted a discrete choice experiment among adult PLHIV engaged in care at an urban HIV clinic in Kampala, Uganda. Participants chose between two hypothetical TPT regimens with five different features (pills per dose, frequency, duration, need for adjusted antiretroviral therapy [ART] dosage and side effects), organized across nine random choice tasks. We analysed preferences using hierarchical Bayesian estimation, latent class analysis and willingness-to-trade simulations. Of 400 PLHIV, 392 (median age 44, 72% female, 91% TPT-experienced) had high-quality choice task responses. Pills per dose was the most important attribute (relative importance 32.4%, 95% confidence interval [CI] 31.6-33.2), followed by frequency (20.5% [95% CI 19.7-21.3]), duration (19.5% [95% CI 18.6-20.5]) and need for ART dosage adjustment (18.2% [95% CI 17.2-19.2]). Latent class analysis identified three preference groups: one prioritized less frequent, weekly dosing (N = 222; 57%); another was averse to ART dosage adjustment (N = 107; 27%); and the last prioritized short regimens with fewer side effects (N = 63; 16%). All groups highly valued fewer pills per dose. Overall, participants were willing to accept a regimen of 2.8 months' additional duration [95% CI: 2.4-3.2] to reduce pills per dose from five to one, 3.6 [95% CI 2.4-4.8] months for weekly rather than daily dosing and 2.2 [95% CI 1.3-3.0] months to avoid ART dosage adjustment. To align with preferences of PLHIV in Uganda, decision-makers should prioritize the development and implementation of TPT regimens with fewer pills, less frequent dosing and no need for ART dosage adjustment, rather than focus primarily on duration of treatment.

Four-weekly dosing intervals with subcutaneous spesolimab appear to be required for optimal prevention of generalized pustular psoriasis flares: Data from the EFFISAYIL® 2 and EFFISAYIL® ON trials

Generalized pustular psoriasis (GPP) is a rare chronic skin disease characterized by recurrent, acute, and often life-threatening flares of widespread neutrophilic sterile pustules and systemic inflammation. Spesolimab, an anti-interleukin-36 receptor antibody, is approved in adults and adults and pediatric patients 12 years of age and older and weighing at least 40 kg, as a subcutaneous dosage for treatment of GPP when not experiencing a flare, and as an intravenous dosage for GPP flare treatment. In Effisayil 2, a randomized, placebo-controlled trial (NCT04399837), subcutaneous spesolimab was superior to placebo and well tolerated for flare prevention when administered as a 600-mg subcutaneous loading dose followed by 300 mg every 4 weeks (q4w) over 48 weeks. In Effisayil 2, 3/30 (10.0%) patients receiving subcutaneous spesolimab 300 mg q4w had flares, and there were no flares after Week 4 until the end of the study. We assessed the effect on flare recurrence of a longer (q12w) interval between subcutaneous spesolimab doses in Effisayil 2 and Effisayil ON (NCT03886246), an ongoing open-label extension trial. Flares were defined as a ≥2-point increase in GPP Physician Global Assessment total score with pustulation subscore of ≥2, or intravenous spesolimab or standard of care treatment due to GPP worsening. In Effisayil 2, 9/31 (29.0%) patients who received subcutaneous spesolimab 300 mg q12w had a flare; of those, 7/9 (77.8%) experienced a flare before their second subcutaneous dose (Week 12), and 5/7 (71.4%) flares occurred during Weeks 4–12, indicating the need for q4w dosing. In Effisayil ON, 36/108 (33.3%) patients who started q12w dosing were either escalated to a q4w regimen (n=24) or experienced a flare (n=12). These observations suggest that subcutaneous spesolimab 300 mg q4w is the optimal dosing regimen for prevention of GPP flares.

Review of doxycycline for prophylaxis of sexually transmitted infections.

