Citations

Abstract Rational: Talc pleurodesis is an effective intervention for preventing recurrent pleural effusions and pneumothoraces, particularly in non-surgical candidates. Due to its efficacy and safety, it is recommended as the most effective sclerosant for pleurodesis. However, in some cases, the initial pleurodesis fails, necessitating a repeat procedure. The efficacy of repeat talc pleurodesis after an initial failure is an area that requires further exploration. This study explores the safety and efficacy of repeat talc pleurodesis among patients who did not respond to the initial intervention. Methods: This retrospective study analyzed hospitalized patients who underwent 4g talc slurry pleurodesis from 2019 to 2024, focusing on demographics, comorbidities, initial pleurodesis failure, and recurrence rates. Pleurodesis failure was identified by lung sliding, recurrent effusion, or pneumothorax during the same hospitalization. The primary outcome was recurrence post-discharge, assessed by pleural effusion or pneumothorax within 180 days post-repeat pleurodesis. Results: This study included 94 patients (52.1% male, 47.9% female) with a mean age of 67.6. Among them, 79 (84%) received a single 4g dose of talc, while 15 (16%) received multiple 4g talc doses for initial pleurodesis. Recurrence occurred in 20 (25.3%) of the single-dose group and 1 (6.7%) of the multiple-dose group within 180 days, though the difference was not statistically significant (p=0.112). Recurrence-free rates were 93.6% at 30 days, 85.1% at 90 days, and 77.7% at 180 days. Of the 20 patients with recurrence after a single 4g dose of talc, 8 (40%) underwent repeat pleurodesis, with only one recurrence requiring surgical intervention. Additionally, there was no recurrence after repeat talc pleurodesis in the one patient with recurrence after receiving multiple 4g talc doses for initial pleurodesis. No associations were found between recurrence rates and factors like gender (p=0.213) or comorbidities (emphysema, COPD, lung malignancy). Chest pain was a common complaint, but no cases of respiratory distress were reported post-pleurodesis. Conclusion: The efficacy of initial talc pleurodesis (77.7%-93.6%) in this cohort aligns with existing literature. Multiple-dose talc pleurodesis effectively prevented recurrence in 93.3% of patients, with no reported respiratory distress. Additionally, repeat talc pleurodesis was successful in 87.5% of those with recurrence after an initial single 4g dose. These findings support multiple-dose talc pleurodesis and repeat talc pleurodesis as safe and effective options for preventing recurrence post-initial failure and post-repeat talc pleurodesis, respectively. Although no significant recurrence predictors were identified, future research could focus on patient-specific factors to enhance treatment selection and optimize outcomes.

Abstract Introduction Cigarette smoking is highly prevalent among Asian American immigrant subgroups. Previously, Asian-language telephone Quitline services were only available in California. In 2012, the Centers for Disease Control and Prevention (CDC) funded the national Asian Smokers’ Quitline (ASQ) to expand Asian-language Quitline services nationally. However, there are relatively few calls to the ASQ from outside California. Aims and Methods This pilot study assessed the feasibility of two proactive outreach interventions to connect Vietnamese-speaking participants who smoke to the ASQ. Both interventions, (1) proactive telephone outreach with a counselor trained in motivational interviewing (PRO-MI) and (2) proactive telephone outreach with interactive voice response (PRO-IVR), were adapted to be culturally and linguistically appropriate for Vietnamese-speaking participants. Participants were randomly assigned 2:1 to PRO-IVR versus PRO-MI. Assessments were conducted at baseline and 3 months post-enrollment. Feasibility indicators were the recruitment rate and initiation of ASQ treatment. Results Using the HealthPartners electronic health record, a large health system in Minnesota, we identified approximately 343 potentially eligible Vietnamese participants who were mailed invitation letters and baseline surveys with telephone follow-up. We enrolled 86 eligible participants (25% recruitment rate). In the PRO-IVR group 7/58 participants were directly transferred to the ASQ (12% initiation rate) and in the PRO-MI group 8/28 participants were warm transferred to the ASQ (29% initiation rate). Conclusions This pilot study demonstrates the feasibility of our recruitment methods and of implementing proactive outreach interventions to promote the initiation of smoking cessation treatment with the ASQ. Implications This pilot study contributes novel data on the uptake of Asian Smokers’ Quitline (ASQ) services among Vietnamese-speaking people who smoke (PWS) with two proactive outreach interventions: (1) proactive telephone outreach with a counselor trained in motivational interviewing (PRO-MI) and (2) proactive telephone outreach with interactive voice response (PRO-IVR). We found that it is feasible to implement these proactive outreach interventions to promote the initiation of ASQ cessation treatment among Vietnamese-language speaking PWS. Future large trials are needed to rigorously compare PRO-MI and PRO-IVR and conduct budget impact analyses to understand the most efficient strategies for incorporation into health system settings.

Albumin-interferon-α (alb-IFN) is a novel recombinant protein derived from IFN-α2b genetically fused to human albumin. The resulting single polypeptide combines in one molecule the antiviral properties of IFN-α with the long serum half-life of albumin. IFN-mediated biological responses stem from the engagement of IFN-α with its target receptor and subsequent modulation of IFN-specific gene (ISG) expression. To evaluate the pharmacodynamics of alb-IFN during the Phase I/II study conducted in patients with chronic hepatitis C (CHC) who had previously failed IFN-α-containing regimens, ISG induction was evaluated in peripheral blood and compared with antiviral response. Whole blood was obtained at day 0, day 7 and day 28 from 21 patients enrolled in the higher dose (500–900 μg) alb-IFN cohort, who received two injections on day 0 and day 14. Taqman real-time PCR was used to assess candidate ISG expression. There was sustained induction on day 7 and day 28 of the ISG's OAS1, IRF-7, IFI44 and IFI27. Although all patients showed a molecular response to alb-IFN, individual variability in pretreatment gene expression levels and fold of modulation during treatment was observed. At day 28, induction of OAS1, IFI44 and IRF7 showed pairwise correlation in individual patients ( P<0.05). Moreover, the induction of expression at day 28, and pretreatment levels of OAS1 and IFI44 correlated with hepatitis C virus RNA reduction at day 28 ( P<0.05). In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the response associated with an IFN-α.

