Challenges in the management of idiopathic pulmonary fibrosis from a low- and middle-income country.

Idiopathic pulmonary fibrosis (IPF) is the most common progressive form of interstitial lung disease (ILD) that leads to gradual deterioration of lung function and ultimately death. Data from low- and middle-income countries (LMIC) on IPF is scarce. In this communication, we report the challenges encountered in managing IPF from Pakistan's largest tertiary care centre. A total of 108 patients with IPF were evaluated at the Aga Khan University Hospital in Karachi, Pakistan from January 2017 to March 2020. A significant concern was that most patients with IPF presented late during their disease. A bigger challenge encountered in clinical practice was the cost and nonavailability of antifibrotic therapy in the country until mid-2020. Successfully addressing these limitations, it is anticipated that better care will be available for the patients suffering from IPF in this part of the world.

Cytokines assets in PLWH in two-drug dolutergravir based or three-drug antiretroviral regimen.

To minimize the toxicity and impact of combined antiretroviral therapy (cART) on the lifestyle of people living with Human Immunodeficiency Virus (PLWH), scientific community evaluated the efficacy, safety and sustained virologic response of two drugs antiretroviral regimens, in particular dolutegravir (DTG). The effects of deintensification therapy on inflammatory settings are currently unknown in PLWH. Thus, our study explored the inflammatory state in virologically suppressed HIV individuals between patients in treatment with a DTG-containing dual therapy (2DR) versus triple regimen therapies (3DR). We enrolled a total of 116 subjects in 2DRs or 3DRs regimens, and the plasma levels of pro- and anti-inflammatory cytokines (in particular IL-1ß, IL-10, IL-18, IL-33, IL-36 and IFN-γ) have been evaluated. CD4 + cell's median value was 729.0 cell/µL in the 3DR group and 771.5 cell/µL in 2DR group; the viral load was negative in all patients. Significant differences were found in levels of IL-18 (648.8 cell/µL in 3DR group vs. 475.0 cell/µL in 2DR group, p = 0.034) and IL-36 (281.7 cell/µL in 3DR group vs. 247.0 cell/µL in 2DR group, p = 0.050), and a correlation between IL-18 and IL-36 was found in 3DR group (rho = 0.266, p = 0.015). This single-center retrospective pharmacological study confirms the absence of significant differences in IL-1ß, IL-10, IL-33, and IFN-γ levels between patients on two-drug antiretroviral regimens compared to patients on 3DR antiretroviral regimens. Patients in 2DR show greater control over IL-18 and IL-36 serum levels, cytokines related to an increased cardiovascular risk and development of age-related chronic diseases. Based on our results, we suggest that DTG-based 2DR antiretroviral regimens could be associated with better control of the chronic inflammation that characterizes the population living with HIV in effective ART.

Impact of patient selection in clinical trials: application of ROCKET AF and ARISTOTLE criteria in GARFIELD-AF.

BACKGROUND: The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry. METHODS: Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA. RESULTS: Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs. CONCLUSION: Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.

Pirfenidone use in fibrotic diseases: What do we know so far?

BACKGROUND: Pirfenidone has demonstrated significant anti-inflammatory and antifibrotic effects in both animal models and some clinical trials. Its potential for antifibrotic activity positions it as a promising candidate for the treatment of various fibrotic diseases. Pirfenidone exerts several pleiotropic and anti-inflammatory effects through different molecular pathways, attenuating multiple inflammatory processes, including the secretion of pro-inflammatory cytokines, apoptosis, and fibroblast activation. OBJECTIVE: To present the current evidence of pirfenidone's effects on several fibrotic diseases, with a focus on its potential as a therapeutic option for managing chronic fibrotic conditions. FINDINGS: Pirfenidone has been extensively studied for idiopathic pulmonary fibrosis, showing a favorable impact and forming part of the current treatment regimen for this disease. Additionally, pirfenidone appears to have beneficial effects on similar fibrotic diseases such as interstitial lung disease, myocardial fibrosis, glomerulopathies, aberrant skin scarring, chronic liver disease, and other fibrotic disorders. CONCLUSION: Given the increasing incidence of chronic fibrotic conditions, pirfenidone emerges as a potential therapeutic option for these patients. However, further clinical trials are necessary to confirm its therapeutic efficacy in various fibrotic diseases. This review aims to highlight the current evidence of pirfenidone's effects in multiple fibrotic conditions.

