Telehealth-Delivered Program and Accompanying Patients to Enhance the Clinical Condition of Patients Throughout a Liver Transplant: Protocol for a Mixed Methods Study.

BACKGROUND: Liver transplantation (LT) is indicated in patients with severe acute or chronic liver failure for which no other therapy is available. With the increasing number of LTs in recent years, liver centers worldwide must manage their patients according to their clinical situation and the expected waiting time for transplantation. The LT clinic at the Centre hospitalier de l'Université de Montréal (CHUM) is developing a new health care model across the entire continuum of pre-, peri-, and posttransplant care that features patient monitoring by an interdisciplinary team, including an accompanying patient; a digital platform to host a clinical plan; a learning program; and data collection from connected objects. OBJECTIVE: This study aims to (1) evaluate the outcomes following the implementation of a patient platform with connected devices and an accompanying patient, (2) identify implementation barriers and facilitators, (3) describe service outcomes in terms of health outcomes and the rates and nature of contact with the accompanying patient, (4) describe patient outcomes, and (5) assess the intervention's cost-effectiveness. METHODS: Six types of participants will be included in the study: (1) patients who received transplants and reached 1 year after transplantation before September 2023 (historical cohort or control group), (2) patients who will receive an LT between December 2023 and November 2024 (prospective cohort/intervention group), (3) relatives of those patients, (4) accompanying patients who have received an LT and are interested in supporting patients who will receive an LT, (5) health care professionals, and (6) decision makers. To describe the study sample and collect data to achieve all the objectives, a series of validated questionnaires, accompanying patient logbooks, transcripts of interviews and focus groups, and clinical indicators will be collected throughout the study. RESULTS: In total, 5 (steering, education, clinical-technological, nurse prescription, and accompanying patient) working committees have been established for the study. Recruitment of patients is expected to start in November 2023. All questionnaires and technological platforms have been prepared, and the clinicians, stakeholders, and accompanying patient personnel have been recruited. CONCLUSIONS: The implementation of this model in the trajectory of LT recipients at the CHUM may allow for better monitoring and health of patients undergoing transplantation, ultimately reducing the average length of hospital stay and promoting better use of medical resources. In the event of positive results, this model could be transposed to all transplant units at the CHUM and across Quebec (potentially affecting 888 patients per year) but could also be applied more widely to the monitoring of patients with other chronic diseases. The lessons learned from this project will be shared with decision makers and will serve as a model for other initiatives involving accompanying patients, connected objects, or digital platforms. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/54440.

Mixed-methods evaluation of a transition and young adult clinic for kidney transplant recipients.

The aims of the present study were to describe the experiences of kidney transplant patients attending a young adult clinic or a regular adult clinic, to explore similarities and differences between the groups, and to conduct an evaluation of the clinical and psychosocial outcomes of the young adult clinic, by comparing these outcomes to those of the regular adult clinic. A mixed-methods design combining qualitative and quantitative data was used. Empirically validated questionnaires measuring self-determination theory variables, quality of life, and adherence were distributed to all consenting patients attending the YAC (n = 17) and RAC (n = 16). Semi-structured interviews were conducted with a subsample of the first (n = 10) and second group (n = 8), and analyzed using thematic analysis. Clinical outcomes were retrieved from medical records. Descriptive, correlational, and comparative analyses were performed. We found clinically significant differences on tacrolimus blood levels variability, self-reported adherence, and physical quality of life. Small and medium effect sizes were detected. No statistical differences were found. Statistically significant correlations were found between self-determination theory variables and both physical quality of life and different measures of adherence. Four themes characterized patients' experiences: resilience; relational needs and the therapeutic alliance; quest for balance; and quest for normalcy. The young adult clinic seems to meet its initial objectives and to make a difference particularly in the early period post-transition, but over time what matters most for patients is therapeutic alliance. Mental health issues need to be better addressed, and special attention should be paid to youths transplanted in an adult setting.

Stabilization of renal function after the first year of follow-up in kidney transplant recipients treated for significant BK polyomavirus infection or BK polyomavirus-associated nephropathy.

BACKGROUND: BK polyomavirus virus (BKPyV) screening and immunosuppression reduction effectively prevent graft loss due to BKPyV-associated nephropathy (BKPVAN) during the first year after transplantation. The aim of our study was to evaluate the impact of this infection during longer follow-up periods. METHODS: We reviewed the outcome of our screening and immunosuppression reduction protocol in 305 patients who received a kidney transplant between March 2008 and January 2013. Quantitative BKPyV DNA surveillance in plasma was performed at 1, 2, 3, 6, 9, and 12 months after transplantation. Patients with significant viremia and/or biopsy-proven BKPVAN were treated with immunosuppression reduction and leflunomide. RESULTS: During the first post-transplant year, 24 patients (7.9%) developed significant viremia at a median time of 95 days, and 18 patients had BKPVAN; 23 of the 24 (7.5%) were treated according to our protocol (group BKV+); 225 patients (73.8%) did not develop any BK viremia (group BKV-). Allograft function was similar in both groups at 1 month post transplantation (P=.87), but significantly worse at 1 year in the BKV+ group (P=.002). Thereafter, kidney function stabilized in the BKV+ group and no differences in patient and graft survival were seen between the groups after a median follow-up of 4 years. CONCLUSIONS: We confirm the early occurrence of BKPyV replication after transplantation and the short-term decline in renal function. However, early detection of BKPyV replication, prompt diagnosis, and reduction in immunosuppression may offer long-term benefits for graft function.

