Household air pollution (HAP), particularly from cooking-related particulate matter (PM2.5), poses significant health risks but remains understudied compared to ambient air pollution. We evaluated the short-term cardiorespiratory effects of exposure to cooking-generated PM2.5 and examined the efficacy of automated indoor air quality interventions. Using a crossover design, seven cohorts of two participants each were exposed to two residential conditions over four weeks in a Living Lab: the Standard Control Condition (SCC), featuring basic HVAC, and the Advanced Control Condition (ACC), which included automated range hoods, portable air cleaners and exhaust systems activated by PM2.5 sensors. PM2.5 concentrations were continuously monitored in the breathing zone at the room level. The physiological markers, blood pressure (BP), heart rate (HR), heart rate variability (HRV) and fractional exhaled nitric oxide (FeNO), were measured on the occupant before and after cooking events. Cooking events caused substantial short-term increases in PM2.5 levels, median concentrations rose from < 1 µg/m³ to 263.7 µg/m³ under SCC and to 168.9 µg/m³ under ACC during HRV measurement periods, with exposure levels exceeding WHO 24-hour guidelines up to 82% of the time. Compared to SCC, the ACC significantly reduced PM2.5 exposure (p < 0.05). Systolic blood pressure (SBP) decreased significantly post-cooking under ACC (ΔSBP = -3.1 ± 10.0 mmHg) but not in the SCC (ΔSBP = -0.9 ± 8.0 mmHg; p < 0.05). HR and HRV showed no statistically significant differences between conditions, though trends in RMSSD, SDNN and LF/HF ratio suggested improved autonomic balance under ACC. HR decreased post-cooking under ACC but increased slightly under SCC (ΔHR = -4.5 ± 6.5 bpm vs. 1.0 ± 1.1 bpm; 95% CI: (-9.8 to -1.2)). FeNO decreased significantly within both conditions pre- to post-cooking, but the difference in reduction between conditions did not reach statistical significance, despite a trend toward greater decline in the ACC. These findings suggest that semi-chronic exposure to cooking-related PM2.5 can adversely affect cardiovascular function, particularly systolic BP and HR, and that automated indoor air quality interventions can meaningfully reduce pollutant exposure and associated physiological impacts. Our results support the implementation of HAP mitigation strategies in residential settings and highlight the need for further research among populations with existing cardiopulmonary conditions.

The ability of cancer cells to undergo identity changes (i.e., lineage plasticity) plays a key role in tumor progression and response to therapy. Loss of the pulmonary lineage specifier NKX2-1 in KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and causes a FoxA1/2-dependent pulmonary-to-gastric lineage switch. However, the mechanisms by which FoxA1/2 activate a latent gastric identity in the lung remain largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of gastric-specific genes after NKX2-1 loss in mouse models by facilitating ten-eleven translocation (TET)2/3 recruitment, DNA demethylation, histone 3 lysine 27 acetylation (H3K27ac) deposition, and three-dimensional (3D) chromatin interactions. FoxA1/2-mediated DNA methylation changes are highly conserved in human endodermal development and in progression of human lung and pancreatic neoplasia. Furthermore, oncogenic signaling is required for specific elements of FoxA1/2-dependent epigenetic reprogramming. This work demonstrates the role of FoxA1/2 in rewiring the DNA methylation and 3D chromatin landscape of NKX2-1-negative LUAD to drive cancer cell lineage switching.

Lung cancer, the leading cause of cancer mortality, exhibits diverse histological subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. Here we established the Lung Cancer Mouse Model Database (LCMMDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMMs), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors have produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCMMDB aligns 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in GEMMs. Accompanying this resource, we developed a web application that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCMMDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance.