Effectiveness and safety of dolutegravir plus lamivudine in treating HIV in China, including outcomes of patients coinfected with tuberculosis.

Antiretroviral regimens for human immunodeficiency virus (HIV) infection have continuously evolved; however, antiretrovirals can cause severe adverse reactions. Two-drug regimen therapy can decrease lifetime cumulative drug exposure and long-term toxicities associated with multiple antiretrovirals. The preferred 2-drug regimen constitutes dolutegravir (DTG) and lamivudine (3TC). This study determined the rate of virological suppression and incidence of adverse events at week 48 in treatment-naïve people living with HIV initiated on DTG + 3TC. This was a single-center, retrospective, observational study. Treatment-naïve people aged ≥18 years who received at least 1 DTG + 3TC dose between May 2020 and May 2022 were included. Eighty-nine people living with HIV were enrolled. Twenty-five (28.1%) patients with a DTG + 3TC regimen at baseline were analyzed because of comorbidities, and 48% because of concomitant tuberculosis (TB). Viral suppression at 48 weeks was achieved in 91.67% of patients, and TB was well controlled. At week 48, 84 (94.38%) patients had viral loads < 50 copies/mL, and 21 (91.31%) of the 23 participants with a baseline HIV-1-RNA level ≥ 1 × 105 copies/mL achieved virological success. Fifteen (88.23%) of the 17 participants with a baseline CD4 + cell count of <200 cells/µL achieved virological suppression. The median CD4 + cell count change from baseline was 539.5 cells/µL. No significant changes in triglycerides, low-density lipoprotein cholesterol, weight, or creatinine were observed from baseline to 48 weeks. One patient had severe insomnia at 4 weeks. Our findings support the real-world effectiveness and low metabolic impact of DTG + 3TC. Using DTG + 3TC in patients coinfected with TB and HIV has favorable therapeutic outcomes.

Trametinib boosts palbociclib's efficacy in breast cancer via autophagy inhibition.

Breast cancer, a predominant global health issue, requires ongoing exploration of new therapeutic strategies. Palbociclib (PAL), a well-known cyclin-dependent kinase (CDK) inhibitor, plays a critical role in breast cancer treatment. While its efficacy is recognized, the interplay between PAL and cellular autophagy, particularly in the context of the RAF/MEK/ERK signaling pathway, remains insufficiently explored. This study investigates PAL's inhibitory effects on breast cancer using both in vitro (MCF7 and MDA-MB-468 cells) and in vivo (tumor-bearing nude mice) models. Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib (TRA), an MEK inhibitor, our research seeks to address the challenge of PAL-induced drug resistance. Our findings reveal that PAL significantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells. However, PAL also induces protective autophagy, potentially leading to drug resistance via the RAF/MEK/ERK pathway activation. Introducing TRA effectively neutralized this autophagy, enhancing PAL's anti-tumor efficacy. A combination of PAL and TRA synergistically reduced cell viability and proliferation, and in vivo studies showed notable tumor size reduction. In conclusion, the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance, offering a new horizon in breast cancer treatment.

Weight change with antiretroviral switch from integrase inhibitor or tenofovir alafenamide-based to Doravirine-Based regimens in people with HIV.

BACKGROUND: Weight gain has been well-described with integrase strand transfer inhibitors (INSTIs) and tenofovir alafenamide (TAF). Doravirine (DOR) has been identified as a relatively "weight-neutral" drug; however, there is little data describing its effect on weight change in routine clinical practice. METHODS: We conducted a retrospective chart review of weight change among people with HIV changing from an INSTI- to a non-INSTI regimen with DOR. RESULTS: At the time of ART switch, among 49 people with HIV, the mean age was 47 years, 24% were female, and 75% had HIV-1 viral load <200 copies/mL. Most (55%) people with HIV were taking bictegravir/TAF/emtricitabine prior to the switch. Although 84% switched due to concerns about weight gain, only 16% had a weight gain of ≥10% in the year preceding, and 49% had no substantial change in weight. 86% switched to DOR/lamivudine/tenofovir disoproxil fumarate. A weight decrease (-2.6% [95% CI: -5.1, -0.1%, p = .041] was seen over the year following the ART switch. Weight change prior to switch was greatest in the year 2021 compared to 2019, 2020, and 2022. CONCLUSIONS: Overall, modest changes in weight were seen following ART switch from INSTI-based regimen to a DOR-based, non-INSTI regimen. Further investigations with larger people with HIV cohorts will be helpful to guide clinical practice, while the impact of the COVID-19 pandemic on weight change should also be considered.

