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BACKGROUND: Post-liver transplant (LT) immunosuppression is necessary to prevent rejection; however, a major consequence of this is tumor recurrence. Although recurrence is a concern after LT for patients with hepatocellular carcinoma (HCC), the oncologically optimal tacrolimus (FK) regimen is still unknown. METHOD: This retrospective study included 1,406 LT patients with HCC (2002-2019) at four U.S. institutions utilizing variable post-LT immunosuppression regimens. ROC analyses were performed to investigate the influences of post-LT time-weighted average FK (TWA-FK) level on HCC recurrence. A competing risk analysis was employed to evaluate the prognostic influence of TWA-FK while adjusting for patient and tumor characteristics. RESULTS: The area under the curve (AUC) for TWA-FK was greatest at 2 weeks (0.68), followed by 1 week (0.64) post-LT. Importantly, this was consistently observed across the institutions despite immunosuppression regimen variability. Additionally, the TWA-FK at 2 weeks was not associated with rejection within 6 months of LT. A competing risk regression analysis showed that TWA-FK at 2 weeks post-LT is significantly associated with recurrence (HR: 1.31, 95% CI: 1.21-1.41 p<0.001). The TWA-FK effect on recurrence varied depending on the exposure level and the individual's risk of recurrence, including vascular invasion and tumor morphology. CONCLUSION: Although previous studies have explored the influence of FK levels at 1 to 3 months post-LT on HCC recurrence, this current study suggests that earlier time points and exposure levels must be evaluated. Each patient's oncological risk must also be considered in developing an individualized immunosuppression regimen.
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BACKGROUND: Guidelines recommend pharmacologic VTE prophylaxis for acutely ill medical patients at acceptable bleeding risk, but only the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) model has been validated for bleeding risk assessment. OBJECTIVES: We developed and internally validated a risk assessment model (RAM) to predict major in-hospital bleeding using risk factors at admission and compared our model with IMPROVE. METHODS: We selected patients admitted to medical services at 10 hospitals in the Cleveland Clinic Health System from 2017 to 2020. We identified major bleeding according to the International Society on Thrombosis and Haemostasis criteria, using a combination of diagnostic codes and laboratory values, and confirmed events with chart review. We fit a least absolute shrinkage selection operator logistic regression model in the training set and compared the discrimination and calibration of our model with the IMPROVE model in the validation set. RESULTS: Among 46 314 admissions, 268 (0.58%) had a major bleed. The final RAM included 16 risk factors, of which prior bleeding (odds ratio [OR] = 4.83), peptic ulcer (OR = 3.82), history of sepsis (OR = 3.26), and steroid use (OR = 2.59) were the strongest. The Cleveland Clinic Bleeding Model had better discrimination than IMPROVE (area under the receiver operating characteristics curve = 0.85 vs 0.70; P < .001) and, at equivalent sensitivity (52%), categorized fewer patients as high risk (7.2% vs 11.8%; P < .001). Calibration was adequate (Brier score = 0.0057). CONCLUSION: Using a large population of medical inpatients with verified major bleeding events, we developed and internally validated a RAM for major bleeding whose performance surpassed the IMPROVE model.
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Background: Venous thromboembolism (VTE) is the leading cause of preventable hospital death in the US. Guidelines from the American College of Chest Physicians and American Society for Hematology recommend providing pharmacological VTE prophylaxis to acutely or critically ill medical patients at acceptable bleeding risk, but there is currently only one validated risk assessment model (RAM) for estimating bleeding risk. We developed a RAM using risk factors at admission and compared it with the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) model. Methods: A total of 46,314 medical patients admitted to a Cleveland Clinic Health System hospital from 2017-2020 were included. Data were split into training (70%) and validation (30%) sets with equivalent bleeding event rates in each set. Potential risk factors for major bleeding were identified from the IMPROVE model and literature review. Penalized logistic regression using LASSO was performed on the training set to select and regularize important risk factors for the final model. The validation set was used to assess model calibration and discrimination and compare performance with IMPROVE. Bleeding events and risk factors were confirmed through chart review. Results: The incidence of major in-hospital bleeding was 0.58%. Active peptic ulcer (OR = 5.90), prior bleeding (OR = 4.24), and history of sepsis (OR = 3.29) were the strongest independent risk factors. Other risk factors included age, male sex, decreased platelet count, increased INR, increased PTT, decreased GFR, ICU admission, CVC or PICC placement, active cancer, coagulopathy, and in-hospital antiplatelet drug, steroid, or SSRI use. In the validation set, the Cleveland Clinic Bleeding Model (CCBM) had better discrimination than IMPROVE (0.86 vs. 0.72, p < .001) and, at equivalent sensitivity (54%), categorized fewer patients as high-risk (6.8% vs. 12.1%, p < .001). Conclusions: From a large population of medical inpatients, we developed and validated a RAM to accurately predict bleeding risk at admission. The CCBM may be used in conjunction with VTE risk calculators to decide between mechanical and pharmacological prophylaxis for at-risk patients.
