Effectiveness of combined plasma cell therapy and costimulation blockade based desensitization regimen in heart transplant candidates.

BACKGROUND: Desensitization is one of the strategies to reduce antibodies and facilitate heart transplantation in highly sensitized patients. We describe our center's desensitization experience with combination of plasma cell (PC) depletion therapy (with proteasome inhibitor or daratumumab) and costimulation blockade (with belatacept). METHODS: We reviewed five highly sensitized patients who underwent desensitization therapy with plasma cell depletion and costimulation blockade. We evaluated the response to therapy by measuring the changes in cPRA, average MFI, and number of positive beads > 5000MFI. RESULTS: Five patients, mean age of 56 (37-66) years with average cPRA of 98% at 5000 MFI underwent desensitization therapy. After desensitization, mean cPRA decreased from 98% to 70% (p = .09), average number of beads > 5000 MFI decreased from 59 to 37 (p = .15), and average MFI of beads > 5000 MFI decreased from 16713 to 13074 (p = .26). CONCLUSION: Combined PC depletion and CoB could be a reasonable strategy for sustained reduction in antibodies in highly sensitized patients being listed for heart transplantation.

Enhanced recovery after surgery may mitigate the risks associated with robotic-assisted fundoplication in lung transplant patients.

INTRODUCTION: A history of lung transplantation is a risk factor for poor outcomes in patients undergoing laparoscopic fundoplication. We wanted to determine whether enhanced recovery after a robotic-assisted surgery program would mitigate these risks. METHODS: We performed a single-center retrospective analysis of the Society of Thoracic Surgery database for patients who underwent elective antireflux procedures from 1/2018 to 2/2021 under the enhanced recovery after surgery program using robotic assistance. We identified the patient and surgical characteristics, morbidity, length of stay, and 30-day readmission rates. RESULTS: Among 386 patients who underwent barrier creation, 41 had previously undergone a lung transplant, either bilateral (n = 28) or single (n = 13). There were no significant differences in postoperative complications (9.8% vs. 5.2%, p = 0.27), median hospital length of stay (1 d vs. 1 d, p = 0.28), or 30-day readmission (7.3% vs. 4.9%, p = 0.46). Bivariate analysis showed that older age (p = 0.03), history of DVT/PE (p < 0.001), history of cerebrovascular events (p = 0.03), opioid dependence (p = 0.02), neurocognitive dysfunction (p < 0.001), and dependent functional status (p = 0.02) were associated with postoperative complications. However, lung transplantation was not associated with an increased risk of postoperative complications (p = 0.28). DISCUSSION: The risk of surgical complications in patients with a history of lung transplantation may be mitigated by the combination of ERAS and minimally invasive surgery such as robot-assisted surgery.

Anti-Tuberculosis Potential of OJT008 against Active and Multi-Drug-Resistant Mycobacterium Tuberculosis: In Silico and In Vitro Inhibition of Methionine Aminopeptidase.

Despite the recent progress in the diagnosis of tuberculosis (TB), the chemotherapeutic management of TB continues to be challenging. Mycobacterium tuberculosis (Mtb), the etiological agent of TB, is classified as the 13th leading cause of death globally. In addition, 450,000 people were reported to develop multi-drug-resistant TB globally. The current project focuses on targeting methionine aminopeptidase (MetAP), an essential protein for the viability of Mtb. MetAP is a metalloprotease that catalyzes the excision of the N-terminal methionine (NME) during protein synthesis, allowing the enzyme to be an auspicious target for the development of novel therapeutic agents for the treatment of TB. Mtb possesses two MetAP1 isoforms, MtMetAP1a and MtMetAP1c, which are vital for Mtb viability and, hence, a promising chemotherapeutic target for Mtb therapy. In this study, we cloned and overexpressed recombinant MtMetAP1c. We investigated the in vitro inhibitory effect of the novel MetAP inhibitor, OJT008, on the cobalt ion- and nickel ion-activated MtMetAP1c, and the mechanism of action was elucidated through an in silico approach. The compound's potency against replicating and multi-drug-resistant (MDR) Mtb strains was also investigated. The induction of the overexpressed recombinant MtMetAP1c was optimized at 8 h with a final concentration of 1 mM Isopropyl ß-D-1-thiogalactopyranoside. The average yield from 1 L of Escherichia coli culture for MtMetAP1c was 4.65 mg. A preliminary MtMetAP1c metal dependency screen showed optimum activation with nickel and cobalt ions occurred at 100 µM. The half-maximal inhibitory concentration (IC50) values of OJT008 against MtMetAP1c activated with CoCl2 and NiCl2 were 11 µM and 40 µM, respectively. The in silico study showed OJT008 strongly binds to both metal-activated MtMetAP1c, as evidenced by strong molecular interactions and a higher binding score, thereby corroborating our result. This in silico study validated the pharmacophore's metal specificity. The potency of OJT008 against both active and MDR Mtb was <0.063 µg/mL. Our study reports OJT008 as an inhibitor of MtMetAP1c, which is potent at low micromolar concentrations against both active susceptible and MDR Mtb. These results suggest OJT008 is a potential lead compound for the development of novel small molecules for the therapeutic management of TB.