Purpose: Evusheld (tixagevimab/cilgavimab), a combination of two monoclonal antibodies against SARS-CoV-2, was authorized in January 2022 as prophylaxis in immunocompromised patients.Data on Evusheld efficacy in lung transplant patients is lacking.This study aimed to determine if Evusheld reduces SARS-CoV-2 infection or is associated with improved clinical outcomes in lung transplant recipients.Methods: We performed a single-center retrospective study of lung transplant recipients at our institution who were alive in 2022.SARS-CoV-2 diagnoses from 1/1/2022 to 6/30/22 were recorded.Demographics, number of COVID vaccine doses, Evusheld administration, and COVID-19 clinical outcomes were recorded.The primary outcome was rate of SARS-CoV-2 infection between patients who received Evusheld and those who did not.Secondary outcomes included death, hospitalization, hospital length of stay, and decline in FEV1.Data were analyzed using Fisher's exact test or logistic regression controlling for age and vaccine doses.Results: 336 patients were included in the study (57% male, 84% double lung transplants, 51% prior interstitial lung disease, median of 3 years post-transplant, median of 3 COVID vaccine doses).136 (40%) received Evusheld 600mg.Among patients who received Evusheld, 7 (5%) were diagnosed with SARS-CoV-2 infection, compared to 30 (15%) of patients without Evusheld (p=0.005,Figure).After controlling for age and COVID vaccine doses received, Evusheld reduced the risk of SARS-CoV-2 by 92% (OR 0.084, 95%CI 0.02-0.29,p<0.001).There were no significant differences between groups in symptom development (86% with Evusheld vs 93%, p=0.47), hospitalization rate (14% vs 23%, p=1.0), hospital length of stay (1 vs 9 days, p=0.29), >10% decline in FEV1 (18% vs 29%, p=0.61), or death (0% vs 13%, p=0.57).Conclusion: After controlling for age and COVID vaccine doses received, Evusheld substantially lowered the risk of SARS-CoV-2 infection, with limited impact on clinical outcomes once infected.

Several factors occurring in early life, including lower respiratory tract illnesses (LRIs), are involved in determining lung structure and function in adulthood, but the effects of these factors on lung development remain largely unknown. Hereby, we evaluated the parameters from computed tomography (CT) scans performed at the age of 26 years in 39 subjects from the birth cohort of the Tucson Children's Respiratory Study (TCRS) in order to determine the relationship between early childhood factors and lung structural changes in young adult life. We found that participants with LRIs in childhood had increased air trapping at the age of 26 suggesting an association between childhood infections and lung development.

Assessment of heart rate variability (HRV) during exercise is an emerging area of study. Measurements of HRV are characterized by domain (time, frequency, and nonlinear) or time scale (short or long-term). The purpose of this study was to compare methods of HRV analysis during submaximal running before and after 18 weeks of marathon training. Pre and post-training, 42 recreational runners (21.1 ± 1.5 years, 28 f) completed a 2-mile (3218 m) time trial (2MI) and a submaximal run (SUBMAX) at 75

There is an urgent clinical need to identify patients likely to benefit from immune checkpoint inhibitor ICI treatment. Approaches available in the clinic today, such as PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB), are insufficient for this task, in part as differences in microenvironments expressed by individual tumors may lead to heterogeneous response patterns. Recent efforts exploring the utility of quantitative imaging (radiomic) biomarkers to predict response to ICIs have shown promise to provide a more accurate and scalable method. In contrast to previously published models, our work focuses on generalizable models for predicting individual lesion-level as well as patient-level response at 3-month follow-up per RECIST criteria, using a large multi-institutional “real-world” dataset. The models combine radiomics features with demographic, molecular, and laboratory values routinely available in patients’ electronic medical records. We analyzed radiomic characteristics of 6,295 primary and metastatic lesions from 1,206 metastatic NSCLC patients treated with anti-PD-1/anti-PD-L1 ICIs from 8 institutions across the US and Europe. Patients with unavailable PD-L1 IHC, imaging