Preventive Treatment 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.

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.

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

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

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.

Mixed methods study on latent tuberculosis among agate stone workers and advocacy for testing silica dust exposed individuals in India

The 2021 tuberculosis (TB) preventive treatment guidelines in India included silicosis as a screening group, yet latent TB infection (LTBI) testing for silica-dust-exposed individuals is underemphasized. Focusing on an estimated 52 million silica-dust-exposed workers, particularly agate-stone workers in Khambhat, Gujarat, our study aims to estimate LTBI prevalence, identify predictors, and gather insights from TB and silicosis experts. Employing a sequential explanatory mixed-methods approach, a cross-sectional study involved 463 agate-stone workers aged ≥ 20 years in Khambhat, using IGRA kits for LTBI testing. In-depth interviews with experts complemented quantitative findings. Among agate-stone workers, 58% tested positive for LTBI, with predictors including longer exposure, type of work, and BCG vaccination. Our findings reveal a nearly double burden of LTBI compared to the general population, particularly in occupations with higher silica dust exposure. Experts advocate for including silica-dust-exposed individuals in high-risk groups for LTBI testing, exploring cost-effective alternatives like improved skin sensitivity tests, and shorter TB preventive treatment regimens to enhance compliance. Future research should explore upfront TB preventive treatment for silica-dust-exposed individuals with high LTBI prevalence and optimal exposure duration. This study underscores the urgent need for policy changes and innovative approaches to TB prevention among silica-dust-exposed populations, impacting global occupational health strategies.

Cancer-Associated Stroke: Thrombosis Mechanism, Diagnosis, Outcome, and Therapeutic Strategies.

Cancer can induce hypercoagulability, which may lead to stroke. This occurs when tumor cells activate platelets as part of their growth and metastasis. Tumor cells activate platelets by generating thrombin and expressing tissue factor, resulting in tumor cell-induced platelet aggregation. Histopathological studies of thrombi obtained during endovascular thrombectomy in patients with acute stroke and active cancer have shown a high proportion of platelets and thrombin. This underscores the crucial roles of platelets and thrombin in cancer-associated thrombosis. Cancer-associated stroke typically occurs in patients with active cancer and is characterized by distinctive features. These features include multiple infarctions across multiple vascular territories, markedly elevated blood D-dimer levels, and metastasis. The presence of cardiac vegetations on echocardiography is a robust indicator of cancer-associated stroke. Suspicion of cancer-associated stroke during endovascular thrombectomy arises when white thrombi are detected, particularly in patients with active cancer. Cancer-associated stroke is almost certain when histopathological examination of thrombi shows a very high platelet and a very low erythrocyte composition. Patients with cancer-associated stroke have high risks of mortality and recurrent stroke. However, limited data are available on the optimal treatment regimen for stroke prevention in these patients. Thrombosis mechanism in cancer is well understood, and distinct therapeutic targets involving thrombin and platelets have been identified. Therefore, direct thrombin inhibitors and/or antiplatelet agents may effectively prevent stroke recurrence. Additionally, this strategy has potential benefits in cancer treatment as accumulating evidence suggests that aspirin use reduces cancer progression, metastasis, and cancer-related mortality. However, clinical trials are necessary to assess the efficacy of this strategy involving the use of direct thrombin inhibitors and/or antiplatelet therapies.

Factors Associated with Non-Adherence to Tuberculosis Preventive Treatment among Adult Contacts of Pulmonary Tuberculosis Cases with Latent Tuberculosis Infection in Catalonia, Spain, in 2019-2021.

The aim of this study was to identify factors associated with non-adherence to tuberculosis (TB) preventive treatment among contacts with latent TB infection for new cases of pulmonary TB cases reported in Catalonia in 2019-2021. All contacts aged 18 years or older with a latent TB infection who received a TB preventive treatment were included in the study. The Chi square test and the odds ratios (OR) were used to assess the association between non-adherence to TB preventive treatment and the study variables; a p < 0.05 was considered statistically significant. Multiple logistic regression analysis was used to detect the independent factors associated with TB preventive treatment non-adherence; a p < 0.05 was considered statistically significant. The percentage of non-adherence to TB preventive treatment found in this study was 23.7%. A multivariable logistic regression analysis determined that the following factors were significantly associated with TB preventive treatment non-adherence among adult contacts: "exposure at school or workplace" (aOR = 3.34), "exposure to an index case without laboratory confirmation of TB" (aOR = 2.07), "immigrant contact" (aOR = 1.81), "male gender" (aOR = 1.75) and "exposure duration < 6 h per week or sporadic" (aOR = 1.60. By contrast, the factor "short-term TB preventive treatment regimen" (aOR = 0.38) was significantly associated with a lower treatment non-adherence. Adherence to TB preventive treatment should be improved among adult contacts of TB pulmonary cases with latent TB infection by recommending short-term treatment regimens and by developing health education activities, with a greater focus on contacts with factors associated with treatment non-adherence.