The surging rates of STIs necessitate medical practitioners in the appropriate specialties to focus on rapid recognition, treatment and prevention of these conditions. Through both pre- and post-exposure prophylaxis with doxycycline, dermatologists can provide up-to-date treatment in the field of venereology. Herein, we review the results of clinical trials in the available literature that investigate doxycycline prophylaxis in the prevention of bacterial STIs. A search was performed using the PubMED and Scopus databases which yielded six clinical trials for our review. Based on the results of these clinical trials, doxycycline prophylaxis offers significant reductions in bacterial STIs, specifically in men who have sex with men (MSM). Additional research is needed in other high-risk groups, including females. Moreover, additional research is needed to determine the effects of doxycycline prophylaxis on tetracycline resistance in STI-causing bacteria. As the utilization of doxycycline prophylaxis for STIs becomes more common, it is important that dermatologists become familiar with the data surrounding this prevention regimen and patient populations who may seek to know more about it. More research is needed to determine benefits in other subpopulations, antimicrobial resistance and cost effectiveness.

Efficacy of dual antiplatelet therapy after ischemic stroke according to hsCRP levels and CYP2C19 genotype

Both high-sensitive C-reactive protein (hsCRP) and CYP2C19 genotypes are independent predictors of clinical outcomes after ischemic stroke. We aim to evaluate the association of CYP2C19 loss-of-function alleles (LoFA) carrying status with the effects of dual/single antiplatelet therapy at different hsCRP levels using the CHANCE trial. Subjects with both of CYP2C19 major alleles information (*2, *3, and *17) and hsCRP measurements were enrolled from the prespecified subgroup. CYP2C19 LoFA carriers were defined as patients with either*2 or *3 allele. Cox proportional hazards models were used to assess the interaction of CYP2C19 LoFA carrying status with the effects of dual/single antiplatelet therapy at different hsCRP levels. The primary outcome was recurrent stroke within 90 days. Among 2,801 patients, 1,646 (58.8%) were LoFA carriers, and 922 (32.9%) had elevated hsCRP. In patients with nonelevated hsCRP, there was a significant interaction effect between CYP2C19 LoFA carrying status and dual/single antiplatelet regimens for prevention of recurrent stroke and combined vascular events (P = .048, .048, respectively), but, not in patients with elevated hsCRP (P = .502, .472, respectively). Only among patients with nonelevated hsCRP and noncarrier of CYP2C19 LoFA, dual antiplatelets significantly reduced the risk of recurrent stroke compared with aspirin alone (hazard ratio = 0.44 [0.26-0.74], P = .003). No significant differences in bleeding were found. Nonelevated hsCRP and noncarrier of CYP2C19 LoFA may predict a better response to dual antiplatelet therapy in reducing stroke recurrence and composite vascular events for patients with minor stroke and high-risk TIA. clinicaltrials.gov Identifier: NCT00979589.

Oral health-related quality of life in children and adolescent with autism spectrum disorders and neurotypical peers: a nested case-control questionnaire survey.

Oral health-related quality of life (OHRQoL) of children with autism following an oral preventive regimen (ASDsP) was compared to that of children with autism without a preventive regimen (ASDsNP) and of neurotypical peers (NT). An online survey was carried out using the Parental/Caregiver Perception Questionnaire (P-CPQ) and the Family Impact Scale (FIS). Scores were assigned to items, with the total score ranging from 0 to 120 (worst QoL). The median scores were compared amongst groups using the Mann-Whitney and Kruskal-Wallis tests. A multivariate linear regression assessed the relationship between questionnaire scores and demographical variables. Overall, 168 questionnaires from the ASDsP and the ASDsNP groups, respectively, and 336 from the NT group were selected ASDsP compared to ASDsNP showed lower P-CPQ Emotional wellbeing, FIS Emotion (p < 0.01) and Conflict (p < 0.05), and FIS total score (p < 0.01). In addition, they were less nervous (p < 0.05), shy (p < 0.01), with better sleep (p < 0.05), and with happier parents (p < 0.01). Compared to NT, ASDsP showed higher P-CPQ + FIS, P-CPQ, and FIS total scores (p < 0.01) and P-CPQ Functional limitation, Social wellbeing (p < 0.01), Emotional wellbeing (p < 0.05), and FIS Activity, Emotion and Conflict (p < 0.01). The preventive regimen reduces parental stress, improving the quality of life of children and families.