Gestational weight gain and adverse birth outcomes in South African women with HIV on antiretroviral therapy and without HIV: a prospective cohort study.

INTRODUCTION: Outside of pregnancy, evidence shows that persons with HIV initiating or switching to dolutegravir (DTG)-based antiretroviral therapy (ART) experience greater weight gain compared to those on other ART classes. However, there are few data on the impact of DTG-based ART on gestational weight gain (GWG) in sub-Saharan Africa where HIV is most common. According to the National Academy of Medicine (NAM), GWG below and above NAM guidelines is associated with adverse birth outcomes. Therefore, the objective of this study was to describe GWG by HIV status and ART regimen, and examine the associations with adverse birth outcomes. METHODS: We enrolled pregnant women with HIV (WHIV) and without HIV (≥18 years) in a peri-urban primary healthcare facility in Cape Town, South Africa between 2019 and 2022. GWG was study-measured at 24-28 (baseline) and 33-38 weeks gestation and converted to GWG rate (kg/week) in accordance with NAM guidelines. GWG z-scores were generated using the INTEGROWTH-21 and US standards to account for differing lengths of gestation. Birth outcome data were obtained from medical records. Associations of GWG z-score with adverse birth outcomes were assessed using multivariable linear or log-binomial regression. RESULTS: Among 292 participants (48% WHIV), median age was 29 years (IQR, 25-33), median pre-pregnancy body mass index (BMI) was 31 kg/m2 (IQR, 26-36) and 20% were primiparous at baseline. The median weekly rate of GWG was 0.30 kg/week (IQR, 0.12-0.50), 35% had GWG below NAM standards (59% WHIV) and 48% had GWG above NAM standards (36% WHIV). WHIV gained weight more slowly (0.25 vs. 0.37 kg/week, p<0.01) than women without HIV. Weekly rate of GWG did not differ by ART regimen (DTG-based ART 0.25 vs. efavirenz-based ART 0.27 kg/week, p = 0.80). In multivariable analyses, GWG z-score was positively associated with continuous birth weight (mean difference = 68.53 95% CI 8.96, 128.10) and categorical high birth weight of >4000 g (RR = 2.18 95% CI 1.18, 4.01). CONCLUSIONS: Despite slower GWG among WHIV, nearly half of all women gained weight faster than recommended by the NAM. GWG was positively associated with infant birth weight. Interventions to support healthy GWG in sub-Saharan Africa are urgently needed.

Willingness to Use Long-Acting Injectable Cabotegravir and Associated Factors Among Men Who Have Sex with Men in Guangxi, China.

Cabotegravir (CAB-LA), the first long-acting injectable pre-exposure prophylaxis (PrEP), has been approved for use in the USA and is not currently on the market in China. However, willingness to use CAB-LA and associated factors among men who have sex with men (MSM) have not yet been evaluated in China. A cross-sectional study was conducted in Guangxi, China, in 2022 recruiting 1,006 MSM. Their mean age was 30.2 years, 74.2% had college or above education, and 48.6% had a monthly income between 3,000 and 5,999 Chinese yuan (CNY). Most (73.4%) had previously heard of PrEP while few (8.3%) had ever used this type of preventative medication. Willingness to use CAB-LA was 79.8% and was positively associated with eight variables: younger age, being married to a woman, having a low monthly income, having six or more male partners in the past six months, having only regular male partners in the past month, having a high perceived risk of HIV infection, and history of using PrEP. Ten other variables were not significantly associated with willingness to use CAB-LA. Among 894 participants who were willing to use or did not definitely reject using CAB-LA, the main concerns about CAB-LA were its side effects (90.2%), efficacy (63.6%), and high cost (58.2%). Only 14.7% were willing to pay more than 1,200 CNY (~US$180) every two months to use CAB-LA. The preferred injection places were centers for disease control facilities, hospitals, and social organizations. Many (89.0%) said that they would recommend CAB-LA to their male sexual partners. We conclude that willingness to use CAB-LA was high among MSM in Guangxi. However, implementation of CAB-LA faces tough challenges due to its high cost and the low use of PrEP. Peer education may play a large role in the implementation of CAB-LA in China.