Experience of Fixed-Dose Combinations of Anti-Tuberculosis Drugs for Preventive Treatment in Children

The objective: to evaluate the effectiveness and safety of preventive treatment with fixed-dose combination of anti-tuberculosis drugs (FDCs) in children from groups at high risk of developing tuberculosis.Subjects and Methods. Effectiveness of preventive treatment was analyzed in 318 children from groups at high risk of developing tuberculosis. Also, we studied the possibility of successful completion of the full course of treatment using FDCs and preventive treatment regimens containing at least two single drugs. Inclusion criteria were as follows: the child at high risk of developing tuberculosis; no clinical and radiological signs of active tuberculosis; lack of information about the resistance to first-line drugs at the suspected source of infection; and negative HIV status. A group of children (172 people) underwent preventive treatment using FDCs, of them 126 patients received FDCs containing isoniazid 150 mg + pyrazinamide 500 mg + pyridoxine hydrochloride 15 mg, and 46 patients received FDCs containing isoniazid 150 mg + ethambutol 400 mg + pyridoxine hydrochloride 15 mg. The comparison group (CG) included 146 children who received preventive treatment with single drugs: 111 children received isoniazid and pyrazinamide, and 35 children received isoniazid and ethambutol.Results. When assessing the safety and effectiveness, no statistically significant differences were found when using FDCs and single-drug regimens. 91.9% of children receiving FDCs and 86.3% of children receiving single-drug regimens successfully completed the full course of treatment. When taking FDCs, there was a tendency to lower incidence of adverse events. With the FDC (isoniazid 150 mg + pyrazinamide 500 mg + pyridoxine hydrochloride 15 mg), the proportion of adverse events did not exceed 4.0%. There were no adverse events with the FDC (isoniazid 150 mg + ethambutol 400 mg + pyridoxine hydrochloride 15 mg).Conclusion. Preventive treatment of children with tuberculosis infection with FDC is a modern and effective technology.

Latent tuberculosis infection treatment completion in Biscay: differences between regimens and monitoring approaches.

Contact tracing and treatment of latent tuberculosis infection (LTBI) is a key element of tuberculosis (TB) control in low TB incidence countries. A TB control and prevention program has been active in the Basque Country since 2003, including the development of the nurse case manager role and a unified electronic record. Three World Health Organization-approved LTBI regimens have been used: isoniazid for 6 months (6H), rifampicin for 4 months (4R), and isoniazid and rifampicin for 3 months (3HR). Centralized follow-up by a TB nurse case manager started in January 2016, with regular telephone follow-up, telemonitoring of blood test results, and monitoring of adherence by electronic review of drugs dispensed in pharmacies. To estimate LTBI treatment completion and toxicity of different preventive treatment regimens in a real-world setting. Secondary objective: to investigate the adherence to different approaches to preventive treatment monitoring. A multicentre retrospective cohort study was conducted using data collected prospectively on contacts of patients with TB in five hospitals in Biscay from 2003 to 2022. A total of 3,066 contacts with LTBI were included. The overall completion rate was 66.8%; 86.5% of patients on 3HR (n = 699) completed treatment vs. 68.3% (n = 1,260) of those on 6H (p < 0.0001). The rate of toxicity was 3.8%, without significant differences between the regimens. A total of 394 contacts were monitored by a TB nurse case manager. In these patients, the completion rate was 85% vs. 67% in those under standard care (p < 0.001). A multivariate logistic regression model identified three independent factors associated with treatment completion: being female, the 3HR regimen, and nurse telemonitoring. 3HR was well tolerated and associated with a higher rate of treatment completion. Patients with nurse telemonitoring follow-up had better completion rates.