Adverse Events Reported During Weekly Isoniazid-Rifapentine (3HP) Tuberculosis Preventive Treatment Among People With Human Immunodeficiency Virus in Uganda.

Short-course tuberculosis (TB) prevention regimens, including 12 weeks of isoniazid and rifapentine (3HP), are increasingly used in high-TB-burden countries. Despite established safety and tolerability in efficacy trials, 3HP-related adverse events (AEs) could differ in routine settings. Real-world data on AE type, frequency, and timing are crucial for health systems considering 3HP programmatic scale-up. We reviewed AEs among people with human immunodeficiency virus (HIV) participating in a pragmatic implementation trial of facilitated 3HP taken by directly observed therapy (DOT) or self-administered therapy (SAT) in Kampala, Uganda, and classified them using the Common Terminology Criteria for Adverse Events. We assessed AE timing and summarized related clinical actions including laboratory tests, diagnoses made, medications prescribed, and treatment interruptions. Among 1655 people with HIV treated between July 2020 and September 2022, 270 (16.3%) reported 451 events; main issues included general (7%), nervous system (6%), musculoskeletal (5%), gastrointestinal (5%), and dermatologic (3%) disorders. Most (61%) occurred within 6 weeks of initiating 3HP. Among those with events, 211 (78%) required further clinician evaluation, 202 (75%) required laboratory testing, 102 (38%) had medications prescribed, 40 (15%) had treatment paused, and 14 (5%) discontinued 3HP. Women, those multidimensionally impoverished, and DOT recipients were more likely to report an AE. SAT users and later enrollees were more likely to have 3HP interrupted or stopped due to an AE. In a routine setting, 3HP was safe, with 16% of people with HIV reporting AEs and only 3% requiring temporary or permanent treatment interruption. These findings support 3HP expansion in routine HIV/AIDS care settings for TB prevention. Clinical Trials Registration. NCT03934931.

REverse transcriptase ACTivity (REACT) assay for point-of-care measurement of established and emerging antiretrovirals for HIV treatment and prevention.

Maintaining adequate levels of antiretroviral (ARV) medications is crucial for the efficacy of HIV treatment and prevention regimens. Monitoring ARV levels can predict or prevent adverse health outcomes like treatment failure or drug resistance. However, conventional ARV measurement using liquid chromatography-tandem mass spectrometry (LC-MS/MS) is slow, expensive, and centralized delaying clinical and behavioral interventions. We previously developed a rapid enzymatic assay for measuring nucleotide reverse transcriptase inhibitors (NRTIs) - the backbone of HIV treatment and prevention regimens - based on the drugs' termination of DNA synthesis by HIV reverse transcriptase (RT) enzyme. Here, we expand our work to include non-nucleoside reverse transcriptase inhibitors (NNRTIs) - an ARV class used in established and emerging HIV treatment and prevention regimens. We demonstrate that the REverse Transcriptase ACTivity (REACT) assay can detect NNRTIs including medications used in oral and long-acting/extended-release HIV treatment and prevention. We demonstrate that REACT can measure NNRTIs spiked in either buffer or diluted plasma and that fluorescence can be measured on both a traditional plate reader and an inexpensive portable reader that can be deployed in point-of-care (POC) settings. REACT measured clinically relevant concentrations of five NNRTIs spiked in aqueous buffer. REACT measurements showed excellent agreement between the plate reader and the portable reader, with a high correlation in both aqueous buffer (Pearson's r = 0.9807, P < 0.0001) and diluted plasma (Pearson's r = 0.9681, P < 0.0001). REACT has the potential to provide rapid measurement of NNRTIs in POC settings and may help to improve HIV treatment and prevention outcomes.

Aptamer-Encapsulated Cellular Nanoparticles for Neurotoxin Neutralization.