The incidence, management, and evolution of rapamycin-related side effects in kidney transplant recipients.

Conversion from a calcineurin-inhibitor-based immunosuppression to a rapamycin-based immunosuppression may preserve kidney graft function. The side effects of rapamycin can limit its usefulness, but their management and evolution are rarely reported in clinical trials. We performed a retrospective cohort study in patients transplanted before December 31, 2008 and who received rapamycin to replace calcineurin inhibitors. In 219 patients studied, 98% presented ≥1 side effects after starting rapamycin. Side effects occurring in ≥10% of patients were dyslipidemia (52%, 95% confidence interval (CI): 45-59%), peripheral edema (37%, 95%CI: 31-43%), cytopenia (36%, 95% CI: 30-42%), acne (29%, 95% CI: 23-35%), proteinuria (23%, 95% CI: 17-29%), and oral ulcers 14% (95% CI: 10-18%). Proteinuria, ulcers, and edema were difficult to manage and were more likely to cause cessation of rapamycin. Rapamycin was discontinued in 46% of patients (95% CI: 40-52%). Age (odds ratio [OR] per 10-yr increase: 1.29, 95% CI: 1.05-1.59) and obesity (OR: 2.57, 95% CI: 1.10-6.01) were independently associated with cessation of rapamycin. We conclude that successful control of dyslipidemia and cytopenia can be achieved without discontinuing rapamycin. Most other side effects are harder to manage. Leaner and younger patients are less likely to discontinue rapamycin due to side effects.

Factors associated with progression of interstitial fibrosis in renal transplant patients receiving tacrolimus and mycophenolate mofetil.

BACKGROUND: We recently reported a randomized study in renal transplant patients (RTP) receiving tacrolimus, mycophenolate mofetil, and prednisone in which patients who had early protocol biopsies (PBx) derived no benefit compared with controls (no PBx) at 6 months, likely due to the low prevalence of subclinical rejection. We report on the follow-up of these patients to 24 months at which time a repeat PBx and tests of renal function were performed. METHODS: Of the 240 RTP randomized, 22 were excluded for a protocol violation. Approximately 75% of the remaining 218 (111 PBx and 107 controls) completed the study. RESULTS: At 24 months, graft function was excellent with a mean creatinine clearance of approximately 74 mL/min and negligible proteinuria; however, the prevalence of interstitial fibrosis and tubular atrophy (IF/TA)-ci + ct more than or equal to 2-increased from approximately 3% at baseline to up to 40% to 50%. By logistic regression analysis, the only independent positive correlate of IF/TA was transplantation with a deceased donor. However, by post hoc analysis, use of angiotensin-II-converting enzyme inhibitors or angiotensin II receptor blockers was negatively correlated with both the prevalence of IF/TA at 24 months and its progression between 6 and 24 months in RTP that had paired biopsies. CONCLUSIONS: A regimen of tacrolimus, mycophenolate mofetil, and prednisone results in excellent renal function at 24 months posttransplant but with a progressive increase in IF/TA. A potential inhibitory effect of angiotensin-II-converting enzyme inhibitor/angiotensin II receptor blockers on IF/TA is suggested that requires confirmation in a randomized study.

Gamma irradiation induces acetylcholine-evoked, endothelium-independent relaxation and activates K-channels of isolated pulmonary artery of rats.

PURPOSE: To test the effects of irradiation (R*) on the pulmonary artery (PA). METHODS AND MATERIALS: Isolated PA rings were submitted to gamma irradiation (cesium, 8 Gy/min(-1)) at doses of 20 Gy-140 Gy. Rings were placed in an organ chamber, contracted with serotonin (10(-4) M 5-hydroxytryptamine [5-HT]), then exposed to acetylcholine (ACh) in incremental concentrations. Smooth muscle cell (SMC) membrane potential was measured with microelectrodes. RESULTS: A high dose of irradiation (60 Gy) increased 5HT contraction by 20%, whereas lower (20 Gy) doses slightly decreased it compared with control. In the absence of the endothelium, 5-HT precontracted rings exposed to 20 Gy irradiation developed a dose-dependent relaxation induced by acetylcholine (EI-ACh) with maximal relaxation of 60 +/- 17% (n = 13). This was totally blocked by L-NAME (10(-4) M), partly by 7-nitro indazole; it was abolished by hypoxia and iberiotoxin, decreased by tetra-ethyl-ammonium, and not affected by free radical scavengers. In irradiated rings, hypoxia induced a slight contraction which was never observed in control rings. No differences in SMC membrane potential were observed between irradiated and nonirradiated PA rings. CONCLUSION: Irradiation mediates endothelium independent relaxation by a mechanism involving the nitric oxide pathway and K-channels.