follow-up, or with oncogenic driver mutations were excluded from analysis, resulting in a total dataset of 766 subjects randomly assigned to training (N=514) and validation sets (N=252). Using gradient-boosted decision tree algorithms, we developed a multi-modal predictive model to identify patients responding to ICI therapy at 3-months and evaluated its performance against an imaging-only CT radiomics model and the clinical standard of care, biopsy-based PD-L1 IHC. The multi-modal model contains CT radiomic features capturing lesion heterogeneity and spicularity, patient demographics, PD-L1 TPS, and tumor burden volume in the lung, lymph nodes, and the liver. Under the two-tailed DeLong test, the multi-modal model demonstrated statistically significant benefit over the current standard of care (PD-L1 IHC) in predicting multi-lesion 3-month response: 0.81 (P=.005) area under the receiver operating characteristic curve (ROC-AUC) in first-line ICI monotherapy patients, 0.72 (P=.044) in all-lines ICI monotherapy, and 0.71 (P=.025) in all-lines ICI-chemotherapy combination. The imaging-only model demonstrated predictive performance comparable to PD-L1 IHC: 0.71 (P=.226), 0.61 (P=.905), 0.62 (P=.674) on the same cohorts respectively. A multi-modal CT radiomics-based approach demonstrated predictive accuracy benefit over the current clinical standard and may provide an opportunity for more personalized patient management, such as risk-based escalation/de-escalation of concurrent chemotherapy in NSCLC patients. We will evaluate this methodology in prospective studies. Citation Format: Ravi B. Parikh, Petr Jordan, Rita J. Ciaravino, Ryan A. Beasley, Arpan A. Patel, Dwight H. Owen, Arya Amini, Brendan D. Curti, Ray Page, Aurelie Swalduz, Jean-Paul Beregi, Jan Chrusciel, Eric Snyder, Pritam Mukherjee, Heather M. Selby, Soohee Lee, Roshanthi Weerasinghe, Shwetha Pindikuri, Jakob B. Weiss, Andrew L. Wentland, Anish Kirpalani, An Liu, Olivier Gevaert, George Simon, Hugo JWL Aerts. Multi-institutional validation of a radiomics-based artificial intelligence method for predicting response to PD-1/PD-L1 immune checkpoint inhibitor (ICI) therapy in stage IV NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5618.

Background Currently approved biomarkers that predict response to ICIs in mNSCLC are limited to PD-L1 expression levels by immunohistochemistry (IHC) and tumor mutation burden (TMB). However, the predictive performance of PD-L1 IHC and TMB are limited, and rates of testing are suboptimal. Radiomic biomarkers may offer an automated and scalable method to predict ICI response.1,2 We developed and validated multi-modal models predicting responses to ICIs in mNSCLC. In contrast to previously published models, our work focuses on generalizable models using a large multi-institutional “real-world” dataset and combines radiomics features with demographic, molecular, and laboratory values routinely available in patients’ electronic medical records [EMR]. Methods We analyzed radiomic characteristics of 6,028 primary and metastatic lesions from 1,169 mNSCLC patients treated with anti-PD-1/anti-PD-L1 ICIs from 8 institutions across the US and Europe. Data were randomly split into training (N=707 patients, n=3,625 lesions) and validation (N=462 patients, n=2,403 lesions) sets. Baseline and follow-up CT scans were manually annotated by board-certified radiologists using RECIST 1.1 criteria and all lesion volumes were manually segmented. We developed two predictive models using gradient-boosted decision tree algorithms, using 1) only manually curated baseline radiomic features quantifying textural heterogeneity and spicularity; and 2) a multi-modal model with radiomic features combined with known demographic, molecular (e.g. PD-L1 IHC), and laboratory (e.g. neutrophil-to-lymphocyte ratio) predictors of ICI response. Primary endpoints were 3- and 6-month radiological progression, defined by a 20% increase in lesion diameter. The primary evaluation metric was the area under the receiver operating characteristic curve (AUC). Models predicting response of lung lesions and lymph nodes were validated on two cohorts: ICI monotherapy and ICI plus concurrent chemotherapy. Patients with unavailable PD-L1 IHC, imaging follow-up, or oncogenic driver mutations were excluded from analysis. Results The radiomics model showed predictive accuracy comparable to tissue-based PD-L1 IHC for both endpoints