Aptamers are single-stranded oligonucleotides that fold into defined architectures for specific target binding. In this study, aptamers are selected that specifically bind to small-molecule neurotoxins and encapsulate them into cell membrane-coated nanoparticles (referred to as 'cellular nanoparticles' or 'CNPs') for effective neutralization of neurotoxins. Specifically, six different aptamers are selected that bind to saxitoxin (STX) or tetrodotoxin (TTX) and encapsulate them into metal-organic framework cores, which are then coated with neuronal cell membrane. The resulting CNPs exhibit high colloidal stability, minimal aptamer leakage, and effective protection of aptamer payloads against enzyme degradation. This detoxification platform combines membrane-enabled broad-spectrum neutralization with aptamer-based specific toxin binding, offering dual-modal neutralization mechanisms for efficient neurotoxin neutralization. The in vitro neutralization efficacy is demonstrated using a neuron osmotic swelling assay, a Na+ flux fluorescence assay, and a cytotoxicity assay. The in vivo neutralization efficacy is further validated using mouse models of STX and TTX intoxication in both therapeutic and preventative regimens. Overall, integrating aptamers with CNPs combines the strengths of both technologies, resulting in a robust solution for broad-spectrum toxin-neutralization applications.

Impact of Antibiotic Choice at the Time of Sacral Neuromodulation Implantation on Rates of Surgical Site Infection.

To evaluate the efficacy of specific antibiotic regimens in preventing infection following sacral neuromodulation. This is a retrospective cohort study utilizing the Premier Healthcare Database. Patients who underwent sacral neuromodulation placement between January 2016 and March 2020. The patients were grouped by those who received dual antibiotic therapy per 2019 AUA guidelines (Gram positive + broad Gram negative coverage), first- or second-generation cephalosporins or any other regimen. Comparison between groups was performed using Kruskal-Wallis and χ2 tests for continuous and categorical variables, respectively. Inverse probability of treatment weighted (IPTW) analysis was used to estimate the average treatment effect of AUA guidelines regimens versus the use the first- or second-generation cephalosporins alone. The sample included 14 179 patients, with 2211 patients receiving prophylaxis that followed the AUA guideline recommendations. There was no significant difference in surgical site infection rates within 3 months (p = 0.28) or within 12 months (p = 0.53) between the groups. On IPTW, the probability of an infection at 3 months was lower with the AUA guideline regimens compared to those who received first- or second-generation cephalosporins alone, but this difference was not statistically significant (OR = 0.73, 95% CI: [0.43, 1.24]). In the absence of allergies to cephalosporins or penicillin, first- or second-generation cephalosporins alone may be a sufficient preoperative antibiotic regimen for prevention of infection at the time of sacral neuromodulation. Not applicable due to being a database study.

Nanoscale lipid-methylprednisolone conjugates: Effective anti-inflammatory, antioxidant, and analgesic agents

In this study, we have investigated new lipid-drug conjugates (LDCs) of methylprednisolone. Methylprednisolone is a corticosteroid, used for the potential treatment of inflammatory diseases. The LDCs 1–2; methylprednisolone palmitate (1) and methylprednisolone palmityl carbonate (2), were designed by conjugating a C16 aliphatic chain via an ester or carbonate bond, respectively. Their structures were comprehensively characterized using mass spectrometry, nuclear magnetic resonance spectroscopy, and infrared spectroscopy. These LDCs 1–2 were subsequently formulated into nanoscale particles (NPs) using ethanol injection method. Hydrogenated soybean phosphatidylcholine (HSPC) and tween-80 served as excipients in the NPs formulation. Characterization via dynamic light scattering, scanning electron microscopy, and atomic force microscopy confirmed the formation of spherical NPs with a diameter ranging from 100 to 120 nm. The LDCs NPs 1–2 exhibited excellent stability for about a month, with good polydispersity (around 0.2) and a negative zeta potential between −20 mV and −34 mV. Encapsulation efficiency of the LDCs within the LDCs NPs 1–2 surpassed 90 %, as determined by HPLC analysis. In vitro cytotoxicity studies utilizing LPS-activated THP-1 cells demonstrated no adverse effects associated with LDCs NPs 1–2 at concentrations up to 100 μg/mL. Furthermore, the LDCs NPs 1–2 effectively retained the anti-inflammatory activity, as evidenced by the suppression of IL-1β, TNF-α, and MCP-1 secretion in LPS-stimulated THP-1 cells. The therapeutic potential of these LDCs NPs 1–2 was further evaluated in rat intervertebral disc-derived nucleus pulposus cells (NPCs). Curative and preventive treatment regimens with the free drug and LDCs NPs 1–2 were employed. Quantitative PCR analysis revealed a significant downregulation of pain and inflammation markers (Substance P and COX-2) along with a concomitant upregulation of antioxidant markers (GPX1, PRDX1, and SOD1) in NPCs treated with both the drug and LDCs NPs 1–2 compared to oxidative stress-induced and control NPCs. Our novel LDCs NPs 1–2 exhibited promising therapeutic potential for treating inflammatory and pain related complications, (including intervertebral disc degeneration). This promise stems from their multifaceted properties, encompassing anti-inflammatory, antioxidant, and analgesic effects. Further research is warranted to fully explore LDCs NPs 1–2 as potential drug candidates in future pre-clinical and clinical trials.