Relationship of LVEF and Myocardial Scar to Long-Term Mortality Risk and Mode of Death in Patients With Nonischemic Cardiomyopathy.

BACKGROUND: Nonischemic cardiomyopathy is a leading cause of reduced left ventricular ejection fraction (LVEF) and is associated with high mortality risk from progressive heart failure and arrhythmias. Myocardial scar on cardiovascular magnetic resonance imaging is increasingly recognized as a risk marker for adverse outcomes; however, left ventricular dysfunction remains the basis for determining a patient's eligibility for primary prophylaxis with implantable cardioverter-defibrillator. We investigated the relationship of LVEF and scar with long-term mortality and mode of death in a large cohort of patients with nonischemic cardiomyopathy. METHODS: This study is a prospective, longitudinal outcomes registry of 1020 consecutive patients with nonischemic cardiomyopathy who underwent clinical cardiovascular magnetic resonance imaging for the assessment of LVEF and scar at 3 centers. RESULTS: During a median follow-up of 5.2 (interquartile range, 3.8, 6.6) years, 277 (27%) patients died. On survival analysis, LVEF ≤35% and scar were strongly associated with all-cause (log-rank test P=0.002 and P<0.001, respectively) and cardiac death (P=0.001 and P<0.001, respectively). Whereas scar was strongly related to sudden cardiac death (SCD; P=0.001), there was no significant association between LVEF ≤35% and SCD risk (P=0.57). On multivariable analysis including established clinical factors, LVEF and scar are independent risk markers of all-cause and cardiac death. The addition of LVEF provided incremental prognostic value but insignificant discrimination improvement by C-statistic for all-cause and cardiac death, but no incremental prognostic value for SCD. Conversely, scar extent demonstrated significant incremental prognostic value and discrimination improvement for all 3 end points. On net reclassification analysis, the addition of LVEF resulted in no significant improvement for all-cause death (11.0%; 95% CI, -6.2% to 25.9%), cardiac death (9.8%; 95% CI, -5.7% to 29.3%), or SCD (7.5%; 95% CI, -41.2% to 42.9%). Conversely, the addition of scar extent resulted in significant reclassification improvement of 25.5% (95% CI, 11.7% to 41.0%) for all-cause death, 27.0% (95% CI, 11.6% to 45.2%) for cardiac death, and 40.6% (95% CI, 10.5% to 71.8%) for SCD. CONCLUSIONS: Myocardial scar and LVEF are both risk markers for all-cause and cardiac death in patients with nonischemic cardiomyopathy. However, whereas myocardial scar has strong and incremental prognostic value for SCD risk stratification, LVEF has no incremental prognostic value over clinical measures. Scar assessment should be incorporated into patient selection criteria for primary prevention implantable cardioverter-defibrillator placement.

Survival following liver transplantation for locally advanced, unresectable intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) has previously been considered a contraindication to liver transplantation (LT). However, recent series showed favorable outcomes for LT after neoadjuvant therapy. Our center developed a protocol for neoadjuvant therapy and LT for patients with locally advanced, unresectable iCCA in 2010. Patients undergoing LT were required to demonstrate disease stability for 6 months on neoadjuvant therapy with no extrahepatic disease. During the study period, 32 patients were listed for LT and 18 patients underwent LT. For transplanted patients, the median number of iCCA tumors was 2, and the median cumulative tumor diameter was 10.4 cm. Patients receiving LT had an overall survival at 1-, 3-, and 5-years of 100%, 71%, and 57%. Recurrences occurred in seven patients and were treated with systemic therapy and resection. The study population had a higher than expected proportion of patients with genetic alterations in fibroblast growth factor receptor (FGFR) and DNA damage repair pathways. These data support LT as a treatment for highly selected patients with locally advanced, unresectable iCCA. Further studies to identify criteria for LT in iCCA and factors predicting survival are warranted.

Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG.

Coronavirus disease 2019 (COVID-19) convalescent plasma has emerged as a promising therapy and has been granted Emergency Use Authorization by the US Food and Drug Administration for hospitalized COVID-19 patients. We recently reported results from interim analysis of a propensity score-matched study suggesting that early treatment of COVID-19 patients with convalescent plasma containing high-titer anti-spike protein receptor binding domain (RBD) IgG significantly decreases mortality. We herein present results from a 60-day follow-up of a cohort of 351 transfused hospitalized patients. Prospective determination of enzyme-linked immunosorbent assay anti-RBD IgG titer facilitated selection and transfusion of the highest titer units available. Retrospective analysis by the Ortho VITROS IgG assay revealed a median signal/cutoff ratio of 24.0 for transfused units, a value far exceeding the recent US Food and Drug Administration-required cutoff of 12.0 for designation of high-titer convalescent plasma. With respect to altering mortality, our analysis identified an optimal window of 44 hours after hospitalization for transfusing COVID-19 patients with high-titer convalescent plasma. In the aggregate, the analysis confirms and extends our previous preliminary finding that transfusion of COVID-19 patients soon after hospitalization with high-titer anti-spike protein RBD IgG present in convalescent plasma significantly reduces mortality.

Anatomic Pulmonary Resection is Associated With Improved Survival in Typical Carcinoid Lung Tumor Patients.

BACKGROUND: The optimal extent of resection for a patient with a typical carcinoid tumor has been controversial. Studies suggest that wedge resection is an adequate oncologic operation for this tumor type. MATERIALS AND METHODS: We analyzed the National Cancer Database to determine an optimal surgical resection for patients with a typical carcinoid tumor. We determined the number of patients who had typical carcinoid tumors. We then performed a survival analysis of the propensity-matched group of patients having a pathologic stage I typical carcinoid tumor who had undergone anatomic pulmonary resection (lobectomy and segmentectomy) or wedge resection. RESULTS: A total of 10,265 patients met the inclusion and exclusion criteria: 8956 (87%) had a typical carcinoid tumor, while 1309 patients (13%) had an atypical carcinoid tumor. Among patients with typical carcinoid tumors, there were 7163 patients (80%) who underwent anatomic pulmonary resection (6755 patients with lobectomy, 94% and 408 patients with segmentectomy, 6%) and 1793 patients (20%) who underwent wedge resection. In this cohort, patients who had an anatomic resection had significantly improved 5-y survival compared to patients who had wedge resection (91% versus 84%, P < 0.001). In the propensity score-matched group of stage I typical carcinoid tumors (n = 1348), the patients who had an anatomic resection had significantly improved survival compared to patients who had wedge resections (89% versus 85%, P = 0.01) at 5 y. CONCLUSIONS: The anatomic resection compared to wedge resection was associated with improved survival in patients with early-stage typical carcinoid lung cancer. Surgically fit patients should be considered for anatomic resection for typical carcinoid tumors.

Outcomes of Heart Transplant Recipients with Class II Obesity: A United Network for Organ Sharing Database Analysis.