Apixaban Versus Vitamin K Antagonists in Patients With Antiphospholipid Syndrome: A Cohort Study.

ABSTRACT: Current guidelines recommend that direct anticoagulants should not be used in prevention of recurrent thrombosis in patients with antiphospholipid syndrome (APS). However, except for triple-positive APS and rivaroxaban use, little evidence supports such recommendation. In a real-life cohort study, we evaluated the risk of thromboembolism and bleeding in patients with APS on apixaban versus vitamin K antagonists (VKA). We enrolled 152 patients with APS (aged 44 years [interquartile range 36-56], 83% women), including 66 patients treated with apixaban 5 mg bid and 86 with warfarin (target international normalized ratio [INR] 2-3). During a median follow-up of 53 months, we recorded venous thromboembolism, ischemic stroke, or myocardial infarction, along with major bleeding. We observed 4 thrombotic events (6.1%, 3 venous thromboembolism and 1 ischemic stroke) in patients on apixaban and 12 events (14%, 9 venous thromboembolism, 2 ischemic strokes and 1 myocardial infarction) in VKA patients. Patients with APS on apixaban had similar risk of recurrent thromboembolism compared with those on warfarin (hazard ratio [HR] = 0.327, 95% confidence interval [CI]: 0.104-1.035). Thromboembolic events occurred less commonly in statin users (8% vs. 50%, P = 0.01) and more frequently in triple-positive APS (50% vs. 22.1%, P = 0.028) and in patients with higher D-dimer at baseline ( P = 0.023); the latter difference was present in the apixaban group ( P = 0.02). Patients on apixaban had similar risk of major bleeding compared with warfarin (HR = 0.54, 95% CI: 0.201-1.448). In real-life patients with APS, apixaban appears to be similar to VKA for the prevention of thromboembolism and risk of bleeding, which might suggest that some patients with APS could be treated with apixaban.

Selection criteria for anticoagulants: survey of Japanese cardiologists based on their daily clinical practice: the Selection DOAC study.

BACKGROUND: In patients with atrial fibrillation (AF), direct oral anticoagulants (DOACs) have been utilized as an alternative to warfarin, which is known to have several limitations. This study aimed to clarify the selection criteria for anticoagulants, considering both individual patient factors and the differences between various drugs. METHODS: This study conducted a web-based questionnaire from September 20, 2023 to October 3, 2023, among physicians who were members of a cardiology-specific website. RESULTS: In total, 172 respondents were enrolled in this study. Edoxaban was the most frequently selected anticoagulant (39.1%), followed by apixaban (32.7%) and rivaroxaban (16.8%). Logistic regression analysis revealed that increased concern for adherence enhanced the frequency of selecting edoxaban (odds ratio [OR] = 2.42; p = 0.047), with the opposite trend observed for dabigatran (OR = 0.404; p = 0.029). The selection of apixaban is related to whether the patient is able to maintain a regular lifestyle, including adherence to medication schedules (OR = 1.874; p = 0.031). Furthermore, detailing activities from a medical representative, especially regarding a new indication, were found to influence drug selection for rivaroxaban (OR = 2.422; p = 0.047). CONCLUSION: This study revealed that edoxaban is the most frequently selected anticoagulant. Although prescribing cardiologists select drugs based on background factors, adherence to medication and information from medical representatives were also crucial factors in the selection process.

Tolerability and efficacy of switching anti-fibrotic treatment from nintedanib to pirfenidone for idiopathic pulmonary fibrosis.