β-Caryophyllene Inhibits Oxaliplatin-Induced Peripheral Neuropathy in Mice: Role of Cannabinoid Type 2 Receptors, Oxidative Stress and Neuroinflammation.

Peripheral neuropathy is an important adverse effect caused by some chemotherapeutic agents, including oxaliplatin (OXA). OXA-induced peripheral neuropathy (OIPN) is a challenging condition due to diagnostic complexities and a lack of effective treatment. In this study, we investigated the antiallodynic effect of β-caryophyllene (BCP), a cannabinoid type 2 (CB2) receptor agonist, in a mouse model of OIPN. BCP treatment inhibited OXA-induced mechanical and cold allodynia in both preventive and therapeutic drug treatment regimens. Experiments with the CB2 receptor agonist GW405833 confirmed the role of CB2 receptors in OIPN. The CB2 antagonist SR144528 abrogated the anti-nociceptive effect of BCP on mechanical allodynia, without impacting OXA-induced sensitivity to cold. BCP decreased neuroinflammation, as inferred from TNF, IL-1β, IL-6, and IL-10 profiling, and also reduced ROS production, lipid peroxidation, and 4-hydroxynonenal protein adduct formation in the spinal cords of OXA-treated mice. BCP did not affect the antitumor response to OXA or its impact on blood cell counts, implying that the cytotoxicity of OXA was preserved. These results underscore BCP as a candidate drug for OIPN treatment via CB2 receptor-dependent mechanisms, and anti-inflammatory and antioxidant responses in the spinal cord.

Research priorities regarding the use of bisphosphonates for osteoporosis: a UK priority setting exercise.

Worldwide, many people who would benefit from osteoporosis drugs are not offered or receiving them, resulting in an osteoporosis care gap. Adherence with bisphosphonates is particularly low. This study aimed to identify stakeholder research priorities relating to bisphosphonate treatment regimens for prevention of osteoporotic fractures. A three-step approach based on the James Lind Alliance methodology for identification and prioritisation of research questions was used. Research uncertainties were gathered from a large programme of related research studies about bisphosphonate regimens and from recent published international clinical guidelines. Clinical and public stakeholders refined the list of uncertainties into research questions. The third step prioritised the questions using a modified nominal group technique. In total, 34 draft uncertainties were finalised into 33 research questions by stakeholders. The top 10 includes questions relating to which people should be offered intravenous bisphosphonates first line (1); optimal duration of treatment (2); the role of bone turnover markers in treatment breaks (3); support patient need for medicine optimisation (4); support primary care practitioner need regarding bisphosphonates (5); comparing zoledronate given in community vs hospital settings (6); ensuring quality standards are met (7); the long-term model of care (8); best bisphosphonate for people aged under 50 (9); and supporting patient decision-making about bisphosphonates (10). This study reports, for the first time, topics of importance to stakeholders in the research of bisphosphonate osteoporosis treatment regimens. These findings have implications for research into implementation to address the care gap and education of healthcare professionals. Using James Lind Alliance methodology, this study reports prioritised topics of importance to stakeholders in the research of bisphosphonate treatment in osteoporosis. The priorities address how to better implement guidelines to address the care gap, understanding patient factors influencing treatment selection and effectiveness, and how to optimise long-term care.

Completion, safety, and efficacy of tuberculosis preventive treatment regimens containing rifampicin or rifapentine: an individual patient data network meta-analysis