Albumin-interferon-α (IFN-α) is a novel 85.7–kDa recombinant protein consisting of IFN-α that is genetically fused to human serum albumin. In this Phase I/II, multicentre, open-label study, we evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics of albumin-IFN-α in IFN-α-experienced patients with chronic hepatitis C. Albumin-IFN-α was administered in 22 escalating doses (7–900 μg) in a single injection or in two injections 14 days apart. In the 119 patients studied, there were no discontinuations because of adverse events, and albumin-IFN-α had a favourable safety profile at doses up to 900 μg. The most common adverse events were headache (56%), fatigue (52%), injection site erythema (38%), arthralgias (32%) and pyrexia (27%). Reduced clearance resulted in a mean elimination half-life of 159h, which supports dosing at 2- to 4-week intervals. Induction of the IFN-specific gene OAS1 was maintained for ≥28 days following a single injection of albumin-IFN-α at doses of ≥40 μg. Dose-dependent antiviral activity was observed in this IFN-α-experienced study population. Antiviral activity of ≥1.0–log reductions in HCV RNA was observed in 47% (37/78) of patients in the 120- to 900-μg cohorts and in 59% (16/27) in the 400- to 900-μg double-injection cohorts. These results support further clinical studies of albumin-IFN-α for the treatment of patients with chronic hepatitis C.

The mammalian liver's regenerative ability has led researchers to engineer animals as incubators for expansion of human hepatocytes. The expansion properties of human hepatocytes in immunodeficient mice are well known. However, little has been reported about larger animals that are more scalable and practical for clinical purposes. Therefore, we engineered immunodeficient swine to support expansion of human hepatocytes and identify barriers to their clinical application. Immunodeficient swine were engineered by knockout of the recombinase-activating gene 2 ( RAG2 ) and fumarylacetoacetate hydrolase (FAH). Immature human hepatocytes (ihHCs) were injected into fetal swine by intrauterine cell transplantation (IUCT) at day 40 of gestation. Human albumin was measured as a marker of engraftment. Cytotoxicity against ihHCs was measured in transplanted piglets and control swine. We initially detected higher levels of human albumin in cord blood of newborn FAH/ RAG2 -deficient (FR) pigs compared with immunocompetent controls (196.26 ng/dL vs. 39.29 ng/dL, p = 0.008), indicating successful engraftment of ihHCs after IUCT and adaptive immunity in the fetus. Although rare hepatocytes staining positive for human albumin were observed, levels of human albumin did not rise after birth, but declined, suggesting rejection of xenografted ihHCs. Cytotoxicity against ihHCs increased after birth by 3.8% (95% CI: [2.1%–5.4%], p < 0.001) and inversely correlated with declining levels of human albumin ( p = 2.1 × 10 −5 , R 2 = 0.17). Circulating numbers of T cells and B cells were negligible in FR pigs. However, circulating natural killer (NK) cells exerted cytotoxicity against ihHCs. NK cell activity was lower in immunodeficient piglets after IUCT than in naive controls (30.4% vs. 40.1%, p = 0.011, 95% CI for difference [2.7%–16.7%]). In conclusion, ihHCs were successfully engrafted in FR swine after IUCT. NK cells were a significant barrier to expansion of hepatocytes. New approaches are needed to overcome this hurdle and allow large-scale expansion of human hepatocytes in immunodeficient swine. Impact statement There is currently a need for robust expansion of human hepatocytes. We describe an immunodeficient swine model into which we engrafted immature human hepatocytes (ihHCs). We identified the mechanism of the eventual graft rejection by the intact NK cell population, which has not been previously shown to have a significant role in xenograft rejection. By both improving engraftment and reducing NK cell-mediated cytotoxicity toward the graft through intrauterine cell transfer, we confirmed the presence of residual adaptive immunity in this model of immunodeficiency and the ability to induce hyposensitization in the NK cell population by taking advantage of the fetal microenvironment.

Zebrafish are increasingly utilized to model cardiomyopathies and regeneration. Current methods evaluating cardiac function have known limitations, fail to reliably detect focal mechanics, and are not readily feasible in zebrafish. We developed a semiautomated, open-source method — displacement analysis of myocardial mechanical deformation (DIAMOND) — for quantitative assessment of 4D segmental cardiac function. We imaged transgenic embryonic zebrafish in vivo using a light-sheet fluorescence microscopy system with 4D cardiac motion synchronization. Our method permits the derivation of a transformation matrix to quantify the time-dependent 3D displacement of segmental myocardial mass centroids. Through treatment with doxorubicin, and by chemically and genetically manipulating the myocardial injury–activated Notch signaling pathway, we used DIAMOND to demonstrate that basal ventricular segments adjacent to the atrioventricular canal display the highest 3D displacement and are also the most susceptible to doxorubicin-induced injury. Thus, DIAMOND provides biomechanical insights into in vivo segmental cardiac function scalable to high-throughput research applications.