Effect of immunostimulatory RNA on the fibrosis development in Bleomycin- or LPS-induced mouse models

Previously, we described a 19-base pair double-stranded RNA with 3′-trinucleotide overhangs, acting as immunostimulatory RNA (isRNA). This molecule demonstrated notable antiproliferative effects on cancer cells, inhibited tumor growth, and elicited immunostimulatory and antiviral responses by inducing cytokine and interferon production. Within this study, we compared the efficiency of lung fibrosis development, initiated in mice by BLM or LPS using different schemes of induction. Then we compared the effect of isRNA used in a preventive or therapeutic regimen on the development of fibrosis in selected BLM- and LPS-induced mouse models and showed that isRNA can be used in pathological conditions accompanied by the development of inflammation and the risk of fibrosis formation, without adverse side effects. Prophylactic regimen of isRNA application is beneficial for prevention of the development of pulmonary fibrosis.

Intermittent preventive treatment regimens for malaria in HIV-positive pregnant women.

Intermittent preventive treatment regimens for malaria in HIV-positive pregnant women.

Dynamics of Nakaseomyces glabratus biofilm formation

Formation of biofilms of microorganisms, including those of Nakaseomyces glabratus, is responsible for the development of local and systemic pathologies in humans and animals. The system of gene expression coordination (quorum sensing) in the representation of signaling molecules allows regulation of the amount and composition of biofilm populations thus expanding the adaptive capacity of microorganisms. In the presence of gingivitis and odontolithiasis clinical signs in dogs, excessive growth of gram-positive yeast microorganisms is a differential sign of the decreased resistance of the digestive system mucous membranes to colonization. Examination of the densitometric and morphometric parameters revealed general patterns of biofilm formation, regardless of the source of Nakaseomyces glabratus isolates. Depending on the time of cultivation of the microorganisms, a gradual increase in the optic density absolute values was established. Intercellular communications were achieved by coaggregation of the heteromorphic structures, which formed clusters with rounded liquid-containing formations detected among them. The population immobilization of the architectonics of the mature three-dimensional biofilm, as consistent with cultivation conditions, was accompanied by the differentiation of numerous cells of different sizes and shapes depending on the stage of the cell cycle. Results of the examination of the general patterns of the heterogeneous micromycete population development are promising for expanding the boundaries of knowledge of the adaptation mechanisms of ubiquitous microorganisms to long-term in vivo and in vitro persistence. Methods for studying morphometric and densitometric indicators avoiding interfering into the natural biofilm architectonics are recommended to optimize the long-term and retrospective mycological studies, as well as to develop effective mycosis treatment and prevention regimens.