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BACKGROUND: Hepatocellular carcinoma (HCC) is predominantly seen in males but has a better prognosis in females. No prior studies have investigated HCC recurrence based on sex combination following liver transplant donated after brain death (DBDLT). This study sought to elucidate the effects of donor and recipient sex on HCC recurrence rates. METHODS: 9232 adult recipients from the United Network for Organ Sharing (UNOS) database who underwent DBDLT for HCC from 2012 to 2018 were included. Donor-recipient pairs were divided into (1) female donor/female recipient (F-F) (n = 1089); (2) male donor/female recipient (M-F) (n = 975); (3) female donor/male recipient (F-M) (n = 2691); (4) male donor/male recipient (M-M) (n = 4477). The primary prognostic outcome was HCC recurrence. A multivariable competing risk regression analysis was used to assess prognostic influences. RESULTS: The median recipient age and model for end-stage liver disease (MELD) scores were similar among the four groups. Livers of male recipients demonstrated greater in size and number of HCC (both p-values were <.0001). There was also a higher rate of vascular invasion in male recipients compared to female (p < .0001). Competing risk analyses showed that the cumulative HCC recurrence rate was significantly lower in the M-F group (p = .013). After adjusting for tumor characteristics, liver grafts from male donors were associated with a lower HCC recurrence rate in female recipients (HR: .62 95%CI: .42-.93) (p = .021). CONCLUSION: In DBDLT, male donor to female recipient pairing exhibited lower HCC recurrence rates. SUMMARY: Lowest rates of HCC recurrence were confirmed among the female recipients of male donor grafts group in the deceased donor LT cohort. A competing risk multivariable regression analysis demonstrated that male donor sex was significantly associated with low HCC recurrence in female but not male recipients.
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Carcinoma Hepatocelular , Enfermedad Hepática en Estado Terminal , Neoplasias Hepáticas , Trasplante de Hígado , Adulto , Masculino , Humanos , Femenino , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Muerte Encefálica , Índice de Severidad de la Enfermedad , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The current liver allocation system may be disadvantaging younger adult recipients as it does not incorporate the donor-recipient age difference. Given the longer life expectancy of younger recipients, the influences of older donor grafts on their long-term prognosis should be elucidated. This study sought to reveal the long-term prognostic influence of the donor-recipient age difference in young adult recipients. Adult patients who received initial liver transplants from deceased donors between 2002 and 2021 were identified from the UNOS database. Young recipients (patients 45 years old or below) were categorized into 4 groups: donor age younger than the recipient, 0-9 years older, 10-19 years older, or 20 years older or above. Older recipients were defined as patients 65 years old or above. To examine the influence of the age difference in long-term survivors, conditional graft survival analysis was conducted on both younger and older recipients. Among 91,952 transplant recipients, 15,170 patients were 45 years old or below (16.5%); these were categorized into 6,114 (40.3%), 3,315 (21.9%), 2,970 (19.6%), and 2,771 (18.3%) for groups 1-4, respectively. Group 1 demonstrated the highest probability of survival, followed by groups 2, 3, and 4 for the actual graft survival and conditional graft survival analyses. In younger recipients who survived at least 5 years post-transplant, inferior long-term survival was observed when there was an age difference of 10 years or above (86.9% vs. 80.6%, log-rank p <0.01), whereas there was no difference in older recipients (72.6% vs. 74.2%, log-rank p =0.89). In younger patients who are not in emergent need of a transplant, preferential allocation of younger aged donor offers would optimize organ utility by increasing postoperative graft survival time.
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Trasplante de Riñón , Trasplante de Hígado , Humanos , Adulto Joven , Anciano , Recién Nacido , Lactante , Preescolar , Niño , Persona de Mediana Edad , Trasplante de Hígado/efectos adversos , Donadores Vivos , Factores de Tiempo , Donantes de Tejidos , Análisis de Supervivencia , Supervivencia de Injerto , Factores de Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Previous infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provides strong protection against future infection. There is limited evidence on whether such protection extends to the Omicron variant. METHODS: This retrospective cohort study included 635 341 patients tested for SARS-CoV-2 via polymerase chain reaction from 9 March 2020 to 1 March 2022. Patients were analyzed according to the wave in which they were initially infected. The primary outcome was reinfection during the Omicron period (20 December 2021-1 March 2022). We used a multivariable model to assess the effects of prior infection and vaccination on hospitalization. RESULTS: Among the patients tested during the Omicron wave, 30.6% tested positive. Protection of prior infection against reinfection with Omicron ranged from 18.0% (95% confidence interval [CI], 13.0-22.7) for patients infected in wave 1 to 69.2% (95% CI, 63.4-74.1) for those infected in the Delta wave. In adjusted models, previous infection reduced hospitalization by 28.5% (95% CI, 19.1-36.7), whereas full vaccination plus a booster reduced it by 59.2% (95% CI, 54.8-63.1). CONCLUSIONS: Previous infection offered less protection against Omicron than was observed in past waves. Immunity against future waves will likely depend on the degree of similarity between variants.