and patient cohorts (tables 1, 2). However, the multi-modal model predicted lung and lymph node radiological progression with significantly higher AUC than PD-L1 IHC in all cohorts and endpoints, with 3- and 6-month progression AUCs of 0.86 (P=.00007) and 0.79 (P= .00001) in lung lesions and 0.78 (P=.003) and 0.80 (P=.002) in lymph nodes. Conclusions Radiomics-based multi-modal prediction of ICI response is feasible and accurate and may provide an opportunity for more personalized management, such as risk-based escalation/de-escalation of concurrent chemotherapy in mNSCLC patients. We will evaluate this methodology in prospective studies. References Trebeschi S, Drago S, Birkbak N, Kurilova I, Cǎlin A, Delli Pizzi A, Lalezari F, Lambregts D, Rohaan M, Parmar C, Rozeman E, Hartemink K, Swanton C, Haanen J, Blank C, Smit E, Beets-Tan R, Aerts H. Predicting response to cancer immunotherapy using noninvasive radiomic biomarkers. Ann. Oncol. 2019; 30(6): 998–1004. Sun R, Limkin E, Vakalopoulou M, Dercle L, Champiat S, Han SR, Verlingue L, Brandao D, Lancia A, Ammari S, Hollebecque A, Scoazec J, Marabelle A, Massard C, Soria J, Robert C, Paragios N, Deutsch E, Ferté C. A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: an imaging biomarker, retrospective multicohort study. Lancet Oncol. 2018; 19(9): 1180–1191. Ethics Approval Ethics approval for US data: The study was conducted under IRB-approved procedures using de-identified data for patients diagnosed with Stage-IV NSCLC and treated between Jan. 1, 2017 and December 31, 2021. All records were de-identified per HIPAA guidelines at the institution level. Upon transfer, the data was quarantined and then re-inspected by authorized personnel prior to ingestion to ensure compliance and that no PHI was present in the records. Ethics approval for EU data: The study was conducted under IRB-approved procedures using de-identified data for patients diagnosed with Stage-IV NSCLC and treated between Jan. 1, 2017 and December 31, 2021. All records were de-identified per GDPR requirements at the institution level. The patients were also notified that their de-identified data would be part of a study and were given the required time and opportunity to respond if they had any objection. Upon transfer, the data was quarantined and then re-inspected by authorized personnel prior to processing to ensure compliance and that no PHI was present in the records. Consent N/A

Purpose The 2018 UNOS heart allocation policy intended to prioritize recipients of highest acuity in addition to broader geographic sharing. As such, 6 tiers were developed from 3 to try and account for this heterogeneous population. We sought to assess the impact of this change on post-transplant outcomes in the highest urgency statuses (Status 1-3 vs prior Status 1A). Methods 7710 patients were identified in the UNOS registry that were either prior status 1A (n=3764) or status 1-3 in the current system (n=3946) during a 2-year period immediately prior and following the policy change. Comparisons between cohorts were assessed using standard statistical methods, survival analysis was censored at 1-year using the Kaplan-Meier method, and multivariate Cox proportional hazard regression analysis (adjusted for age, sex, diabetes, race, ischemic time, dialysis, life support, waiting time & HLA mismatch) were performed. Results Waitlist times were significantly shorter following the policy change for the status 1-3 group (21.0 vs 54.5 days, p<0.001). With the current policy, recipients were less likely to be female (24.1% vs 29.1%, p<0.001). Additionally, recipients were more likely to have longer ischemic times (p<0.001), to be supported with intraaortic ballon pumps (IABP) (p<0.001) as well as elevated pulmonary arterial pressures (p<0.001). Notably, recipients were less likely to be supported with an LVAD (35.8% vs 42.7%, p<0.001). There was no difference in survival (p=0.144). Unadjusted analysis demonstrated HR 1.13 (CI 0.96-1.32) and following adjustment HR 1.03 (CI 0.87-1.23). Conclusion The new UNOS heart allocation policy change did not adversely affect post-transplant outcomes in this intermediate term analysis. In the highest acuity statuses, waitlist time decreased. However, further study is warranted to better understand implications and perhaps unintended consequences for gender as well as change in therapeutic strategies (increased IABPs, less VADs).

