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Daptomycin-resistant Enterococcus faecium (DRE) poses an increasing therapeutic challenge, particularly in immunocompromised patients and solid organ transplant recipients. Surveillance data from the Centers for Disease Control and Prevention indicate that approximately 6.5% of E. faecium isolates are daptomycin-resistant, underscoring the need for heightened clinical vigilance, particularly for prompt identification and treatment. In this case series, three patients with advanced liver disease, including two status post orthotopic liver transplantation, are described who developed DRE during treatment for bloodstream infection. These cases illustrate the dynamic nature of antimicrobial susceptibility under daptomycin exposure and highlight the contributions of persistent source control issues, intravascular infection, and altered host factors to treatment failure. All patients were successfully managed by escalating to combination therapy with high-dose daptomycin and ceftaroline, alongside appropriate source control. This series emphasizes the importance of periodic susceptibility reassessment during daptomycin therapy and cautions clinicians against assuming sustained susceptibility in patients with prolonged bacteremia or complex infections. Early recognition of evolving resistance and timely therapeutic adjustment may improve outcomes in this high-risk population.

Abstract Objective: Suppressive antibiotic therapy (SAT) is used to prevent recurrent prosthetic joint infections (PJI) among patients who undergo debridement, antibiotics, and implant retention (DAIR). We aimed to assess SAT outcomes among younger, immunocompetent patients. Design: Retrospective cohort study. Patients: Immunocompetent patients <65 years of age who received DAIR for PJI of the hip, knee, or shoulder. Setting: Veterans Affairs hospitals. Methods: SAT was divided into short-term (oral antibiotics given for <3 months after guideline concordant therapy) and long-term SAT (>3 months to 5 years of oral antibiotics). The primary outcome was treatment failure (TF) and mortality combined. SAT was a time-dependent covariate in Cox proportional hazards models. Results: Of the 938 patients, 15% received short-term SAT, 20% received long-term SAT, and 65% did not receive SAT. Short- and long-term SAT were significantly associated with decreased hazards of TF or mortality (short-term SAT adjusted hazard ratio (aHR) = 0.27; 95% confidence interval (CI): 0.11, 0.67; Long-term SAT aHR = 0.52; 95% CI: 0.30, 0.89). Short-term SAT was significantly associated with C. difficile infection (aHR: 3.47; 95% CI: 1.38, 8.74). Short-term SAT (aHR: 7.83; 95% CI: 4.80, 12.77) and long-term SAT (aHR: 1.68; 95% CI: 1.19, 2.38) were significantly associated with antibiotic-associated diarrhea. Long-term SAT was not significantly associated with TF alone (aHR = 0.61; 95% CI: 0.32, 1.16). Conclusions: SAT was significantly associated with decreased death or TF and increased side effects. Benefits and risks must be weighed before prescribing SAT to younger, immunocompetent patients.

