Design and implementation of a digital health home spirometry intervention for remote monitoring of lung transplant function.

BACKGROUND: We developed an automated, chat-based, digital health intervention using Bluetooth-enabled home spirometers to monitor for complications of lung transplantation in a real-world application. METHODS: A chat-based application prompted patients to perform home spirometry, enter their forced expiratory volume in 1 second (FEV1), answer symptom queries, and provided patient education. The program alerted patients and providers to substantial FEV1 decreases and concerning symptoms. Data was integrated into the electronic health record (EHR) system and dashboards were developed for program monitoring. RESULT: Between May 2020 and December 2021, 544 patients were invited to enroll, of whom 427 were invited remotely and 117 were enrolled in-person. 371 (68%) participated by submitting ≥1 FEV1 values. Overall engagement was high, with an average of 197 unique patients submitting FEV1 data per month. In-person enrollees submitted an average of 4.6 FEV1 values per month and responded to 55% of scheduled chats. Home and laboratory FEV1 values correlated closely (rho = 0.93). There was an average of 133 ± 59 FEV1 decline alerts and 59 ± 23 symptom alerts per month. 72% of patients accessed education modules, and the program had a high net promoter score (53) amongst users. CONCLUSIONS: We demonstrate that a novel, automated, chat-based, and EHR-integrated home spirometry intervention is well accepted, generates reliable assessments of graft function, and can deliver automated feedback and education resulting in moderately-high adherence rates. We found that in-person onboarding yields better engagement and adherence. Future work will aim to demonstrate the impact of remote care monitoring on early detection of lung transplant complications.

Intercostal Nerve Cryoanalgesia Versus Thoracic Epidural Analgesia in Lung Transplantation: A Retrospective Single-Center Study.

INTRODUCTION: The optimal pain management strategy after lung transplantation is unknown. This study compared analgesic outcomes of intercostal nerve blockade by cryoanalgesia (Cryo) versus thoracic epidural analgesia (TEA). METHODS: Seventy-two patients who underwent bilateral lung transplantation via clamshell incision at our center from 2016 to 2018 were managed with TEA (N = 43) or Cryo (N = 29). We evaluated analgesic-specific complications, opioid use in oral morphine equivalents (OME), and pain scores (0-10) through postoperative day 7. Adjusted linear regression was used to assess for non-inferiority of Cryo to TEA. RESULTS: The overall mean pain scores (Cryo 3.2 vs TEA 3.8, P = 0.21), maximum mean pain scores (Cryo 4.7 vs TEA 5.5, P = 0.16), and the total opioid use (Cryo 484 vs TEA 705 OME, P = 0.12) were similar in both groups, while the utilization of postoperative opioid-sparing analgesia, measured as use of lidocaine patches, was lower in the Cryo group (Cryo 21% vs TEA 84%, P < 0.001). Analgesic outcomes remained similar between the cohorts after adjustment for pertinent patient and analgesic characteristics (P = 0.26), as well as after exclusion of Cryo patients requiring rescue TEA (P = 0.32). There were no Cryo complications, with four patients requiring subsequent TEA for pain control. Two TEA patients experienced hemodynamic instability following a test TEA bolus requiring code measures. Additionally, TEA placement was delayed beyond postoperative day 1 in 33% owing to need for anticoagulation or clinical instability. CONCLUSIONS: In lung transplantation, Cryo was found to be safe with analgesic effectiveness similar to TEA. Cryo may be advantageous in this complex patient population, as it can be used in all clinical scenarios and eliminates risks and delays associated with TEA.

Early Postoperative Management of Lung Transplant Recipients.

The early postoperative period after lung transplantation is a critical time. Prompt recognition and treatment of primary graft dysfunction can alter long-term allograft function. Cardiovascular, gastrointestinal, renal, and hematologic derangements are common and require close management to limit their negative sequelae.

Risk Factors and Outcomes of Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation.