Purpose Circulating donor-derived cell-free DNA (dd-cfDNA) levels have been proposed as a potential tool for the diagnosis of graft injury (rejection, infection, ischemia/reperfusion injury). In this study, we prospectively investigated dd-cfDNA plasma levels and their association with severe primary graft dysfunction at 72 hours and acute cellular rejection in the first month after lung transplant. Methods Thirty-five subjects undergoing double lung transplants at our institution between Jun.2020-Oct.2021 were included in this study. Primary Graft Dysfunction (PGD) was graded according to ISHLT criteria. Our protocol includes a surveillance bronchoscopy with transbronchial biopsy at 3 weeks post-transplant. Acute cellular rejection was diagnosed and graded by a pulmonary pathologist after evaluation of histopathology slides. Blood samples were collected at various time points before and after lung transplant. Dd-cfDNA in samples were determined using AlloSure dd-cfDNA test kits (CareDx, Inc.). Results We observed a rapid increase of dd-cfDNA in blood of recipients after lung transplantation compared to baseline. The levels of dd-cfDNA decreased during the first two weeks (Figure A). The peak was observed within 72 hours after transplantation. The peak values of dd-cfDNA varied among subjects and had no correlation with PGD grade 3 occurrences at 72 hours. (Figure B, p=0.85). We observed an association between levels of dd-cfDNA from blood collected at the time of transbronchial biopsy and the histological diagnosis of ACR at 3 weeks. (Figure C, mean 2.7% versus 1.5%, p=0.015) Conclusion This preliminary data shows that circulating dd-cfDNA levels are associated with ACR early after transplantation but not with severe PGD at 72hours. Plasma levels of dd-cfDNA may be a less invasive tool to estimate graft rejection after lung transplantation however larger studies are still necessary to better identify thresholds.

Purpose The purpose of this study was to compare the outcomes of patients waitlisted for heart transplantation (HT) with durable left ventricular assist devices (dLVAD) before and after the heart allocation policy change. Methods The UNOS database was queried to identify two cohorts of adult patients with isolated dLVAD listed for HT within same-length time periods under the "old policy" (12/05/2016 - 10/17/2018) and "new policy" (10/18/2018-9/4/2020) eras. Candidates waitlisted with any other forms of mechanical support were excluded. Cumulative hazards of waitlist outcomes were compared at one year. Kaplan Meier analysis was used to compare a composite outcome of overall freedom from death or delisting due to worsening clinical condition. Of patients that underwent HT, post-transplant survival was compared at one year. Results 3,551 patients were analyzed, 2,010 listed under the old policy and 1,541 under the new policy. Demographics were similar, but Heartmate II (n=935, 46.5%) was more commonly used under the old policy and Heartmate III (n=788, 51.1%) under the new (P<0.001). From time of waitlisting, patients listed under the new policy had a lower freedom from death or delisting due to clinical status (Figure A; P=0.05). At one-year, new policy patients were less likely to be transplanted (Figure B), however, the risk of death or delisting was comparable (Figure C). A total of 991 patients were waitlisted and transplanted under the old policy era, and 728 under the new. At one-year post-transplant, patients with a dLVAD that were transplanted in the new era had worse survival (Figure D; 86.6% vs 92.5%; P<0.001). Conclusion Under the new policy, patients with a dLVAD are less likely to be transplanted and are more likely to die or be delisted. This appears to be driven by higher post-transplant mortality rather than waitlist mortality, which should be considered in future iterations of the allocation policy.