Individualized regimen of Posaconazole oral suspension in Chinese HSCT patients based on population pharmacokinetic model

To establish a population pharmacokinetic (PopPK) model of posaconazole suspension in Chinese hematopoietic stem cell transplantation (HSCT) patients and to recommend an optimal dosing regimen. A single-center, retrospective, model-based study was conducted in 62 Chinese patients, including 103 with posaconazole plasma concentrations. PopPK analysis using NONMEM software. A one-compartment model of first-order elimination and absorption was in good agreement with the experimental data. Analysis of covariance showed that body weight (WT), creatinine clearance (CCR), and proton pump inhibitor (PPI) had a significant effect on the pharmacokinetics of posaconazole. The dose simulation results show that patients with CCR ≥ 90 mL/min require at least 3 mg/kg TID and 7 mg/kg BID dosing regimens for prevention and treatment, respectively. However, when combined with PPI, at least 5 mg/kg BID and 5 mg/kg TID dosing regimens are required for prevention and treatment, respectively. Regardless of whether it is used in combination with PPI or not, patients with a CCR of 60–90 mL/min can achieve PTA goals by using a 4 mg/kg BID and 4 mg/kg TID regimen for prevention and treatment, respectively. A dosing regimen of 3 mg/kg BID in patients with a CCR of 30–60 mL/min is sufficient to meet the PTA goal of prophylaxis, and the dose needs to be elevated to 4 mg/kg BID for the treatment of fungal infections, and there is no need to change the dose according to the coadministration of PPI. When the patient's CCR is less than 30 mL/min, whether or not combined with PPI, the administration regimen of 2 mg/kg BID and 3 mg/kg BID can meet the PTA goals for prevention and treatment, respectively.

Cost-effectiveness of dapagliflozin as part of various treatment regimens for prevention of cardiovascular death and achieving the target indicator "Reduction of cardiovascular mortality" of the State Program "HealthCare Development" in patients with heart failure with reduced ejection fraction

Aim. To evaluate the dapagliflozin as part of various treatment regimens in patients with heart failure (HF) with reduced ejection fraction (HFrEF) ≤40% receiving medications within federal preferential drug program to achieve the "Reduction of cardiovascular mortality" of the State Program "HealthCare Development". To estimate the costs of reducing the cardiovascular mortality rate by 1 death per 100 thousand of population and achieving 1 percentage point of the target indicator "Reduction of cardiovascular mortality".Material and methods. The target patient population was Russian patients aged over 18 years diagnosed with NYHA class II-IV HFrEF (≤40%), included in the federal preferential drug program. We used model developed based on the DAPA-HF study results. We assessed the costs of drugs, the number of lives saved, the impact of therapy on achievement of the target indicator "Reduction of cardiovascular mortality" and other indicators in the Russian Federation (RF) as a whole and in each subject of the Russian Federation while using dapagliflozin as part of various treatment regimens for HFrEF including angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitor (ARNi), beta blockers, diuretics, mineralocorticoid antagonists, cardiac glycosides.Results. In 2024, the treatment cost of 181351 patients with HFrEF included in the federal preferential drug program with dapagliflozin in combination with standard therapy (ST) will be RUB9265,4 million; in combination with ST without ARNi (ST including ACEi/ARB) — RUB8161,7 million; in combination with ST including ARNi — RUB17837,3 million. The additional number of lives saved when using dapagliflozin in combination with standard therapy was 2394, in combination with standard therapy without ARNi — 2340, in combination with standard therapy, including ARNi — 2913. Costs of therapy per patient per year when using dapagliflozin in combination with standard therapy amounted to RUB51090,90; in combination with standard therapy without ARNI — RUB45004,72; in combination with standard therapy, including ARNI — RUB98358,00. In 2024, the percentage (%) of achievement of the federal target for dapagliflozin in combination with ST is 11,22%, while in combination with standard therapy without ARNi (ST including ACEi/ARB) — 10,96%, in combination with ST including ARNi — 13,65%. Achievement of a 1% target reduction in cardiovascular mortality in 2024 reqiored RUB828,1 million for dapagliflozin in combination with ST, while in combination with ST without ARNI (ST including ACEi/ARB) — RUB748,2 million, in combination with ST including ARNi — RUB1293,3 million.Conclusion. Among the 3 options considered for adding dapagliflozin to ST (ARNi or ACEi/ARB, including ACEi/ARB, including ARNi), ST without ARNI (ST including ACEi/ARB) has the lowest cost required to achieve a 1% target reduction in cardiovascular mortality. At the same time, the standard therapy with ARNI has the highest cost required to achieve a 1% target reduction in cardiovascular mortality, which indicates its least cost-effectiveness.