3 months of weekly rifapentine plus isoniazid (3HP) and 4 months of daily rifampicin (4R) are recommended for tuberculosis preventive treatment. As these regimens have not been compared directly, we used individual patient data and network meta-analysis methods to compare completion, safety, and efficacy between 3HP and 4R. We conducted a network meta-analysis of individual patient data by searching PubMed for randomised controlled trials (RCTs) published between Jan 1, 2000, and Mar 1, 2019. Eligible studies compared 3HP or 4R to 6 months or 9 months of isoniazid and reported treatment completion, adverse events, or incidence of tuberculosis disease. Deidentified individual patient data from eligible studies were provided by study investigators and outcomes were harmonised. Methods for network meta-analysis were used to generate indirect adjusted risk ratios (aRRs) and risk differences (aRDs) with their 95% CIs. We included 17 572 participants from 14 countries in six trials. In the network meta-analysis, treatment completion was higher for people on 3HP than for those on 4R (aRR 1·06 [95% CI 1·02-1·10]; aRD 0·05 [95% CI 0·02-0·07]). For treatment-related adverse events leading to drug discontinuation, risks were higher for 3HP than for 4R for adverse events of any severity (aRR 2·86 [2·12-4·21]; aRD 0·03 [0·02-0·05]) and for grade 3-4 adverse events (aRR 3·46 [2·09-6·17]; aRD 0·02 [0·01-0·03]). Similar increased risks with 3HP were observed with other definitions of adverse events and were consistent across age groups. No difference in the incidence of tuberculosis disease between 3HP and 4R was found. In the absence of RCTs, our individual patient data network meta-analysis indicates that 3HP provided an increase in treatment completion over 4R, but was associated with a higher risk of adverse events. Although findings should be confirmed, the trade-off between completion and safety must be considered when selecting a regimen for tuberculosis preventive treatment. None. For the French and Spanish translations of the abstract see Supplementary Materials section.

The Amount of Knowledge Awareness on the Caries Risk Assessment Tools and It’s Management Strategies in Children among Dental Students

Introduction: Early detection of risk factors and implementation of oral health preventative activities can help to slow or stop the spread of caries. As a result, dentists must be well-versed in a variety of approaches and early preventative methods.&#x0D; Aim of the Study: The aim of the study is to create knowledge and awareness on the caries risk assessment tools and it’s management strategies in children among dental students.&#x0D; Methodology: A questionnaire survey was carried out online containing 10 questions and was sent to 100 students on the caries risk assessment tools and it’s management strategies in children among dental students. An online survey was conducted using survey planet software and the data was collected and completely analysed for statistical difference.&#x0D; Results: According to our findings, the majority of undergraduates believe that a child should see a dentist between the ages of 12 and 22, and that specific information gained from a systematic assessment of caries risk guides the dentist in the decision-making process for treatment and preventive protocols for children (66 percent of undergraduates and 18 percent of postgraduates).&#x0D; Conclusion: Dental practitioners have a critical role in preventing and minimising the severity of ECC in young children, and they can use preventive treatment regimens to assess their paediatric patients' caries risk.

Towards Shorter, Child-Friendly Regimens for Treatment of Tuberculosis Disease and Infection in Children.

Towards Shorter, Child-Friendly Regimens for Treatment of Tuberculosis Disease and Infection in Children.

Effectiveness and safety of available preventive tuberculosis treatment regimens for children and adolescents: protocol for a systematic review and network meta-analysis

IntroductionApproximately 5%–10% of individuals with untreated latent tuberculosis infection (LTBI) will progress to active tuberculosis (TB). Children are at a higher risk for progression to TB disease than adults. Isoniazid...

Scaling up target regimens for tuberculosis preventive treatment in Brazil and South Africa: An analysis of costs and cost-effectiveness.