BACKGROUND: With pulmonary hypertension (PH), a pulmonary artery wedge pressure (PAWP)>15 mm Hg is used to diagnose left heart dysfunction, but some patients with adjudicated group 1 PH demonstrate PAWP>15 mm Hg. The primary objective of the study was to evaluate group 1 PH with high PAWP>15 mm Hg. METHODS: Patients with adjudicated group 1 PH from PVDOMICS between 2016 and 2019 were separated into high PAWP(>15 mm Hg) or normal PAWP and compared with adjudicated combined pre- and postcapillary (Cpc) PH related to heart failure with preserved ejection fraction (HFpEF). Participants underwent dynamic right heart catheterization and metabolomics. Findings were validated in 3 independent cohorts with adjudicated group 1 PH (validation cohorts 1 and 2 with exercise right heart catheterization and validation cohort 3 with resting right heart catheterization). RESULTS: Of 325 patients with group 1 PH (73% women, mean age 53.0±14.3 years), 15% (n=48) had high PAWP. Group 1 PH+high PAWP demonstrated greater obesity, left ventricular hypertrophy ( P <0.0002), left ventricular strain impairment ( P <0.0001), and decreased left ventricular compliance ( P <0.0001) compared with group 1 PH+normal PAWP, with changes comparable to Cpc-PH HFpEF (n=75). Compared with Cpc-PH HFpEF, left atrial function was better in group 1 PH+high PAWP with lower PAWP V wave, higher left atrial compliance, and left atrial ejection fraction ( P <0.0001 for all). Metabolomics demonstrated little difference between group 1 PH with high versus normal PAWP but large differences between group 1 PH+high PAWP versus Cpc-PH HFpEF (100 metabolites altered at false discovery rate P <0.05). Elevated PAWP was also observed in 18% of group 1 PH in the validation cohort 1 (n=402), with exercise PAWP response intermediately abnormal in group 1 PH+high PAWP relative to Cpc-PH HFpEF and group 1 PH+normal PAWP (interaction P <0.0001). Elevated PAWP was similarly observed in 22% and 19% of group 1 PH in validation cohorts 2 (n=55) and 3 (n=787), respectively. CONCLUSIONS: Approximately 1 in 5 adjudicated patients with group 1 PH has elevation in resting PAWP despite severe pulmonary vascular dysfunction and metabolomics consistent with traditionally defined group 1 PH. Despite resting PAWP elevation, these patients with group 1 PH were metabolomically and biologically distinct from Cpc PH HFpEF, with better left atrial function and diastolic reserve during exercise. These data emphasize the limitations of using resting PAWP alone to separate group 1 PH from HFpEF and call for development of more integrated clinical diagnostic criteria.

Background. Acute cellular rejection (ACR) remains a major cause of morbidity after heart transplantation despite advances in immunosuppression. Whole genome transcriptomic profiling offers a systems-based, unbiased approach to elucidate the molecular mechanisms underlying ACR. However, noninvasive, longitudinal biomarker assessments capable of capturing the temporal dynamics of rejection biology remain scarce. Methods. RNA sequencing of peripheral blood from heart transplant recipients before, during, and after ACR was compared with nonrejection controls. Pathway analysis was conducted using differentially expressed genes (DEGs), and a machine learning approach was applied to assess gene-based prediction of ACR. Results. A total of 235 rejection-specific significant DEGs and 863 postrejection DEGs (false discovery rate < 0.05) were identified. During ACR, DEGs were enriched for T-cell activation/differentiation, apoptosis, and B-cell receptor signaling pathways. By combining the 2 sets of DEGs, a panel of 71 common genes was identified that reflected the significant, longitudinal transcriptomic dynamics of ACR. In an elastic net machine learning–based classifier, DYNLL1 and SERF2 were identified as ACR predictive genes, and achieved a cross-validated area under the receiver operating characteristic curve of 0.63. Conclusions. Peripheral blood transcriptomics identify dynamic temporal responses in ACR including T- and B-cell pathways with potential ACR predictive genes that warrant further investigation.