BACKGROUND: In the 2016 ISHLT listing criteria guidelines for heart transplantation, recipients were recommended to have a body mass index (BMI) <35 kg/m². However, outcomes data for subgroups of transplant recipients with a BMI >35 kg/m² are limited. We examined the outcomes of heart transplant recipients who had a BMI of 35 to 39.9 kg/m² or ≥40 kg/m² and compared their outcomes with recipients who had a BMI <35 kg/m2. METHODS: Using data from the United Network for Organ Sharing database, we performed a retrospective cohort analysis of 23,009 adults who underwent cardiac transplantation between 2009 and 2018. Transplant recipients were stratified by BMI categories (<35 kg/m², 35-39.9 kg/m², and ≥40 kg/m²). Patient survival was depicted by Kaplan-Meier curves. Cox proportional-hazards modeling was used to determine the prognostic factors associated with mortality within 90 days, 1 year, and 5 years after transplantation. RESULTS: Survival at 90 days, 1 year, and 5 years after transplantation was better in recipients who had a BMI <35 kg/m² than in those who had a BMI of 35 to 39.9 kg/m² (P values ranged from 0.01 to < 0.001) or ≥40 kg/m² (P < 0.001). Additionally, survival at 90 days (P < 0.001) and 1 year (P = 0.002) was significantly better in recipients who had a BMI of 35 to 39.9 kg/m² than in those who had a BMI ≥40 kg/m². In multivariate analysis, a BMI of 35 to 39.9 was significantly associated with increased 90-day mortality (HR = 1.53; 95% CI 1.12, 2.08; P = 0.01) but not increased 1-year (HR = 1.28; 95% CI 0.99, 1.66; P = 0.06) or 5-year mortality (HR = 1.11; 95% CI 0.91, 1.36; P = 0.29). CONCLUSIONS: Although heart transplant recipients with class II obesity (BMI 35-39.9 kg/m²) may have suboptimal survival compared with those who have a BMI <35 kg/m², these patients have better outcomes than do those with class III obesity (BMI ≥40 kg/m²). Thus, contrary to current guidelines, selected patients with class II obesity should be considered for transplantation.

Intravenous immunoglobulin in heart transplant recipients with mild to moderate hypogammaglobulinemia and infection.

BACKGROUND: Hypogammaglobulinemia (HGG) is a complication of solid organ transplantation leading to increased risk of infections. Intravenous immunoglobulin G (IVIG) replacement in patients with HGG may be able to reduce risk and morbidity associated with infection; however, there is scarce data about IVIG in mild to moderate HGG (IgG 400-700 mg/dl) and heart transplant recipients. METHODS: A single center, retrospective study was performed in heart transplant recipients with mild (IgG 500-700 mg/dl) to moderate (IgG 400-499 mg/dl) HGG in the presence of an infection. RESULTS: Forty-two patients were included in this study; 19 patients (45.2%) received IVIG and 23 (54.8%) patients did not. Patients in the IVIG group received on average one dose of IVIG at 0.5 g/kg. No differences in incidence of new infection at 3 months (26.3% vs. 17.4%; P = .71) and 6 months (42.1% vs. 34.8%; P = .63) were observed between the IVIG and non-IVIG groups. Infections based on mild or moderate HGG also had no differences at 3 and 6 months. CONCLUSION: Our findings suggest that a single infusion of IVIG in mild to moderate HGG may have little to no benefit in reducing incidence of new infections. Larger prospective studies are needed to confirm these findings.

Outcomes of kidney donors with sickle cell trait: A preliminary analysis.

Most transplant centers do not screen kidney donor candidates for sickle cell trait (SCT) and many decline candidates with SCT since it may associate with kidney disease. We compared 17 kidney donors with SCT to propensity score matched donor controls on mortality, reduced eGFR, proteinuria and kidney failure. The prevalence of SCT in African American (AA) donors was 11 per 1000 compared to 73 per 1000 in non-donor AA. Donors with SCT were younger; 33 versus 35 years in controls, nine were AA, six were White, and two were listed as other or unknown ethnicities. After a follow-up period of 18.2 ± 10.5 years, the proportions of donors with SCT and controls who were alive, developed hypertension or cardiovascular disease were similar. No donor with SCT developed an eGFR <30 mL/min/1.73 m2 or kidney failure. SCT was, however, associated with increased risk of proteinuria; RR 5.71 (95% CI 5.7 - 22.7), P = .01. This small and preliminary case series suggest that donors with SCT should perhaps be considered more often provided they were aware of the lack of evidence to support liberal acceptance and that these outcomes reported here likely represent a healthy cohort of donors with SCT.

Early humoral immune response to two doses of severe acute respiratory syndrome coronavirus 2 vaccine in a diverse group of solid organ transplant candidates and recipients.