BackgroundShorter, safer, and cheaper tuberculosis (TB) preventive treatment (TPT) regimens will enhance uptake and effectiveness. WHO developed target product profiles describing minimum requirements and optimal targets for key attributes of novel TPT regimens. We performed a cost-effectiveness analysis addressing the scale-up of regimens meeting these criteria in Brazil, a setting with relatively low transmission and low HIV and rifampicin-resistant TB (RR-TB) prevalence, and South Africa, a setting with higher transmission and higher HIV and RR-TB prevalence.Methods and findingsWe used outputs from a model simulating scale-up of TPT regimens meeting minimal and optimal criteria. We assumed that drug costs for minimal and optimal regimens were identical to 6 months of daily isoniazid (6H). The minimal regimen lasted 3 months, with 70% completion and 80% efficacy; the optimal regimen lasted 1 month, with 90% completion and 100% efficacy. Target groups were people living with HIV (PLHIV) on antiretroviral treatment and household contacts (HHCs) of identified TB patients. The status quo was 6H at 2019 coverage levels for PLHIV and HHCs. We projected TB cases and deaths, TB-associated disability-adjusted life years (DALYs), and costs (in 2020 US dollars) associated with TB from a TB services perspective from 2020 to 2035, with 3% annual discounting. We estimated the expected costs and outcomes of scaling up 6H, the minimal TPT regimen, or the optimal TPT regimen to reach all eligible PLHIV and HHCs by 2023, compared to the status quo. Maintaining current 6H coverage in Brazil (0% of HHCs and 30% of PLHIV treated) would be associated with 1.1 (95% uncertainty range [UR] 1.1–1.2) million TB cases, 123,000 (115,000–132,000) deaths, and 2.5 (2.1–3.1) million DALYs and would cost $1.1 ($1.0–$1.3) billion during 2020–2035. Expanding the 6H, minimal, or optimal regimen to 100% coverage among eligible groups would reduce DALYs by 0.5% (95% UR 1.2% reduction, 0.4% increase), 2.5% (1.8%–3.0%), and 9.0% (6.5%–11.0%), respectively, with additional costs of $107 ($95–$117) million and $51 ($41–$60) million and savings of $36 ($14–$58) million, respectively. Compared to the status quo, costs per DALY averted were $7,608 and $808 for scaling up the 6H and minimal regimens, respectively, while the optimal regimen was dominant (cost savings, reduced DALYs). In South Africa, maintaining current 6H coverage (0% of HHCs and 69% of PLHIV treated) would be associated with 3.6 (95% UR 3.0–4.3) million TB cases, 843,000 (598,000–1,201,000) deaths, and 36.7 (19.5–58.0) million DALYs and would cost $2.5 ($1.8–$3.6) billion. Expanding coverage with the 6H, minimal, or optimal regimen would reduce DALYs by 6.9% (95% UR 4.3%–95%), 15.5% (11.8%–18.9%), and 38.0% (32.7%–43.0%), respectively, with additional costs of $79 (−$7, $151) million and $40 (−$52, $140) million and savings of $608 ($443–$832) million, respectively. Compared to the status quo, estimated costs per DALY averted were $31 and $7 for scaling up the 6H and minimal regimens, while the optimal regimen was dominant. Study limitations included the focus on 2 countries, and no explicit consideration of costs incurred before the decision to prescribe TPT.ConclusionsOur findings suggest that scale-up of TPT regimens meeting minimum or optimal requirements would likely have important impacts on TB-associated outcomes and would likely be cost-effective or cost saving.

Prioritising attributes for tuberculosis preventive treatment regimens: a modelling analysis

BackgroundRecent years have seen important improvements in available preventive treatment regimens for tuberculosis (TB), and research is ongoing to develop these further. To assist with the formulation of target product profiles for future regimens, we examined which regimen properties would be most influential in the epidemiological impact of preventive treatment.MethodsFollowing expert consultation, we identified 5 regimen properties relevant to the incidence-reducing impact of a future preventive treatment regimen: regimen duration, efficacy, ease-of-adherence (treatment completion rates in programmatic conditions), forgiveness to non-completion and the barrier to developing rifampicin resistance during treatment. For each regimen property, we elicited expert input for minimally acceptable and optimal (ideal-but-feasible) performance scenarios for future regimens. Using mathematical modelling, we then examined how each regimen property would influence the TB incidence reduction arising from full uptake of future regimens according to current WHO guidelines, in four countries: South Africa, Kenya, India and Brazil.ResultsOf all regimen properties, efficacy is the single most important predictor of epidemiological impact, while ease-of-adherence plays an important secondary role. These results are qualitatively consistent across country settings; sensitivity analyses show that these results are also qualitatively robust to a range of model assumptions, including the mechanism of action of future preventive regimens.ConclusionsAs preventive treatment regimens against TB continue to improve, understanding the key drivers of epidemiological impact can assist in guiding further development. By meeting these key targets, future preventive treatment regimens could play a critical role in global efforts to end TB.

