A randomized, controlled, prehabilitation intervention to maximize early recovery (PRIMER) in liver transplantation.

Frailty and impaired functional status are associated with adverse outcomes on the liver transplant (LT) waitlist and after transplantation. Prehabilitation prior to LT has rarely been tested. We conducted a 2-arm patient-randomized pilot trial to evaluate the feasibility and efficacy of a 14-week behavioral intervention to promote physical activity prior to LT. Thirty patients were randomized 2:1 to intervention (n = 20) versus control (n = 10). The intervention arm received financial incentives and text-based reminders linked to wearable fitness trackers. Daily step goals were increased by 15% in 2-week intervals. Weekly check-ins with study staff assessed barriers to physical activity. The primary outcomes were feasibility and acceptability. Secondary outcomes included mean end-of-study step counts, short physical performance battery, grip strength, and body composition by phase angle. We fit regression models for secondary outcomes with the arm as the exposure adjusting for baseline performance. The mean age was 61, 47% were female, and the median Model for End-stage Liver Disease sodium (MELD-Na) was 13. One-third were frail or prefrail by the liver frailty index, 40% had impaired mobility by short physical performance battery, nearly 40% had sarcopenia by bioimpedance phase angle, 23% had prior falls, and 53% had diabetes. Study retention was 27/30 (90%; 2 unenrolled from intervention, 1 lost to follow-up in control arm). Self-reported adherence to exercise during weekly check-ins was about 50%; the most common barriers were fatigue, weather, and liver-related symptoms. End-of-study step counts were nearly 1000 steps higher for intervention versus control: adjusted difference 997, 95% CI, 147-1847; p = 0.02. On average, the intervention group achieved daily step targets 51% of the time. A home-based intervention with financial incentives and text-based nudges was feasible, highly accepted, and increased daily steps in LT candidates with functional impairment and malnutrition.

Digitally mediated service provision for children's social, emotional and mental health: key indicators for evaluation.

INTRODUCTION: Remote delivery of assessment, consultation and therapy via digital communication technologies in mental health services is important in rural locations, and has rapidly increased due to the COVID-19 pandemic. METHODS: This UK-based research investigated what factors should be considered in the development and evaluation of digitally mediated service provision for children and young people with social, emotional and mental health (SEMH) needs using two approaches: (1) a focus group with five young people (aged 16-19 years) and (2) an online survey with 18 parents/carers of primary-age children with SEMH difficulties. RESULTS: Getting help quickly was most important to both young people and parents/carers when accessing services, with having a say in their care of equal importance to young people but not parents/carers. Analysis identified participants' preferences and perceived positives and negatives of digitally mediated service provision. CONCLUSION: Digitally mediated service provision should be timely and patient-centred to be considered acceptable by young people with SEMH needs and their parents/carers. Evaluations should include comprehensive measures of service efficiency and service user experience to better understand the benefits of digital mediation.

Chronic lymphocytic leukemia/small lymphocytic lymphoma presenting as acute renal failure.

Lymphoma of the urinary bladder is quite rare, accounting for a small percentage of all bladder neoplasms. Here we discuss the case of a 68-year-old male patient who initially presented with acute renal failure and severe bilateral hydronephrosis on ultrasound. Cross-sectional imaging further revealed a diffusely thickened bladder wall with extensive retroperitoneal and mesenteric lymphadenopathy. Bladder biopsies ultimately led to a diagnosis of stage IV chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This is a rare instance of upper tract dilatation being the first sign of a widely disseminated hematologic malignancy.

The Stanford Integrated Psychosocial Assessment for Transplant Is Associated With Outcomes Before and After Liver Transplantation.

The Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) is a standardized psychosocial evaluation tool used in liver transplantation (LT) evaluation. We assessed the impact of the SIPAT score and subdomains on transplant waitlisting decisions and post-LT outcomes including immunosuppression (IS) nonadherence, biopsy-proven rejection, andmortality/graft failure. We conducted a single-center observational cohort study of 1430 patients evaluated for LT. Patients were divided in 2 groups based on a SIPAT cutoff score of <21 or ≥21 (higher SIPAT scores indicate higher psychosocial risk). Regression models assessed relationships between total SIPAT score and domain scores and waitlisting decisions, IS nonadherence, allograft rejection, and death/graft failure. Elevated total SIPAT and SIPAT domain scores were associated not being added to the waitlist (total SIPAT core ≥21 adjusted odds ratio [aOR], 1.78 [95% confidence interval, CI, 1.36-2.33]; readiness score ≥5 aOR, 2.01 [95% CI, 1.36-2.76]; social support score ≥4aOR, 1.50 [95% CI, 1.15-1.94]; psychopathology score ≥7 aOR, 1.45 [95% CI, 1.07-1.94]; lifestyle/substance abuse score ≥12 aOR, 1.72 [95%CI, 1.23-2.39]) and were more likely to experience IS nonadherence as measured by the tacrolimus coefficient of variation (CoV) (total SIPAT score ≥21 aOR, 2.92 [95% CI, 1.69-5.03]; readiness score ≥5 aOR, 3.26 [95% CI, 1.63-6.52]; psychopathology score ≥7 aOR, 1.88 [95% CI, 1.00-3.50]; lifestyle substance abuse score ≥12 aOR, 3.03 [95% CI, 1.56-5.86]). SIPAT readinessscore ≥5 was associated with biopsy-proven allograft rejection (aOR, 2.66; 95% CI, 1.20-5.91). The SIPAT score was independently associated with LT listing decisions and IS nonadherence, and the readiness domain was associated with the risk of allograft rejection. These findings offer insights into higher risk recipients who require additional support before and aftertransplantation.