Here we describe the design and implementation of a novel data management platform for an academic cancer center which meets the needs of multiple stakeholders. A small, cross-functional technical team identified key challenges to creating a broad data management and access software solution: lowering the technical skill floor, reducing cost, enhancing user autonomy, optimizing data governance, and reimagining technical team structures in academia. The Hyperion data management platform was designed to meet these challenges in addition to usual considerations of data quality, security, access, stability, and scalability. Implemented between May 2019 and December 2020 at the Wilmot Cancer Institute, Hyperion includes a sophisticated custom validation and interface engine to process data from multiple sources, storing it in a database. Graphical user interfaces and custom wizards permit users to directly interact with data across operational, clinical, research, and administrative contexts. The use of multi-threaded processing, open-source programming languages, and automated system tasks (normally requiring technical expertise) minimizes costs. An integrated ticketing system and active stakeholder committee support data governance and project management. A co-directed, cross-functional team with flattened hierarchy and integration of industry software management practices enhances problem solving and responsiveness to user needs. Access to validated, organized, and current data is critical to the functioning of multiple domains in medicine. Although there are downsides to developing in-house customized software, we describe a successful implementation of custom data management software in an academic cancer center.

Eric M Snyder and colleagues discuss the results of the 36-month Symplicity SPYRAL HTN-ON MED trial.1Mahfoud F Kandzari DE Kario K et al.Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.Lancet. 2022; 399: 1401-1410Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar They astutely point out that there was no difference in 24 h systolic or diastolic blood pressure at 12 months between the renal denervation and sham control groups and acknowledge that 12 months was the last point where patients remained under blinded conditions. It is worth noting that, although physicians were able to titrate antihypertensive medications following the 6-month visit, there was a higher medication burden at 12 months in the sham control group compared with the renal denervation group when patients and physicians were still under blind conditions (MEDINDEX2 and MEDINDEX3, table 2 in the Article's appendix [p 17]).1Mahfoud F Kandzari DE Kario K et al.Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.Lancet. 2022; 399: 1401-1410Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar We hypothesise that the higher medication burden could explain the insignificant difference in blood pressure between the groups at 12 months.Snyder and colleagues also suggest that the difference in blood pressure between groups could be ascribed to the placebo effect in the treatment group, but the placebo affect only applies to the sham control group, not the treatment group. Notably, sham control patients in the SPYRAL HTN-ON MED pilot study had an average –8·6 mm Hg change in systolic blood pressure and –6·0 mm Hg change in diastolic blood pressure from baseline at 36 months, similar to the cited placebo effect.2Lauder L da Costa BR Ewen S et al.Randomized trials of invasive cardiovascular interventions that include a placebo control: a systematic review and meta-analysis.Eur Heart J. 2020; 41: 2556-2569Crossref PubMed Scopus (11) Google Scholar Despite this placebo effect, renal denervation group participants had a significantly greater average blood pressure reduction than the sham control group at 24 months and 36 months (as shown in figure 1 of the Article).1Mahfoud F Kandzari DE Kario K et al.Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.Lancet. 2022; 399: 1401-1410Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar Of note, unblinding might bias against the renal denervation group, in whom lower medication compliance could be anticipated once the patients had received the therapy.There are admittedly challenges to the analysis of long-term follow-up data in device-based hypertension trials,3Kandzari DE Mahfoud F Weber MA et al.Clinical trial design principles and outcomes definitions for device-based therapies for hypertension: a consensus document from the Hypertension Academic Research Consortium.Circulation. 