This study aimed to identify outcome determinants for extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (BTT) at our institution.This retrospective single-center study reviewed patients on ECMO between 2010 and 2018 and compared clinical characteristics between patients who underwent successful-BTT and those who did not. Additionally, we examined differences between actively versus emergently listed patients and reasons for failure-to-list. Seventy-six patients were placed on ECMO with the intent to bridge to transplant. Of those, 42 were actively on the waitlist (AWL) prior to ECMO initiation, 20 were emergently evaluated and waitlisted (EWL) after ECMO initiation, and 14 failed-to-list. Of the 62 listed patients, 42 (68%) were successfully transplanted. Risk factors of failed-BTT included right ventricular dysfunction prior to ECMO initiation, longer ECMO duration, reduced mobility status, shorter stature, higher prevalence of blood type B, worse kidney and liver function, and increased transfusion requirements. The number of patients transitioned to central VA-ECMO was higher in the failed-BTT group. Thirty-day survival post-transplantation was 98%, with 90% successfully discharged; 1-year survival conditional upon discharge was 97%. AWL and EWL groups had comparable outcomes. Reasons for failure-to-list are not readily modifiable. ECMO-BTT has become a viable option with satisfactory 1-year survival in patients with irreversible lung injury. Our results support rescue transplant for emergently evaluated and waitlisted patients on ECMO. Our data suggests that modification in national organ allocation policies especially as they pertain to high-acuity recipients with rare blood types and short stature could enhance successful outcome.

Alterations in deoxyribonucleic acid (DNA) methylation patterns of Calca, Timp3, Mmp2, and Igf2r are associated with chronic cystitis in a cyclophosphamide-induced mouse model.

OBJECTIVE: To determine whether epigenetic changes occur during cyclophosphamide-induced chronic bladder inflammation in mice. MATERIALS AND METHODS: Epigenetic changes play a role in the regulation of inflammatory genes in noncancer diseases such as asthma and chronic obstructive pulmonary disease. However, epigenetic (deoxyribonucleic acid [DNA] methylation) changes during chronic bladder inflammation have not been previously described. Chronic cystitis was induced in 3 groups of adult CD-1 male mice using multiple weight-based intraperitoneal cyclophosphamide injections during a 3-month period. Histopathologic and MethyLight assays were performed on specimens with chronic bladder inflammation at multiple points to monitor cystitis progression and DNA methylation changes compared with the control specimens. RESULTS: Histopathologic analysis showed the most extensive edema and urothelial sloughing at the 1-month point. MethyLight analyses revealed statistically significant changes in DNA methylation associated with the Calca, Timp3, Mmp2, and Igf2r genes in the chronic bladder injury model. The changes in DNA methylation associated with chronic cystitis were DNA hypomethylation of the Calca gene in the control tissue and DNA hypermethylation for the Calca, Timp3, Mmp2, and Igf2r genes compared with that in the control tissue. CONCLUSION: DNA methylation changes were noted in the Calca, Timp3, Mmp2, and Igf2r genes during chronic cystitis in a murine model. Epigenetic changes appear to play a role in the regulation of inflammatory bladder genes during chronic cystitis; however, additional studies are needed to elucidate the pathways associated with these genes.

DNA methylation analysis by digital bisulfite genomic sequencing and digital MethyLight.

Alterations in cytosine-5 DNA methylation are frequently observed in most types of human cancer. Although assays utilizing PCR amplification of bisulfite-converted DNA are widely employed to analyze these DNA methylation alterations, they are generally limited in throughput capacity, detection sensitivity, and or resolution. Digital PCR, in which a DNA sample is analyzed in distributive fashion over multiple reaction chambers, allows for enumeration of discrete template DNA molecules, as well as sequestration of non-specific primer annealing templates into negative chambers, thereby increasing the signal-to-noise ratio in positive chambers. Here, we have applied digital PCR technology to bisulfite-converted DNA for single-molecule high-resolution DNA methylation analysis and for increased sensitivity DNA methylation detection. We developed digital bisulfite genomic DNA sequencing to efficiently determine single-basepair DNA methylation patterns on single-molecule DNA templates without an interim cloning step. We also developed digital MethyLight, which surpasses traditional MethyLight in detection sensitivity and quantitative accuracy for low quantities of DNA. Using digital MethyLight, we identified single-molecule, cancer-specific DNA hypermethylation events in the CpG islands of RUNX3, CLDN5 and FOXE1 present in plasma samples from breast cancer patients.