A randomized, controlled, behavioral intervention to promote walking after abdominal organ transplantation: results from the LIFT study.

Kidney transplant recipients (KTRs) and liver transplant recipients (LTRs) have significant post-transplant weight gain and low physical activity. We conducted a home-based, remotely monitored intervention using wearable accelerometer devices to promote post-transplant physical activity. We randomized 61 KTRs and 66 LTRs within 24 months of transplant to: (i) control, (ii) accelerometer or (iii) intervention: accelerometer paired with financial incentives and health engagement questions to increase steps by 15% from baseline every 2 weeks. The primary outcome was weight change. A co-primary outcome for the two accelerometer arms was steps. Participants were recruited at a median of 9.5 [3-17] months post-transplant. At 3 months, there were no significant differences in weight change across the three arms. The intervention arm was more likely to achieve ≥7000 steps compared to control with device (OR 1.99, 95% CI: 1.03-3.87); effect remained significant after adjusting for demographics, allograft, time from transplant and baseline weight. Adherence to target step goals was 74% in the intervention arm, 84% of health engagement questions were answered correctly. A pilot study with financial incentives and health engagement questions was feasible and led KTRs and LTRs to walk more, but did not affect weight. A definitive trial is warranted.

Prior Relapse, Ongoing Alcohol Consumption, and Failure to Engage in Treatment Predict Alcohol Relapse After Liver Transplantation.

BACKGROUND: Alcohol-related liver disease (ALD) is the leading indication for liver transplantation (LT) in the USA. Alcohol relapse post-LT can negatively impact long-term outcomes, and prognostic scoring systems are available for further study. AIMS: Our study aims were to: (1) evaluate the relationship between alcohol relapse and rejection and mortality, (2) investigate risk factors for relapse, and (3) assess predictive validity of the SIPAT (Stanford Integrated Psychosocial Assessment for Transplant) and SALT (Sustained Alcohol Use Post-Liver Transplant) scores on post-LT alcohol relapse. METHODS: We conducted a retrospective chart review of 155 patients transplanted for chronic ALD at a single transplant center. Cox proportional hazard models assessed the relationship between alcohol relapse and allograft rejection and psychosocial risk factors for relapse. RESULTS: 20% of patients met criteria for alcohol relapse. Alcohol relapse was associated with allograft rejection (HR 2.33, 95% CI 1.11-4.91, p = .03). Three variables most strongly associated with alcohol relapse: prior relapse, failure to engage in recommended alcohol treatment, and continued drinking with liver disease, which were combined into a psychosocial model. SIPAT score≥ 21 and SALT score ≥ 7 were associated with alcohol relapse (HR 6.40, 95% CI 1.36-30.18, p = .019 and HR 2.30, 95% CI 1.12-4.75, p = .024). Receiver operator characteristic analysis compared predictive ability of our psychosocial model to SIPAT (C-statistic .83 compared to .71) and SALT (C-statistic = .77 compared to .62). CONCLUSION: We identified important psychosocial predictors of post-LT alcohol relapse and validated SIPAT and SALT scores as pre-transplant risk factors for alcohol relapse.

Medication non-adherence among liver transplant recipients.

PURPOSE OF REVIEW: We provide an overview of the recent evidence on the prevalence, risk factors, and consequences of medication non-adherence (NA) in liver transplant (LT) recipients. RECENT FINDINGS: NA in LT is associated with socio-demographic and medication-related factors, low social support, and poor health literacy. Patient-reported adherence is one of the most common methods to measure NA using validated assessments; immunosuppression (IS) drug levels and electronic monitoring may also be used. Simplification of IS regimens such as the conversion from twice daily to once daily has been shown to be safe, effective, and improves adherence. Relatively few studies have prospectively investigated NA predictors or interventions to reduce NA in LT. SUMMARY: Medication non-adherence is a multi-faceted issue that is common among LT recipients and associated with adverse outcomes. NA in LT recipients warrants further study as only a few interventions have been published focused on reducing NA in LT.

Serologic Detection of Antibodies Targeting the Leukocidin LukAB Strongly Predicts Staphylococcus aureus in Children With Invasive Infection.