Abstract Background Cytomegalovirus (CMV) infection remains one of the most prevalent and important infections following solid organ transplant (SOT). Treatment is often challenging, especially when dealing with refractory and resistant CMV infections.Table 1:Univariable logistic regression analyses of associations with early refractory CMV infectionTable 2:Univariable logistic regression analyses of associations with resistant CMV infection Methods We performed a retrospective cohort study of SOT recipients with clinically significant CMV infection (csCMVi) at a tertiary transplant center in the US during 2010-2016. The primary outcome was early refractory CMV infection and secondary outcomes were drug resistance, CMV recurrence, and mortality. Kaplan-Meier estimation, univariable logistic regression analysis, and multivariable Cox regression were used for outcome analysis.Table 3:Multivariable Cox regression analysis of associations with recurrent CMV infection after primary treatment endedNote: Refractory CMV was not included in the model for recurrent CMV as no patients with refractory infection had recurrence. Results A total of 145 SOT recipients with csCMVi were included. Most patients were recipients of liver (49%), followed by kidney (22.1%), heart (6.9%), lung (5.5%), and pancreas (4.1%). Multiple organ transplants accounted for 12.4% of the cohort. Most common induction was an anti-IL-2 antibody (43.9%) followed by ATG (29.5%). 82 (56.5%) had CMV D+/R- mismatch. In total, 34 (23.4%) had CMV syndrome, 38 (26.2%) had tissue-invasive CMV disease, while the rest (50.3%) were asymptomatic. After the initial 3 weeks of antiviral therapy, 13 (8.9%) patients had probable refractory csCMVi; most of them (10 [76.9%]) were CMV D+/R- mismatch. Longer time after transplant had lower risk (OR 0.68; CI 0.48-0.95, p=0.029) while lower absolute lymphocyte count (ALC) was higher risk of early refractory csCMVi (OR 1.54; CI 1.01-2.44, p=0.048) (Table 1). Drug-resistant CMV occurred in 7 patients (4.8%); a high initial CMV DNA level was associated with resistant csCMVi (OR 2; CI 1.08-3.93, p=0.031) (Table 2). Of 144 patients with post-treatment follow-up, 25 (17.2%) experienced recurrent csCMVi within 6 months. Table 3 shows the associations with recurrence of csCMVi after initial treatment. 30 patients (20.7%) died during a median follow-up of 4 years, but refractory, resistant or recurrent CMV were not associated with mortality. Conclusion Refractory csCMVi is associated with low ALC and an earlier onset post-transplant. Resistant csCMVi is associated with high levels of initial CMV DNA. Recurrence of csCMVi is common and possibly associated with low ALC at the end of antiviral treatment. Disclosures All Authors: No reported disclosures

Glutathione synthetase (GSS) deficiency is an extremely rare autosomal recessive inborn error of metabolism. This metabolic disorder is caused by mutations in the GSS gene, which encodes GSS—an enzyme that catalyses the ATP-dependent conversion of γ-glutamyl-cysteine and glycine to glutathione. Low glutathione impairs the cellular antioxidant defence mechanism, leaving cells susceptible to oxidative stress and damage.

Abstract Immune checkpoint inhibitors (ICI) have transformed cancer therapy but can induce a spectrum of endocrine complications. Acquired generalized lipodystrophy (AGL) is a rare adverse effect, leading to severe metabolic derangements including insulin-resistant diabetes, dyslipidemia, and hepatic steatosis. Marked hypoleptinemia is noted in these patients, and leptin-replacement therapy is known to be beneficial in patients with other forms of AGL. Though rare, T-cell lymphoma has been reported in patients with AGL on leptin therapy, and there has been much debate on the association between hyperleptinemia and cancer. The safety and efficacy of leptin therapy in patients with ICI-induced AGL and cancer are therefore not clear. We report a 66-year-old woman with metastatic lung adenocarcinoma who developed multiple endocrine disorders including AGL with metabolic abnormalities following pembrolizumab therapy. Initiation of daily metreleptin led to marked improvement in dyslipidemia, glycemic control, and hepatic steatosis, with no evidence of cancer recurrence after 2 years of leptin-replacement therapy. While further studies are warranted to establish the long-term efficacy and safety of leptin in ICI-induced AGL patients with a history of malignancy, this case report provides useful information for the management of these rare, challenging patients.