Adverse events reported during weekly isoniazid-rifapentine (3HP) tuberculosis preventive treatment among people living with HIV in Uganda.

Short-course tuberculosis (TB) prevention regimens, including 12 weeks of isoniazid and rifapentine (3HP), are increasingly used in high TB-burden countries. Despite established safety and tolerability in efficacy trials, 3HP-related adverse events (AE) could differ in routine settings. Real-world data on AE type, frequency, and timing is crucial for health systems considering 3HP programmatic scale-up. We reviewed AEs among people living with HIV (PLHIV) participating in a pragmatic implementation trial of facilitated 3HP taken by directly observed therapy (DOT) or self-administered therapy (SAT) in Kampala, Uganda, and classified them using the Common Terminology Criteria for Adverse Events. We assessed AE timing and summarized related clinical actions including lab tests, diagnoses made, medications prescribed, and treatment interruptions. Among 1655 PLHIV treated between July 2020-September 2022, 270 (16.3%) reported 451 events; main issues included general (7%), nervous system (6%), musculoskeletal (5%), gastrointestinal (5%), and dermatologic (3%) disorders. Most (61%) occurred within 6 weeks of initiating 3HP. Among those with events, 211 (78%) required further clinician evaluation, 202 (75%) required laboratory testing, 102 (38%) had medications prescribed, 40 (15%) had treatment paused, and 14 (5%) discontinued 3HP. Women, those multidimensionally impoverished, and DOT recipients were more likely to report an AE. SAT users and later enrollees were more likely to have 3HP interrupted or stopped due to an AE. In a routine setting, 3HP was safe with 16% of PLHIV reporting AEs and only 3% requiring temporary or permanent treatment interruption. These findings support 3HP expansion in routine HIV/AIDS care settings for TB prevention.

Reckoning of antiurolithiatic effect of Flemingia Strobilifera R. BR using ethylene glycol-induced urolithiatic animal model: demystifying traditional medicine

BackgroundUrolithiasis is a painful condition and current treatment doesn’t assure the prevention of recurrence. This research aims to demonstrate the scientific reliability of Chloroform leaf extract of Flemingia Strobilifera R.Br. (CEFS) for antiurolithiatic activity using ethylene glycol-induced urolithiasis model.ResultsEthylene glycol (EG) was used to induce hyperoxaluria in male Wistar rats. The rats were grouped into 7-groups containing six each. Group I and II served as negative and positive control, group III received standard treatment, whereas Group IV to VII served as testing groups. CEFS of 30 mg/kg body-weight and 60 mg/kg body-weight was used as a preventive and curative regimen. The urine biochemistry was analysed for the presence of calcium, magnesium, phosphate, and oxalate. The rats were sacrificed for histopathological examination and LDH detection. The 24-hours urine volume was increased in both EG-treated groups as well as CEFS-treated groups, indicating the diuretic activity of plant. CEFS dose-dependently inhibited urine excretion of phosphate, calcium, and oxalate compared to the positive-control group. The histopathological examination of CEFS-treated rats’ kidneys had reduced loss of renal structure and lessened deposition of calcium oxalate crystals.ConclusionCEFS exhibited significant antiurolithiatic activity by reducing supersaturation of urine and excretion of stone forming components.

Challenges with sirolimus experimental data to inform QSP model of post-transplantation cyclophosphamide regimens.

Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure-response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T-cells, including conventional (Tcons) and regulatory T-cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human exvivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T-cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration-effect association are needed for QSP modeling.

Low-dose anti-thymocyte globulin plus low-dose posttransplant cyclophosphamide-based regimen for prevention of graft-versus-host disease in haploidentical peripheral blood stem cell transplantation for pediatric patients with hematologic malignancies.