BACKGROUND: Staphylococcus aureus is among the most commonly identified causes of invasive bacterial infection in children; however, reliable results from cultures of sterile-site samples often cannot be obtained, which necessitates prescription of a broad empiric antimicrobial agent(s). Children with invasive S aureus infection rapidly generate high antibody titers to the cytotoxin LukAB; therefore, the aim of this study was to assess the diagnostic utility of an anti-LukAB antibody assay for children with musculoskeletal infection (MSKI). METHODS: We conducted a 2-year prospective study of all eligible children admitted to Vanderbilt Children's Hospital with an MSKI. Acute and convalescent sera were obtained, and antibodies that target LukAB were measured by an enzyme-linked immunosorbent assay. RESULTS: Forty-two children were enrolled. The median concentrations of LukAB antibodies for children with S aureus infection were 130.3 U/mL in the acute phase and 455 U/mL in the convalescent phase (P < .001). The median concentrations of LukAB antibodies in children with a non-S aureus MSKI were 8.6 U/mL in the acute phase and 9.7 U/mL in the convalescent phase. The assay discriminated between S aureus and non-S aureus infection with areas under the receiver operating characteristic curve of 0.81 (95% confidence interval, 0.67-0.95; P < .001) and 0.95 (95% confidence interval, 0.86-1; P < .001) for samples tested in the acute and follow-up periods, respectively. With no false-negative results, the assay accurately ruled out S aureus in samples obtained during the convalescent phase. CONCLUSION: Culture-independent diagnostics have the potential to improve care by narrowing antimicrobial therapy on the basis of the likelihood of S aureus infection. The results of this proof-of-concept study suggest that a LukAB serologic assay might be useful in the diagnosis of invasive bacterial infections, and larger-scale validation studies are warranted.

Commercial Intravenous Immunoglobulin Preparations Contain Functional Neutralizing Antibodies against the Staphylococcus aureus Leukocidin LukAB (LukGH).

The pathogenesis of Staphylococcus aureus is mediated by an array of important virulence factors, including the two-component leukocidin family of toxins. LukAB (also known as LukGH), the most recently discovered leukocidin, is potently lethal to phagocytes, produced during invasive human disease, and present in all known clinical isolates of S. aureus Intravenous immunoglobulin (IVIg) is often used clinically in severe S. aureus infections. The primary aim of this study was to assess the binding and neutralization potential of IVIg against LukAB. A secondary aim was to examine the lot-to-lot variability of IVIg in the binding and neutralization of LukAB. We studied 24 distinct lots of IVIg and compared them to serum from children with invasive S. aureus infection (in the acute and convalescent phases) and from healthy, uninfected controls. We found that all lots of IVIg contained functional antibodies targeting LukAB. After adjusting for total antibody content per sample, we found that the amount of anti-LukAB antibody in IVIg was similar to that seen with healthy controls and less than that seen with patients with invasive S. aureus infection. IVIg samples had lower neutralization capacity than samples from healthy controls and children with invasive infection. IVIg had remarkably little lot-to-lot variation in LukAB binding but had significantly more variation in toxin neutralization. These results represent the first report of functional antibodies against the important S. aureus leukocidin LukAB in IVIg. Given the frequent clinical use of IVIg for severe S. aureus infections, improving our understanding of functional antibody properties exhibited by this therapeutic is essential.

Monoclonal Antibodies Against the Staphylococcus aureus Bicomponent Leukotoxin AB Isolated Following Invasive Human Infection Reveal Diverse Binding and Modes of Action.

The 2-component leukotoxin LukAB is critical for Staphylococcus aureus targeting and killing of human neutrophils ex vivo and is produced in the setting of human infection. We report 3 LukAB-specific human monoclonal antibodies (mAbs) with distinct mechanisms of toxin neutralization and in vivo efficacy. Three hybridomas secreting mAbs with anti-LukAB activity (designated SA-13, -15, and -17) were generated from B cells obtained from a 12-year-old boy with S. aureus osteomyelitis. Each of the 3 mAbs neutralized LukAB-mediated neutrophil toxicity, exhibited differing levels of potency, recognized different antigenic sites on the toxin, and displayed at least 2 distinct mechanisms for cytotoxic inhibition. SA-15 bound exclusively to the dimeric form of the toxin, suggesting that human B cells recognize epitopes on the dimerized form of LukAB during natural infection. Both SA-13 and SA-17 bound the LukA monomer and the LukAB dimer. Although all 3 mAbs potently neutralized cytotoxicity, only SA-15 and SA-17 significantly inhibited toxin association with the cell surface. Treatment with a 1:1 mixture of mAbs SA-15 and SA-17 resulted in significantly lower bacterial colony counts in heart, liver, and kidneys in a murine model of S. aureus sepsis. These data describe the isolation of diverse and efficacious antitoxin mAbs.