Key Points Health care utilization rates in elderly kidney transplant were no different between the high kidney donor profile index and low kidney donor profile index group. Number of readmissions and surgical interventions in elderly kidney transplant was no different between the high kidney donor profile index and low kidney donor profile index group. Death censored graft loss was higher in the high kidney donor profile index group, whereas the patient survival was no different between the high kidney donor profile index and low kidney donor profile index groups. Background High kidney donor profile index (KDPI) kidneys (KDPI >85%) are often associated with increased risks of post-kidney transplant (KT) complications and greater health care utilization (HCU), particularly in elderly recipients with multiple comorbidities. These concerns frequently lead to underutilization of high KDPI kidneys in older transplant candidates, thereby limiting their access to transplantation despite potential clinical benefits. The aim of this study was to compare post-KT HCU between elderly recipients of high versus low KDPI deceased donor kidneys. The primary outcome included differences in hospital readmissions, surgical interventions, and outpatient service use at multiple post-transplant time points. Secondary outcome included graft function, graft survival, and patient survival. Methods A retrospective analysis of elderly solitary KT recipients (age ≥65 years) between January 1, 2011, and December 31, 2020. Patients were stratified into high KDPI (>85%, n =160) and low KDPI (≤85%, n =453) groups. We assessed inpatient and outpatient HCU, including readmissions at 30, 90, and 365 days post-transplant, surgical interventions, and outpatient visits (emergency department, transplant clinic, endocrine clinic, and ambulatory infusion units). Results There were no statistically significant differences between high and low KDPI groups in rates of hospital readmissions, surgical interventions, or outpatient visits (all P > 0.05). Delayed graft function rates were also similar ( P = 0.61). The low KDPI group had significantly higher eGFR at 4 months, 1, 2, and 3 years post-transplant (all P < 0.001). However, days alive and out of the hospital within 90 and 365 days post-transplant were comparable between the groups (all P > 0.05). Overall patient survival was similar ( P = 0.08), although death-censored graft loss was significantly higher in the high KDPI group ( P = 0.001). Conclusions Among elderly KT recipients, high KDPI kidney recipients had comparable post-transplant HCU and overall survival with those receiving low KDPI kidneys, despite lower long-term graft function. These findings suggest that high KDPI kidneys remain a viable option for older patients, offering timely access to transplantation.