MNK/eIF4E Ser209 Inhibitor eFT-508 Prevents and Therapeutically Treats Fibrosis in a Murine Model of Restrictive Chronic Lung Allograft Rejection

<h3>Purpose</h3> Lung transplant is limited by poor outcomes due to chronic lung allograft dysfunction, CLAD. A fulminant CLAD phenotype, restrictive allograft syndrome (RAS), with limited therapies underscores the need to understand underlying mechanisms. MNK1 kinase is a key translational regulator of cellular functions via eIF4E serine 209 phosphorylation. Here we investigate the role of MNK/eIF4E Ser209 in mesenchymal cell activation and the therapeutic effectiveness of eFT-508 in a murine model of RAS. <h3>Methods</h3> Human lung allograft derived MCs treated with eFT-508 (10uM x 24h) were immunoblotted for collagen I, alpha smooth muscle actin, CD44, autotaxin. A modified boyden chamber assay was utilized for migration. We recently reported a murine RAS model, B6D2F1/J into C57BL6/J. Mice were administered eFT-508 5mg/kg/daily/gavage in a preventive group days 7-28, or therapeutic group days 14-28. <h3>Results</h3> Human allograft derived MCs from CLAD patients demonstrated 4-fold increase in MNK1 (Thr197/202) and eIF4E Ser209 compared to non-fibrotic MCs. Upon eFT-508 treatment, we observed reduced eIF4E Ser209, collagen I, alpha smooth muscle actin and SPARC expression, and migration (n=7; p<0.05). CD44 and autotaxin protein expression was decreased upon eFT-508 treatment, along with secreted autotaxin activity (n=9; p=0.0005). <i>In vivo</i> preventive treatment with eFT-508 decreased airway fibrosis upon histological examination utilizing trichrome staining. Pleural thickness measurements were also reduced compared to vehicle treated controls. A significant reduction in hydroxyproline content, autotaxin secretion, and activity were also noted in eFT-508 treated transplant lung homogenates (n=7; p<0.001). Therapeutic treatment with eFT-508 reduced hydroxyproline content compared to vehicle treated allografts (n=4; p=0.0252). <h3>Conclusion</h3> MNK/eIF4E Ser209 inhibition reduced fibrotic protein expression and migration, demonstrating a role for this pathway in MC activation. <i>In vivo</i> MNK/eIF4E Ser209 inhibition reduced graft fibrosis by preventive and therapeutic treatment regimens in a murine model of RAS. This data highlights a novel therapeutic option for preventing development and progression of RAS.

Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns.

There are limited data about the epidemiology and secondary stroke prevention strategies used for patients with depressed left ventricular ejection fraction (LVEF) and sinus rhythm following an acute ischemic stroke (AIS). We sought to describe the prevalence of LVEF ≤40% and sinus rhythm among patients with AIS and antithrombotic treatment practice in a multi-center cohort from 2002 to 2018. This was a multi-center, retrospective cohort study comprised of patients with AIS hospitalized in the Greater Cincinnati Northern Kentucky Stroke Study and 4 academic, hospital-based cohorts in the United States. A 1-stage meta-analysis of proportions was undertaken to calculate a pooled prevalence. Univariate analyses and an adjusted multivariable logistic regression model were performed to identify demographic, clinical, and echocardiographic characteristics associated with being prescribed an anticoagulant upon AIS hospitalization discharge. Among 14 338 patients with AIS with documented LVEF during the stroke hospitalization, the weighted pooled prevalence of LVEF ≤40% and sinus rhythm was 5.0% (95% CI, 4.1-6.0%; I2, 84.4%). Of 524 patients with no cardiac thrombus and no prior indication for anticoagulant who survived postdischarge, 200 (38%) were discharged on anticoagulant, 289 (55%) were discharged on antiplatelet therapy only, and 35 (7%) on neither. There was heterogeneity by site in the proportion discharged with an anticoagulant (22% to 45%, P<0.0001). Cohort site and National Institutes of Health Stroke Severity scale >8 (odds ratio, 2.0 [95% CI, 1.1-3.8]) were significant, independent predictors of being discharged with an anticoagulant in an adjusted analysis. Nearly 5% of patients with AIS have a depressed LVEF and are in sinus rhythm. There is significant variation in the clinical practice of antithrombotic therapy prescription by site and stroke severity. Given this clinical equipoise, further study is needed to define optimal antithrombotic treatment regimens for secondary stroke prevention in this patient population.

Paediatric tuberculosis preventive treatment preferences among HIV-positive children, caregivers and healthcare providers in Eswatini: a discrete choice experiment

ObjectiveIsoniazid preventive therapy initiation and completion rates are suboptimal among children. Shorter tuberculosis (TB) preventive treatment (TPT) regimens have demonstrated safety and efficacy in children and may improve adherence but...