BACKGROUND: In real-world studies, the rate of discontinuation of nintedanib (NT) varies from 4% to 53%. Switching anti-fibrotic treatment in patients with idiopathic pulmonary fibrosis (IPF) has not been adequately investigated, and data on the tolerability and efficacy of changes in anti-fibrotic treatment is limited in clinical practice. OBJECTIVE: To identify factors associated with poor continuation of NT, efficacy and predictors of deterioration after switching from NT to pirfenidone (PFD) in patients with IPF. SUBJECTS AND METHODS: One hundred and seventy patients with IPF in whom NT was introduced between April 2017 and March 2022 were included to investigate NT continuation status and the effect of switching to PFD. RESULTS: A total of 123 patients (72.4%) continued NT for 1 year and had a significantly higher %forced vital capacity (FVC) at NT introduction than those who discontinued within 1 year (80.9% ± 16.3% vs. 71.9% ± 22.1%, P = 0.004). The determinant of poor NT continuation was the high GAP stage. On the other hand, 28 of 36 patients who discontinued NT because of disease progression switched to PFD. Consequently, FVC decline was suppressed before and after the change. The predictor of deterioration after the switch was a lower body mass index. CONCLUSIONS: In patients with IPF, early NT introduction increased continuation rates, and switching to PFD was effective when patients deteriorated despite initial NT treatment.

Awareness and practical evaluation of correct use of iron chelators; a study to track the ambiguities of thalassemia patients on their medications in Iran.

PURPOSE: This study aimed to evaluate the knowledge, attitude, and practice toward iron chelating agents (ICAs) in Iranian thalassemia major patients. METHODS: A total of 101 patients with thalassemia major were involved in this cross-sectional survey. A deep medication review was done, and participants' knowledge, attitude, and practice were evaluated by a validated instrument based on a 20-scoring system. RESULTS: Statistical analyses showed 52 patients (51.5%) had a poor knowledge level (scores < 10) about their medications, 37 (36.6%) had a moderate level (scores 10-15), and 12 (11.9%) had a satisfactory level (scores > 15). Seventy-seven (76.2%) patients have positive beliefs regarding the dependence of their current health status on taking iron chelators, and 63 (62.4%) believed that they would become very ill without taking medication. The results also showed that the mean practice score in patients who received deferoxamine was 5.81 ± 3.50; in the patients who received deferiprone and those who received deferasirox, the mean scores were 7.36 ± 5.15 and 14.94 ± 4.14. Also, the knowledge and practice level had a direct linear correlation based on the regression analyses (P < 0.001). CONCLUSION: In conclusion, results of the present research suggests that the patients' knowledge about the administration, adverse events, and necessity of ICAs was not satisfactory. Improving the knowledge of thalassemia patients toward their medicines through educational interventions is highly recommended to improve their practice level.

Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.

Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.

Time-in-therapeutic-range defined warfarin and direct oral anticoagulants in atrial fibrillation: a Nationwide Cohort Study.

BACKGROUND: Little is known how individual time-in-therapeutic-range (TTR) impacts the effectiveness and safety of warfarin therapy compared to direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF). OBJECTIVE: To compare the effectiveness and safety of standard dose DOACs to warfarin in patients with AF, while categorizing warfarin treated patients into quartiles based on their individual TTR. MATERIALS AND METHODS: We conducted a nationwide study including all patients with new-onset AF between 2011 and 2018 in Finland. Hazard ratios (HR) were calculated using Cox regression analysis with the inverse probability of treatment weighted method to assess the risks of ischaemic stroke (IS), intracranial haemorrhage (ICH) and mortality for users of apixaban (n = 12,426), dabigatran (n = 4545), rivaroxaban (n = 12,950) and warfarin (n = 43,548). RESULTS: The median TTR for warfarin users was 72%. Compared to the second best TTR quartile (reference), the risk of IS was higher in the two poorest TTR quartiles, and lower in the best TTR quartile and on rivaroxaban [2.35 (95% confidence interval, 1.85-2.85), 1.44 (1.18-1.75), 0.60 (0.47-0.77) and 0.72 (0.56-0.92)]. These differences were non-significant for apixaban and dabigatran. HR of ICH was 6.38 (4.88-8.35) and 1.87 (1.41-2.49) in the two poorest TTR groups, 1.44 (1.02-1.93) on rivaroxaban, and 0.58 (0.40-0.85) in the best TTR group compared to the reference group. Mortality was higher in the two poorest TTR groups and lowest in the best TTR group. CONCLUSIONS: The outcome was unsatisfactory in the two lowest TTR quartiles - in half of the patients treated with warfarin. The differences between the high TTR groups and standard dose DOACs were absent or modest.