2022; 145: 847-863Crossref PubMed Scopus (4) Google Scholar especially when participants in the control group are permitted to cross over as part of the intention-to-treat principle. As would be expected, people that did cross over from the control group to the renal denervation group typically had significantly higher blood pressure values than those that did not cross over, indicating a lack of blood pressure control from medications alone. Furthermore, if participants in the control group were not allowed to cross over, their blood pressure might have continued to increase despite the increasing medication burden. Thus, imputing crossover patients’ blood pressure values could still underestimate the treatment differences between renal denervation and sham control. Although no method to account for missing data is perfect, the choice to impute missing data by use of the last-observation-carried-forward technique was dictated by the present data structure and the amount and nature of missing observations to provide the least biased estimates.4Jakobsen JC Gluud C Wetterslev J Winkel P When and how should multiple imputation be used for handling missing data in randomised clinical trials – a practical guide with flowcharts.BMC Med Res Methodol. 2017; 17: 162Crossref PubMed Scopus (779) Google Scholar It is important to reiterate, as indicated in the Article, that medication values at 36 months for participants that crossed over were also imputed using their pre-crossover measurements. Therefore, unlike Snyder and colleagues suggest, 100% of the sham control group's blood pressure values reflect participants’ most recent pharmacological care. With all crossovers occurring after the 24-month visits, the 24-month outcomes without any imputations indeed show results that are consistent with the 36-month outcomes with imputations.1Mahfoud F Kandzari DE Kario K et al.Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.Lancet. 2022; 399: 1401-1410Summary Full Text Full Text PDF PubMed Scopus (23) Google ScholarFinally, independent of the control group, the durability of the renal denervation procedure is supported by the consistency of the 24 h ambulatory blood pressure findings within the intervention group. This measurement is free from bias since neither the patients nor the investigators had access to this crucial information until well after the monitoring period was completed and the core laboratory had verified the technical adequacy of the data.We cordially invite Snyder and colleagues to vigilantly reconsult the Article and the detailed supplemental information, which provide a clear explanation on all their concerns.FM is supported by Deutsche Gesellschaft für Kardiologie, Deutsche Forschungsgemeinschaft (grant number: SFB TRR219), and Deutsche Herzstiftung; and has received scientific support from Medronic and ReCor Medical and speaker honoraria from Astra-Zeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, and ReCor Medical. DEK reports institutional research or grant support from Biotronik, Boston Scientific, Cardiovascular Systems, Orbus Neich, Teleflex, Medtronic, and Ablative Solutions, and personal consulting honoraria from Ablative Solutions, Cardiovascular Systems, Magenta Medical, Medtronic, and Terumo. MAW is a consultant for Medtronic, ReCor Medical, Ablative Solutions, Johnson & Johnson, and Urovant. MF is an employee of Medtronic. MB is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TRR219, project number 322900939) and reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, ReCor Medical, Servier, and Vifor. Eric M Snyder and colleagues discuss the results of the 36-month Symplicity SPYRAL HTN-ON MED trial.1Mahfoud F Kandzari DE Kario K et al.Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.Lancet. 2022; 399: 1401-1410Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar They astutely point out that there was no difference in 24 h systolic or diastolic blood pressure at 12 months between the renal denervation and sham control groups and acknowledge that 12 months was the last point where patients remained under blinded conditions. It is worth noting that, although physicians were able to titrate antihypertensive medications following the 6-month visit, there was a higher medication burden at 12 months in the sham control group compared with the renal denervation group when patients and physicians were still under blind conditions (MEDINDEX2 and MEDINDEX3, table 2 in the Article's appendix [p 17]).1Mahfoud F Kandzari DE Kario K et al.Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.Lancet. 2022; 399: 1401-1410Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar We hypothesise that the higher medication burden could explain the insignificant difference in blood pressure between the groups at 12 months. Snyder and colleagues also suggest that the difference in blood pressure between groups could be ascribed to the placebo effect in the treatment group, but the placebo affect only applies to the sham control group, not the treatment group. Notably, sham control patients in the SPYRAL HTN-ON MED pilot study had an average –8·6 mm Hg change in systolic blood pressure and –6·0 mm Hg change in diastolic blood pressure from baseline at 36 months, similar to the cited placebo effect.2Lauder L da Costa BR Ewen S et al.Randomized trials of invasive cardiovascular interventions that include a placebo control: a systematic review and meta-analysis.Eur Heart J. 2020; 41: 2556-2569Crossref PubMed Scopus (11) Google Scholar Despite this placebo effect, renal denervation group participants had a significantly greater average blood pressure reduction than the sham control group at 24 months and 36 months (as shown in figure 1 of the Article).1Mahfoud F Kandzari DE Kario K et al.Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.Lancet. 2022; 399: 1401-1410Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar Of note, unblinding might bias against the renal denervation group, in whom lower medication compliance could be anticipated once the patients had received the therapy. There are admittedly challenges to the analysis of long-term follow-up data in device-based hypertension trials,3Kandzari DE Mahfoud F Weber MA et al.Clinical trial design principles and outcomes definitions for device-based therapies for hypertension: a consensus document from the Hypertension Academic Research Consortium.Circulation. 2022; 145: 847-863Crossref PubMed Scopus (4) Google Scholar especially when participants in the control group are permitted to cross over as part of the intention-to-treat principle. As would be expected, people that did cross over from the control group to the renal denervation group typically had significantly higher blood pressure values than those that did not cross over, indicating a lack of blood pressure control from medications alone. Furthermore, if participants in the control group were not allowed to cross over, their blood pressure might have continued to increase despite the increasing medication burden. Thus, imputing crossover patients’ blood pressure values could still underestimate the treatment differences between renal denervation and sham control. Although no method to account for missing data is perfect, the choice to impute missing data by use of the last-observation-carried-forward technique was dictated by the present data structure and the amount and nature of missing observations to provide the least biased estimates.4Jakobsen JC Gluud C Wetterslev J Winkel P When and how should multiple imputation be used for handling missing data in randomised clinical trials – a practical guide with flowcharts.BMC Med Res Methodol. 2017; 17: 162Crossref PubMed Scopus (779) Google Scholar It is important to reiterate, as indicated in the Article, that medication values at 36 months for participants that crossed over were also imputed using their pre-crossover measurements. Therefore, unlike Snyder and colleagues suggest, 100% of the sham control group's blood pressure values reflect participants’ most recent pharmacological care. With all crossovers occurring after the 24-month visits, the 24-month outcomes without any imputations indeed show results that are consistent with the 36-month outcomes with imputations.1Mahfoud F Kandzari DE Kario K et al.Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.Lancet. 2022; 399: 1401-1410Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar Finally, independent of the control group, the durability of the renal denervation procedure is supported by the consistency of the 24 h ambulatory blood pressure findings within the intervention group. This measurement is free from bias since neither the patients nor the investigators had access to this crucial information until well after the monitoring period was completed and the core laboratory had verified the technical adequacy of the data. We cordially invite Snyder and colleagues to vigilantly reconsult the Article and the detailed supplemental information, which provide a clear explanation on all their concerns. FM is supported by Deutsche Gesellschaft für Kardiologie, Deutsche Forschungsgemeinschaft (grant number: SFB TRR219), and Deutsche Herzstiftung; and has received scientific support from Medronic and ReCor Medical and speaker honoraria from Astra-Zeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, and ReCor Medical. DEK reports institutional research or grant support from Biotronik, Boston Scientific, Cardiovascular Systems, Orbus Neich, Teleflex, Medtronic, and Ablative Solutions, and personal consulting honoraria from Ablative Solutions, Cardiovascular Systems, Magenta Medical, Medtronic, and Terumo. MAW is a consultant for Medtronic, ReCor Medical, Ablative Solutions, Johnson & Johnson, and Urovant. MF is an employee of Medtronic. MB is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TRR219, project number 322900939) and reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, ReCor Medical, Servier, and Vifor.

Medication synchronization (med-sync) aligns patients’ chronic medications to a predetermined routine pickup date at a community pharmacy. An appointment-based model (ABM) med-sync service includes a comprehensive medication review or other clinical appointment at the pharmacy. We compared the cost and healthcare utilization outcomes of Medicare beneficiaries enrolled in an ABM med-sync program to beneficiaries not enrolled in such a program.