Acidosis abolishes the effect of repeated applications of ATP on pulmonary artery force and [Ca2+]i.

The purine nucleotide, ATP, can cause receptor-mediated desensitizing contractions of smooth muscle that may be modulated by pH. We investigated in the rat the effect of acidosis upon the contractile and Ca2+ responses induced by ATP upon intrapulmonary artery (PA) smooth muscle. Four successive applications of ATP (300 microM) at pH 7.4 induced desensitising contractile responses that showed progressively decreasing peak amplitudes that correlated with decreases of [Ca2+]i. Acidosis significantly reduced the peak contractile response to the first application of ATP without modifying the rate or degree of desensitisation in response to ATP and without decreasing the [Ca2+]i. Successive applications of ATP did not further reduce contractile force nor [Ca2+]i. These results demonstrated that acidosis abolishes the effect of repeat applications of ATP on pulmonary artery force and [Ca2+]i via alteration in the desensitization-resensitisation characteristics of ATP receptor. This suggest a potentially important physiological role for changes in external pH in the regulation of ATP-mediated control of the pulmonary circulation.

Chronic carbon monoxide exposure of hypoxic rats increases in vitro sensitivity of pulmonary artery smooth muscle.

Exogenous carbon monoxide (CO) induces pulmonary vasodilation by acting directly on pulmonary artery (PA) smooth muscle cells. We investigated the contribution of K+ channels and soluble guanylyl cyclase to the regulation of PA tone by acute CO in chronic hypoxic rats (3 weeks at 0.5 atm (1 atm = 101.325 kPa); hypoxic) and in chronic hypoxic rats exposed to exogenous CO (3 weeks at 0.5 atm + 50 ppm CO; hypoxic-CO). Acute CO induced relaxation in PA rings from all animals. However, the amplitude of CO relaxation was significantly decreased in hypoxic rings and increased in hypoxic-CO rings. This different effect occurred with a decrease and an increase of pD2, respectively, in hypoxic and hypoxic-CO rings. We showed a positive relation between the percentage of inhibition of CO relaxation by a blocker of K+ channels and the increase of CO sensitivity. Thus, we showed for the first time that chronic hypoxia decreases acute CO sensitivity, which in contrast, increases in the presence of chronic CO. The present study provides initial evidence of a link between increased K(+)-channel activity and CO sensitivity.

Measurement of free and membrane-bound cathepsin G in human neutrophils using new sensitive fluorogenic substrates.

Activated human polymorphonuclear neutrophils at inflammatory sites release the chymotrypsin-like protease cathepsin G, together with elastase and proteinase 3 (myeloblastin), from their azurophil granules. The low activity of cathepsin G on synthetic substrates seriously impairs studies designed to clarify its role in tissue inflammation. We have solved this problem by producing new peptide substrates with intramolecularly quenched fluorescence. These substrates were deduced from the sequence of putative protein targets of cathepsin G, including the reactive loop sequence of serpin inhibitors and the N-terminal domain of the protease-activated receptor of thrombin, PAR-1. Two substrates were selected, Abz-TPFSGQ-EDDnp and Abz-EPFWEDQ-EDDnp, that are cleaved very efficiently by cathepsin G but not by neutrophil elastase or proteinase 3, with specificity constants (k(cat)/K(m)) in the 10(5) M(-1).s(-1) range. They can be used to measure subnanomolar concentrations of free enzyme in vitro and at the surface of neutrophils purified from fresh human blood. Purified neutrophils express 0.02-0.7 pg of cathepsin G/cell (n=15) at their surface. This means that about 10(4) purified cells may be enough to record cathepsin G activity within minutes. This may be most important for investigating the role of cathepsin G as an inflammatory agent, especially in bronchoalveolar lavage fluids from patients with pulmonary inflammatory disorders.

Chronic carbon monoxide enhanced IbTx-sensitive currents in rat resistance pulmonary artery smooth muscle cells.

Exogenous carbon monoxide (CO) can induce pulmonary vasodilation by acting directly on pulmonary artery (PA) smooth muscle cells. We investigated the contribution of K+ channels to the regulation of resistance PA resting membrane potential on control (PAC) rats and rats exposed to CO for 3 wk at 530 parts/million, labeled as PACO rats. Whole cell patch-clamp experiments revealed that the resting membrane potential of PACO cells was more negative than that of PAC cells. This was associated with a decrease of membrane resistance in PACO cells. Additional analysis showed that outward current density in PACO cells was higher (50% at +60 mV) than in PAC cells. This was linked to an increase of iberiotoxin (IbTx)-sensitive current. Chronic CO hyperpolarized membrane of pressurized PA from -46.9 +/- 1.2 to -56.4 +/- 2.6 mV. Additionally, IbTx significantly depolarized membrane of smooth muscle cells from PACO arteries but not from PAC arteries. The present study provides initial evidence of an increase of Ca2+-activated K+ current in smooth muscle cells from PA of rats exposed to chronic CO.