Response to two doses of a nucleoside-modified messenger ribonucleic acid (mRNA) vaccine was evaluated in a large solid-organ transplant program. mRNA COVID-19 vaccine was administered to transplant candidates and recipients who met study inclusion criteria. Qualitative anti-SARS-CoV-2 Spike Total Immunoglobulin (Ig) and IgG-specific assays, and a semi-quantitative test for anti-SARS-CoV-2 Spike protein IgG were measured in 241 (17.2%) transplant candidates and 1163 (82.8%) transplant recipients; 55.2% of whom were non-Hispanic White and 44.8% identified as another race. Transplant recipients were a median (IQR) of 3.2 (1.1, 6.8) years from transplantation. Response differed by transplant status: 96.0% versus 43.2% by the anti-SARS-CoV-2 Total Ig (candidates vs. recipients, respectively), 93.5% versus 11.6% by the anti-SARS-CoV-2 IgG assay, and 91.9% versus 30.1% by anti-spike titers after two doses of vaccine. Multivariable analysis revealed candidates had higher likelihood of response versus recipients (odds ratio [OR], 14.6; 95 %CI 2.19, 98.11; P = .02). A slightly lower response was demonstrated in older patients (OR .96; 95 %CI .94, .99; P = .002), patients taking antimetabolites (OR, .21; 95% CI .08, .51; P = .001). Vaccination prior to transplantation should be encouraged.

Postoperative bleeding and leaks in sleeve gastrectomy are independent of both staple height and staple line oversewing.

BACKGROUND: Over 100,000 sleeve gastrectomy procedures are performed annually in the USA. Despite technological advances, postoperative bleeding and gastric staple line leak are complications of this procedure. We analyzed patient-specific and perioperative factors to determine their association with these complications. METHODS: We performed a retrospective cohort analysis of patients who underwent sleeve gastrectomy between 2005 and 2019 at our institution. Patient demographics, comorbidities, and procedure details including type of energy device, staple type, staple height, staple line oversewing, and staple line clipping were compared using multiple logistic regression for combined postoperative complications (blood transfusion, bleeding, and staple line leak). Postoperative bleeding was defined by requiring blood transfusion and/or re-operation to control bleeding. Staple line leak was confirmed radiographically. RESULTS: There were 1213 patients who underwent sleeve gastrectomy. Fifty-two high-risk patients were excluded due to cirrhosis, end-stage renal disease, and anticoagulation use for left ventricular assist device. Of the remaining 1161 patients, twenty-five (2.2%) received postoperative blood transfusion, nine (0.8%) had postoperative bleeding, two (0.2%) had staple line leak, and twenty-eight patients (2.4%) had combined postoperative complications. The median age was significantly higher for patients with combined postoperative complications (43 vs 49; p = 0.02). There was no difference in postoperative blood transfusion, bleeding, staple line leak, or combined postoperative complication with different energy devices (p = 0.92), staple types (p = 0.21), staple heights (p = 0.50), or staple line suturing/clipping (p = 0.95). In addition, there was no difference in bleeding when comparing staple line sewing techniques (p = 0.44). Predictably, patients with combined postoperative complications had increased length of stay (3 days vs 1 day; p < 0.001). CONCLUSION: Sleeve gastrectomy procedure has tremendous variability in technique and devices used. We observed no difference in the combined postoperative complications of bleeding or staple line leak with respect to different energy devices, staple height, or oversewing of the gastric staple line. Patient selection is crucial, as patient age and coagulopathic comorbidities were found to lead to higher combined postoperative complications.

Intraoperative diagnosis and treatment of Achalasia using EndoFLIP during Heller Myotomy and Dor fundoplication.