ATP-induced fibrogenic pathway in circulating cells obtained by idiopathic pulmonary fibrotic (IPF) patients is not blocked by nintedanib and pirfenidone.

Idiopathic pulmonary fibrosis (IPF) is a severe disability due to progressive lung dysfunction. IPF has long been viewed as a non-immune form of pulmonary fibrosis, but nowadays it is accepted that a chronic inflammatory response can exacerbate fibrotic patterns. IL-1-like cytokines and ATP are highly detected in the lung and broncho-alveolar lavage fluid of IPF patients. Because ATP binds the purinergic receptor P2RX7 involved in the release of IL-1-like cytokines, we aimed to understand the role of P2RX7 in IPF. PBMCs from IPF patients were treated with nintedanib or pirfenidone in the presence of ATP. Under these conditions, PBMCs still released IL-1-like cytokines and the pro-fibrotic TGFß. Bulk and scRNAseq demonstrated that lung tissues of IPF patients had higher levels of P2RX7, especially on macrophages, which were correlated to T cell activity and inflammatory response with a TGFBI and IL-10 signature. A subcluster of macrophages in IPF lung tissues had 2055 genes that were not in common with the other subclusters, and that were involved in metabolic and PDGF, FGF and VEGF associated pathways. These data confirmed what observed on circulating cells that, although treated with anti-fibrotic agents, nintedanib or pirfenidone, they were still able to release IL-1 cytokines and the fibrogenic TGFß. In conclusion, these data imply that because nintedanib and pirfenidone do not block ATP-induced IL-1-like cytokines and TGFß induced during P2RX7 activation, it is plausible to consider P2RX7 on circulating cells and/or tissue biopsies as potential pharmacological tool for IPF patients.

The impact of antifibrotic use on long-term clinical outcomes in the pulmonary fibrosis foundation registry.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) with a high mortality rate. The antifibrotic medications pirfenidone and nintedanib have been in use since 2014 for this disorder and are associated with improved rate of lung function decline. Less is known about their long-term outcomes outside of the clinical trial context. METHODS: The Pulmonary Fibrosis Foundation Patient Registry was used for this study. Patients with an IPF diagnosis made within a year of enrollment were included. The treated group was defined as patients receiving either pirfenidone or nintedanib for at least 180 days. The untreated group did not have any record of antifibrotic use. Demographic data, comorbidities, serial lung function, hospitalization, and vital status data were collected from the registry database. The primary outcomes were transplant-free survival, time to first respiratory hospitalization, and time to 10% absolute FVC decline. Time-to-event analyses were performed utilizing Cox proportional hazards models and the log-rank test. Model covariates included age, gender, smoking history, baseline lung function, comorbidities, and oxygen use. RESULTS: The registry contained 1212 patients with IPF; ultimately 288 patients met inclusion criteria for the treated group, and 101 patients were designated as untreated. Patients treated with antifibrotics were significantly younger (69.8 vs. 72.6 years, p = 0.008) and less likely to have smoked (61.1% ever smokers vs. 72.3% never smokers, p = 0.04). No significant differences were seen in race, gender, comorbidities, or baseline pulmonary function between groups. The primary outcome of transplant-free survival was not significantly different between the two groups (adjusted HR 0.799, 95% CI 0.534-1.197, p = 0.28). Time to respiratory hospitalization was significantly shorter in the treated group (adjusted HR 2.12, 95% CI 1.05-4.30, p = 0.04). No significant difference in time to pulmonary function decline was seen between groups. CONCLUSIONS: This multicenter study demonstrated 63% of newly diagnosed IPF patients had continuous antifibrotic usage. Antifibrotics were not associated with improved transplant-free survival or pulmonary function change but was associated with an increased hazard of respiratory hospitalization. Future studies should further investigate the role of antifibrotic therapy in clinically important outcomes in real-world patients with IPF and other progressive ILDs.

In cryptogenic stroke and atrial cardiopathy, apixaban did not reduce recurrent stroke vs. aspirin.

SOURCE CITATION: Kamel H, Longstreth WT Jr, Tirschwell DL, et al; ARCADIA Investigators. Apixaban to prevent recurrence after cryptogenic stroke in patients with atrial cardiopathy: the ARCADIA randomized clinical trial. JAMA. 2024;331:573-581. 38324415.