Dnmt1 deficiency leads to enhanced microsatellite instability in mouse embryonic stem cells.

DNA hypomethylation is frequently seen in cancer and imparts genomic instability in mouse models and some tissue culture systems. However, the effects of genomic DNA hypomethylation on mutation rates are still elusive. We have developed a model system to analyze the effects of DNA methyltransferase 1 (Dnmt1) deficiency on DNA mismatch repair (MMR) in mouse embryonic stem (ES) cells. We generated sibling ES cell clones with and without functional Dnmt1 expression, containing a stable reporter gene that allowed us to measure the slippage rate at a mononucleotide repeat. We found that Dnmt1 deficiency led to a 7-fold increase in the microsatellite slippage rate. Interestingly, the region flanking the mononucleotide repeat was unmethylated regardless of Dnmt1 status, suggesting that it is not the local levels of DNA methylation that direct the increase in microsatellite instability (MSI). The enhanced MSI was associated with higher levels of histone H3 acetylation and lower MeCP2 binding at regions near the assayed microsatellite, suggesting that Dnmt1 loss may decrease MMR efficiency by modifying chromatin structure.

Thymidylate synthase: a novel genetic determinant of plasma homocysteine and folate levels.

The thymidylate synthase gene ( TYMS or TS) encodes a tightly regulated enzyme that catalyzes the conversion of deoxyuridylate to thymidylate, and contains a tandem repeat polymorphism that affects expression of the enzyme. We have investigated the relationship between TYMS genotype and plasma concentrations of homocysteine and folate in a cohort of 505 Chinese from Singapore. TYMS 3/3 genotype was associated with reduced plasma folate and, among individuals with low dietary folate intake, with elevated plasma homocysteine levels. These associations were independent of the well-established methylenetetrahydrofolate reductase ( MTHFR) C677T genotype effects on plasma folate and homocysteine levels. Our results suggest that TYMS and MTHFR compete for limiting supplies of folate required for the remethylation of homocysteine. These genetic determinants of plasma folate and homocysteine levels may be useful in identifying individuals at increased risk for cardiovascular disease.

DNA methyltransferase deficiency modifies cancer susceptibility in mice lacking DNA mismatch repair.

We have introduced DNA methyltransferase 1 (Dnmt1) mutations into a mouse strain deficient for the Mlh1 protein to study the interaction between DNA mismatch repair deficiency and DNA methylation. Mice harboring hypomorphic Dnmt1 mutations showed diminished RNA expression and DNA hypomethylation but developed normally and were tumor free. When crossed to Mlh1(-/-) homozygosity, they were less likely to develop the intestinal cancers that normally arise in this tumor-predisposed, mismatch repair-deficient background. However, these same mice developed invasive T- and B-cell lymphomas earlier and at a much higher frequency than their Dnmt1 wild-type littermates. Thus, the reduction of Dnmt1 activity has significant but opposing outcomes in the development of two different tumor types. DNA hypomethylation and mismatch repair deficiency interact to exacerbate lymphomagenesis, while hypomethylation protects against intestinal tumors. The increased lymphomagenesis in Dnmt1 hypomorphic, Mlh1(-/-) mice may be due to a combination of several mechanisms, including elevated mutation rates, increased expression of proviral sequences or proto-oncogenes, and/or enhanced genomic instability. We show that CpG island hypermethylation occurs in the normal intestinal mucosa, is increased in intestinal tumors in Mlh1(-/-) mice, and is reduced in the normal mucosa and tumors of Dnmt1 mutant mice, consistent with a role for Dnmt1-mediated CpG island hypermethylation in intestinal tumorigenesis.