BACKGROUND: Manometry is the gold standard diagnostic test for achalasia. However, there are incidences where manometry cannot be obtained preoperatively, or the results of manometry is inconsistent with the patient's symptomatology. We aim to determine if intraoperative use of EndoFLIP can provide a diagnosis of achalasia and provide objective information during Heller myotomy and Dor fundoplication. METHODS: To determine the intraoperative diagnostic EndoFLIP values for patients with achalasia, we determined the optimal cut-off points of the distensibility index (DI) between patients with a diagnosis of achalasia and patients with a diagnosis of hiatal hernia. To evaluate the usefulness of EndoFLIP values during Heller myotomy and Dor fundoplication, we obtained a cohort of patients with EndoFLIP values obtained after Heller myotomy and after Dor fundoplication as well as Eckardt score before and after surgery. RESULTS: Our analysis of 169 patients (133 hiatal hernia and 36 achalasia) showed that patients with DI < 0.8 have a >99% probability of having achalasia, while DI > 2.3 have a >99% probability of having hiatal hernia. Patients with a DI 0.8-1.3 have a 95% probability of having achalasia, and patients with a DI of 1.4-2.2 have a 94% probability of having a hiatal hernia. There were 40 patients in the cohort to determine objective data during Heller myotomy and Dor fundoplication. The DI increased from a median of 0.7 to 3.2 after myotomy and decreased to 2.2 after Dor fundoplication (p < 0.001). The median Eckardt score went down from a median of 4.5 to 0 (p < 0.001). CONCLUSIONS: Our study shows that intraoperative use of EndoFLIP can facilitate the diagnosis of achalasia and is used as an adjunct to diagnose achalasia when symptoms are inconsistent. The routine use of EndoFLIP during Heller myotomy and Dor fundoplication provides objective data during the operation in a group of patients with excellent short-term outcomes.

A novel EndoFLIP marker during hiatal hernia repair is associated with short-term postoperative dysphagia.

BACKGROUND: Endoluminal functional lumen imaging probe (EndoFLIP) provides an objective measure of the distensibility index (DI) during different parts of hiatal hernia repair. However, the absolute DI measure above a cut-off after creating a barrier alone has not shown a relationship to dysphagia after surgery. We wanted to determine if the change in DI with volume change is associated with dysphagia. METHODS: We included patients who had hiatal hernia repair with EndoFLIP values, including two values taken at the end of the surgical case with different volumes of fluid in the balloon (30 mL and 40 mL). We compared the absolute and change in DI during hiatal hernia repair and performed an analysis to determine if there was a correlation with short-term clinical outcomes. RESULTS: A total of 103 patients met the inclusion and exclusion criteria. Most of the patients underwent Toupet fundoplication (n = 56, 54%), followed by magnetic sphincter augmentation (LINX, n = 28, 27%) and Nissen fundoplication (n = 19, 18%). There was a significant reduction in the DI from the initial DI taken after mobilization of the hiatus (3 mm2/mmHg) and after the creation of the barrier (1.4 mm2/mmHg, p < 0.001). A minority of patients had a decrease or no change in the DI with an increase in balloon volume increased from 30 to 40 mL (n = 37, 36%). Overall, after 1 month, there was a significant decrease in the GERD-HRQL score from 23 to 4 (p < 0.001) and bloat score from 3 to 2 (p = 0.003) with a non-significant decrease in the dysphagia score from 1 to 0 (p = 0.11). Patients who had a decreased or unchanged DI with an increase in the balloon volume from 30 to 40 mL had a significant decrease in their dysphagia score by 2 points (p = 0.04). CONCLUSION: The decreased or unchanged DI with an increase in the balloon volume on EndoFLIP is associated with a significant reduction in dysphagia after surgery. The decrease in DI denotes the esophagus's ability to create higher pressure relative to the change in the cross-sectional area with a larger bolus across the gastroesophageal junction. This measure may be a new marker that can predict short-term outcomes in patients undergoing hiatal hernia repair.

Intermediate Renal Outcomes, Kidney Failure, and Mortality in Obese Kidney Donors.

BACKGROUND: Obesity is associated with the two archetypal kidney disease risk factors: hypertension and diabetes. Concerns that the effects of diabetes and hypertension in obese kidney donors might be magnified in their remaining kidney have led to the exclusion of many obese candidates from kidney donation. METHODS: We compared mortality, diabetes, hypertension, proteinuria, reduced eGFR and its trajectory, and the development of kidney failure in 8583 kidney donors, according to body mass index (BMI). The study included 6822 individuals with a BMI of <30 kg/m2, 1338 with a BMI of 30-34.9 kg/m2, and 423 with a BMI of ≥35 kg/m2. We used Cox regression models, adjusting for baseline covariates only, and models adjusting for postdonation diabetes, hypertension, and kidney failure as time-varying covariates. RESULTS: Obese donors were more likely than nonobese donors to develop diabetes, hypertension, and proteinuria. The increase in eGFR in obese versus nonobese donors was significantly higher in the first 10 years (3.5 ml/min per 1.73m2 per year versus 2.4 ml/min per 1.73m2 per year; P<0.001), but comparable thereafter. At a mean±SD follow-up of 19.3±10.3 years after donation, 31 (0.5%) nonobese and 12 (0.7%) obese donors developed ESKD. Of the 12 patients with ESKD in obese donors, 10 occurred in 1445 White donors who were related to the recipient (0.9%). Risk of death in obese donors was not significantly increased compared with nonobese donors. CONCLUSIONS: Obesity in kidney donors, as in nondonors, is associated with increased risk of developing diabetes and hypertension. The absolute risk of ESKD is small and the risk of death is comparable to that of nonobese donors.