The low-dose anti-thymocyte globulin (ATG) plus low-dose post transplantation cyclophosphamide (PTCy) -based (low-dose ATG/PTCy-based) regimen had a promising activity in preventing of graft-versus-host disease (GVHD) in adult patients. However, its efficacy in pediatric patients remain to be defined. Here, we presented the findings from 35 pediatric patients undergoing haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with the new regimen for GVHD prophylaxis. The cumulative incidences (CIs) of grades II-III and III-IV acute GVHD (aGVHD) were 34% (95% CI, 17-48%) and 11% (95% CI, 0-21%) within 180 days post-transplantation, respectively. The CIs of chronic GVHD (cGVHD) and moderate-to-severe cGVHD within 2 years were 26% (95% CI, 7-41%) and 12% (95% CI, 0-25%), respectively. The 2-year probabilities of overall survival, relapse-free survival, and graft-versus-host disease and relapse-free survival were 89% (95% CI, 78-100%), 82% (95% CI, 68-98%) and 59% (95% CI, 43-80%), respectively. The CIs of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation by day 180 were 37% (95% CI, 19-51%) and 20% (95% CI, 6-32%) respectively. These results strongly advocate for the efficacy of the low-dose ATG/PTCy-based regimen as a robust strategy for GVHD prevention in haplo-PBSCT for pediatric patients.

Disability and Recurrent Stroke Among Participants in Stroke Prevention Trials

Stroke secondary prevention trials have disproportionately enrolled participants with mild or no disability. The impact of this bias remains unclear. To investigate the association between poststroke disability and the rate of recurrent stroke during long-term follow up. This cohort study is a post hoc analysis of the Prevention Regimen For Effectively Avoiding Second Strokes (PRoFESS) and Insulin Resistance Intervention After Stroke (IRIS) secondary prevention clinical trial datasets. PRoFESS enrolled patients from 2003 to 2008, and IRIS enrolled patients from 2005 to 2015. Data were analyzed from September 23, 2023, to May 16, 2024. The exposure was poststroke functional status at study baseline, defined as modified Rankin Scale (mRS; range, 0-5; higher score indicates more disability) score of 0 vs 1 to 2 vs 3 or greater. The primary outcome was recurrent stroke. The secondary outcome was major cardiovascular events (MACE), defined as recurrent stroke, myocardial infarction, new or worsening heart failure, or vascular death. A total of 20 183 PRoFESS participants (mean [SD] age, 66.1 [8.5] years; 12 931 [64.1%] male) and 3265 IRIS participants (mean [SD] age, 62.7 [10.6] years; 2151 [65.9%] male) were included. The median (IQR) follow-up was 2.4 (1.9-3.0) years in PRoFESS and 4.7 (3.2-5.0) years in IRIS. In PRoFESS, the recurrent stroke rate was 7.2%, among patients with an mRS of 0, 8.7% among patients with an mRS of 1 or 2, and 10.6% among patients with an mRS of 3 or greater (χ22 = 27.1; P < .001); in IRIS the recurrent stroke rate was 6.4% among patients with an mRS of 0, 9.0% among patients with an mRS of 1 or 2, and 11.7% among patients with an mRS of 3 or greater (χ22 = 11.1; P < .001). The MACE rate was 10.1% among patients with an mRS of 0, 12.2% among patients with an mRS of 1 or 2, and 17.2% among patients with an mRS of 3 or greater (χ22 = 103.4; P < .001) in PRoFESS and 10.9% among patients with an mRS of 0, 13.3% among patients with an mRS of 1 or 2, and 15.3% among patients with an mRS of 3 or greater (χ22 = 5.8; P = .06) in IRIS. Compared with patients with an mRS of 0, patients with an mRS of 3 or greater had increased hazard for recurrent stroke in PRoFESS (hazard ratio [HR], 1.63; 95% CI, 1.38-1.92; P < .001) and in IRIS (HR, 1.91; 95% CI, 1.28-2.86; P = .002). There was also increased hazard for MACE in PRoFESS (HR, 1.90; 95% CI, 1.66-2.18; P < .001) and in IRIS (HR, 1.45; 95% CI, 1.03-2.03; P = .03). This cohort study found that higher baseline poststroke disability was associated with increased rates of recurrent stroke and MACE. Including more patients with greater baseline disability in stroke prevention trials may improve the statistical power and generalizability of these studies.