Abstract Introduction Hispanic and non-Hispanic Black (NHB) patients have worse HCT survival compared to non-Hispanic White (NHW) patients and were less likely to utilize an unrelated HCT donor (Khera et al. Blood Adv. 2024; Hahn et al. JAMA Netw Open. 2024), but this difference has not been evaluated in the PTCy era. PTCy reduces graft-versus-host disease (GvHD) and allows for increased availability of allogeneic donors in minority patients. It is important to know the best donor source for each ethnicity. In this study, we investigated the association of race/ethnicity and donor type on overall survival (OS). Methods We performed a secondary analysis of adult patients (&gt;19 yrs) who were selected if they had a peripheral blood allogeneic HCT from 2013-2018 and received PTCy for GVHD prophylaxis using a publicly available dataset from the Center for International Blood and Marrow Transplantation Research Program. Kaplan-Meier curves estimated 2-year OS, and differences were compared using log-rank tests. X2 tests helped identify potential confounders. Analyses were stratified by donor type and self-reported race/ethnicity. The Cox Proportional Hazards model evaluated 2-year OS using a backwards elimination method to build the final prediction model. P&lt;0.05 was considered statistically significant. Results Of 4,031 patients included, 70% were NHW, 16% were NHB, and 13% were Hispanic. The most common donor was Haploidentical (Haplo; 64%), followed by matched unrelated donor (MUD; 19%), matched related donor (MRD; 10%), and mismatched unrelated donor 7%). Hispanic patients were younger than NHW and NHB (P&lt;0.0001) and more were transplanted in CR (P&lt;0.0001). Additionally, most Hispanic and NHB patients received a Haplo HCT (77 and 83%, respectively). NHW patients also received Haplo HCTs (57%) as well as MUD HCTs (24%). Most patients had acute myeloid leukemia (40%) followed by myelodysplastic syndrome (22%) and received reduced intensity conditioning (58%). MUD patients who received PTCy had the highest 2-year OS compared to other donors (65 vs 58-61%; P=0.03). Higher OS was observed in younger patients (20-39 yrs: 69% vs 60+ yrs: 53%; P&lt;0.001) and patients with non-malignant diseases (80%) or Hodgkin lymphoma (79%) compared to patients with plasma cell (52%) and myelodysplastic disorders (55%; P&lt;0.0001). For NHW patients, patients transplanted with a MUD had higher OS than other donor types (67 vs 58-60%; p=0.0006). In contrast, NHB transplanted with MRD, Haplo, or MMUD had the highest OS compared to MUD, although this was not statistically significant (61-66% vs 42%; p=0.4). Hispanic patients transplanted with a related donor (MRD and Haplo) had higher OS compared to patients who had an unrelated donor (MUD and MMUD; 66-67 vs 48-58%; P=0.1). Within each donor source, we tested for a racial disparity in OS. There was no difference in OS by race/ethnicity in MRD or MMUD HCTs. In Haplo HCTs, Hispanic patients had the highest OS followed by NHB and then NHW (66, 61, vs 58%; P=0.005). In MUD HCTs, NHW patients had higher OS than Hispanic or NHB patients (67, 48, vs 42%; P=0.02). Significant factors associated with OS in multivariable analyses included donor type, age, disease, year of transplant, conditioning intensity, Karnofsky Performance Score, donor/recipient CMV serostatus, and disease risk index. Results were stratified by race/ethnicity. For NHW patients, mortality risk was higher for HCT patients receiving a MRD, Haplo, or MMUD compared to a MUD (HR=1.25-1.39; P=0.001). In contrast, NHB patients receiving a MUD had a higher risk of mortality compared to a Haplo, MRD, or MMUD (HR=1.67; P=0.06). In Hispanic patients, MUDs and MMUDs had a higher mortality risk than MRD or Haplo HCT (HR=1.48; P=0.07). Conclusion OS differed by race/ethnicity and donor type. Our findings should be validated by expanding the analysis to include patients treated with PTCy after the publication of BMT CTN 1703 results (Bolaños-Mead et al. NEJM. 2023). When selecting donors for HCT patients, consideration should be given to patient race/ethnicity.

ABSTRACT Purpose The purpose of this study was to evaluate the incidence and risk factors for developing recurrent clinically significant cytomegalovirus infections (csCMVi) in heart transplant recipients. Methods We conducted a retrospective cohort study involving adult heart transplant recipients at three large transplant centers in the United States between January 2011 and March 2019. All patients with a history of csCMVi, defined as CMV disease or CMV infection requiring preemptive therapy, were followed from the date of treatment completion for the primary csCMVi episode. Outcomes of interest were recurrent csCMVi and all‐cause mortality. Results Among 98 heart transplant recipients with csCMVi, 22 (22.4%) episodes of recurrent csCMVi occurred. Median time‐to‐recurrent csCMVi was 31.5 (IQR 21.3–59.8) days following treatment completion. A preceding episode of CMV disease (versus infection) was associated with a lower risk of recurrent csCMVi (HR 0.29, 95% CI 0.08–0.98; p = 0.047). Patients with lymphopenia had higher rates of recurrent csCMVi without statistical significance (HR 2.13, 95% CI 0.88–5.13; p = 0.093). Seroconversion by the end‐of‐therapy among CMV D+/R− mismatched patients was associated with a reduced risk of csCMVi recurrence (HR 0.07, 95% CI 0.02–0.30; p < 0.001). Overall, 17 (17.3%) patients died during follow‐up, which was not significantly higher among those with recurrent csCMVi (HR 2.13, 95% CI 0.78–5.79; p = 0.141). Conclusions About one in five heart recipients with csCMVi developed post‐treatment recurrence. A preceding episode of CMV disease and seroconversion was protective against recurrence. Lymphopenia may be a practical biomarker to stratify recurrence risk. Overall, recurrent csCMVi was not significantly associated with mortality.