Pre-transplant T-cell Clonality: An Observational Study of a Biomarker for Prediction of Sepsis in Liver Transplant Recipients.

OBJECTIVE: This study investigated the ability of pre-transplant T-cell clonality to predict sepsis after liver transplant (LT). SUMMARY BACKGROUND DATA: Sepsis is a leading cause of death in LT recipients. Currently, no biomarkers predict sepsis before clinical symptom manifestation. METHODS: Between December 2013 and March 2018, our institution performed 478 LTs. After exclusions (eg, patients with marginal donor livers, autoimmune disorders, nonabdominal multi-organ, and liver retransplantations), 180 consecutive LT were enrolled. T-cell characterization was assessed within 48 hours before LT (immunoSEQ Assay, Adaptive Biotechnologies, Seattle, WA). Sepsis-2 and Sepsis-3 cases, defined by presence of acute infection plus ≥2 SIRS criteria, or clinical documentation of sepsis, were identified by chart review. Receiver-operating characteristic analyses determined optimal T-cell repertoire clonality for predicting post-LT sepsis. Kaplan-Meier and Cox proportional hazard modeling assessed outcome-associated prognostic variables. RESULTS: Patients with baseline T-cell repertoire clonality ≥0.072 were 3.82 (1.25, 11.40; P = 0.02), and 2.40 (1.00, 5.75; P = 0.049) times more likely to develop sepsis 3 and 12 months post-LT, respectively, when compared to recipients with lower (<0.072) clonality. T-cell repertoire clonality was the only predictor of sepsis 3 months post-LT in multivariate analysis (C-Statistic, 0.75). Adequate treatment resulted in equivalent survival rates between both groups: (93.4% vs 96.2%, respectively, P = 0.41) at 12 months post-LT. CONCLUSIONS: T-cell repertoire clonality is a novel biomarker predictor of sepsis before development of clinical symptoms. Early sepsis monitoring and management may reduce post-LT mortality. These findings have implications for developing sepsis-prevention protocols in transplantation and potentially other populations.

Serum-Based Diagnosis of Pediatric Tuberculosis by Assay of Mycobacterium tuberculosis Factors: a Retrospective Cohort Study.

Diagnosis of pediatric tuberculosis (TB) is often complicated by its nonspecific symptoms, paucibacillary nature, and the need for invasive specimen collection techniques. However, a recently reported assay that detects Mycobacterium tuberculosis virulence factors in serum can diagnose various TB manifestations, including paucibacillary TB cases, in adults with good sensitivity and specificity. The current study examined the ability of this M. tuberculosis biomarker assay to diagnose pediatric TB using archived cryopreserved serum samples drawn from children ≤18 years of age who were screened for suspected TB as part of a prospective population-based active surveillance study. In this analysis, any detectable level of either of the M. tuberculosis virulence factors CFP-10 and ESAT-6 was considered direct evidence of TB. Serum samples from 105 children evaluated for TB (55 TB cases and 50 close contacts without TB) were analyzed. The results of this analysis yielded sensitivity of 85.5% (95% confidence interval [CI], 73.3 to 93.5). Similar diagnostic sensitivities were observed for culture-positive (87.5%; 95% CI, 67.6 to 97.3) and culture-negative (83.9%; 95% CI, 66.3 to 94.5) TB cases and for culture negative pulmonary (77.8%; 95% CI, 40.0 to 97.2) and extrapulmonary (86.4%; 95% CI, 65.1 to 97.1) TB cases. These results suggest that serum biomarker analysis holds significant promise for rapid and sensitive diagnosis of pediatric TB cases, including extrapulmonary or paucibacillary TB cases. The ability to use frozen samples for this analysis should also permit assays to be performed at central sites, without a requirement for strict timelines for sample analysis.

Treatment of Coronavirus Disease 2019 Patients with Convalescent Plasma Reveals a Signal of Significantly Decreased Mortality.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has spread globally, and proven treatments are limited. Transfusion of convalescent plasma collected from donors who have recovered from COVID-19 is among many approaches being studied as potentially efficacious therapy. We are conducting a prospective, propensity score-matched study assessing the efficacy of COVID-19 convalescent plasma transfusion versus standard of care as treatment for severe and/or critical COVID-19. We present herein the results of an interim analysis of 316 patients enrolled at Houston Methodist hospitals from March 28 to July 6, 2020. Of the 316 transfused patients, 136 met a 28-day outcome and were matched to 251 non-transfused control COVID-19 patients. Matching criteria included age, sex, body mass index, comorbidities, and baseline ventilation requirement 48 hours from admission, and in a second matching analysis, ventilation status at day 0. Variability in the timing of transfusion relative to admission and titer of antibodies of plasma transfused allowed for analysis in specific matched cohorts. The analysis showed a significant reduction (P = 0.047) in mortality within 28 days, specifically in patients transfused within 72 hours of admission with plasma with an anti-spike protein receptor binding domain titer of ≥1:1350. These data suggest that treatment of COVID-19 with high anti-receptor binding domain IgG titer convalescent plasma is efficacious in early-disease patients.

Long-term outcomes of kidney donors with fibromuscular dysplasia.

BACKGROUND: Fibromuscular dysplasia (FMD) is a non-atherosclerotic systemic arterial disease that is not infrequently discovered during kidney donor evaluation. Current guidelines do not provide recommendations regarding the use of kidneys from donors with FMD and there is a paucity of data on the outcomes of these donors. METHODS: The Renal and Lung Living Donor Evaluation (RELIVE) study addressed long-term outcomes of 8922 kidney donors who donated between 1963 and 2007. We compared the development of hypertension, cardiovascular disease (CVD), proteinuria and reduced estimated glomerular filtration rate (eGFR) in 113 kidney donors with FMD discovered during donor evaluation versus 452 propensity score matched donors without FMD. Outcomes modeling with logistic and Cox regression analysis and Kaplan-Meier statistics were performed. RESULTS: Donors with FMD were older (51 versus 39 years), were more likely to be women (80% versus 56%) and had a higher systolic blood pressure at donation (124.7 versus 121.3 mmHg) (P < 0.05 for all). After a mean ± standard deviation follow-up of 15.5 ± 8.9 years, a similar proportion of donors with and without FMD were alive, and developed hypertension (22.2% versus 19.8%), proteinuria (20.6% versus 13.7%) and CVD (13.3% versus 13.5%). No donor with FMD developed an eGFR <30 mL/min/1.73 m2 or end-stage kidney disease. The multivariable risk of mortality, CVD and renal outcomes in donors with FMD was not elevated. CONCLUSIONS: Kidney donors with FMD appear to do well, do not appear to incur increased risks of hypertension, proteinuria, CVD or reduced eGFR, and perhaps carefully selected candidates with FMD can safely donate as long as involvement of other vascular beds is ruled out.

Outcomes of kidney donors with pre- and post-donation kidney stones.

Roughly 25% of US transplant centers exclude donor candidates with kidney stones fearing future obstructive consequences and the possible association between stones and CKD. We compared the development of hypertension, proteinuria, and reduced eGFR in 227 kidney donors with kidney stones to 908 propensity score-matched donor controls without kidney stones using data from The Renal and Lung Donor Evaluation (RELIVE) Study which studied intermediate and long-term outcomes of 8922 donors who donated between 1963 and 2007. 200 donors had kidney stones prior to donation, 21 had post-donation stones, and 6 had pre- and post-donation stones. Donors with stones were older, more likely to be Caucasian, less likely to be related to the recipient and had a higher fasting glucose. After 16.5 ± 10.9 years (range 0-44 years) from donation to study close, no ESKD occurred in donors with stones. The multivariable risks of hypertension, proteinuria, and reduced GFR were similar in donors with and without kidney stones. We could not demonstrate an association between stones and adverse renal outcomes in kidney donors, and the occurrence of post-donation stones was distinctly rare. These data may provide a rationale for possibly a wider acceptance of donor candidates with low kidney stones burden.