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COVID-19 , Humanos , COVID-19/prevención & control , SARS-CoV-2 , Reinfección , Estudios RetrospectivosRESUMEN
BACKGROUND: US racial and ethnic minorities have well-established elevated rates of comorbidities, which, compounded with healthcare access inequity, often lead to worse health outcomes. In the current COVID-19 pandemic, it is important to understand existing disparities in minority groups' critical care outcomes and mechanisms behind these-topics that have yet to be well-explored. OBJECTIVE: Assess for disparities in racial and ethnic minority groups' COVID-19 critical care outcomes. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 2125 adult patients who tested positive for COVID-19 via RT-PCR between March and December 2020 and required ICU admission at the Cleveland Clinic Hospital Systems were included. MAIN MEASURES: Primary outcomes were mortality and hospital length of stay. Cohort-wide analysis and subgroup analyses by pandemic wave were performed. Multivariable logistic regression models were built to study the associations between mortality and covariates. KEY RESULTS: While crude mortality was increased in White as compared to Black patients (37.5% vs. 30.5%, respectively; p = 0.002), no significant differences were appraised after adjustment or across pandemic waves. Although median hospital length of stay was comparable between these groups, ICU stay was significantly different (4.4 vs. 3.4, p = 0.003). Mortality and median hospital and ICU length of stay did not differ significantly between Hispanic and non-Hispanic patients. Neither race nor ethnicity was associated with mortality due to COVID-19, although APACHE score, CKD, malignant neoplasms, antibiotic use, vasopressor requirement, and age were. CONCLUSIONS: We found no significant differences in mortality or hospital length of stay between different races and ethnicities. In a pandemic-influenced critical care setting that operated outside conditions of ICU strain and implemented standardized protocol enabling equitable resource distribution, disparities in outcomes often seen among racial and ethnic minority groups were successfully mitigated.
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COVID-19 , Grupos Minoritarios , Adulto , Humanos , Etnicidad , Pandemias , Estudios Retrospectivos , Cuidados CríticosRESUMEN
OBJECTIVE: To generate validity evidence for using patient-reported satisfaction ratings of residents' communication skills to determine progress along the Interpersonal and Communication Skills (ICS) Milestones. DESIGN: A single-institution, retrospective study analyzed a CAHPS Clinician and Group Survey (CG-CAHPS) database which collects inpatients' ratings of residents' communication skills using 6 questions on a scale of 1 (very poor) to 5 (very good). CG-CAHPS results for each resident were averaged for each question as well as across the 6 questions. The averaged ratings were compared between low and high performer groups. SETTING: A large, academic, mid-western General Surgery residency program. PARTICIPANTS: General Surgery residents with 3 or more survey responses from July 2020 to June 2021 were included. Residents were dichotomized into low or high performer groups based on their end-of-year ICS1 sub-competency milestone within their post-graduate year (PGY) cohort. RESULTS: 543 CG-CAHPS responses across 44 residents were analyzed with a median of 9 (Interquartile range 6, 17) responses per resident. When residents were compared based on PGY, ratings for the question "resident's knowledge about your medical care of condition" demonstrated statistically significant differences with PGY5s receiving the lowest score (pâ¯=â¯0.05). PGY5s received the lowest averaged ratings across all questions (pâ¯=â¯0.08, η2â¯=â¯0.10). When residents were dichotomized into low (nâ¯=â¯21) and high performer groups (nâ¯=â¯23) based on ICS1 milestones, statistically significant differences were noted in ratings for the questions "concern the resident showed for your questions or worries" (4.81 vs. 5, pâ¯=â¯0.047) and "courtesy and respect of the resident" (4.75 vs. 5, pâ¯=â¯0.046). CONCLUSIONS: Analysis of patient ratings of surgery residents' communication skills demonstrated concordant findings between ICS1 milestone and 2 domains of CG-CAHPS responses. When low and high performer groups were compared, CG-CAHPS responses demonstrated a similar pattern. These findings provide validity evidence for CG-CAHPS data as a source of information for ICS1 sub-competency assessment.
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Cirugía General , Internado y Residencia , Humanos , Estudios Retrospectivos , Comunicación , Bases de Datos Factuales , Pacientes Internos , Competencia Clínica , Educación de Postgrado en MedicinaRESUMEN
B lymphocytes have long been recognized for their critical contributions to adaptive immunity, providing defense against pathogens through cognate antigen presentation to T cells and Ab production. More recently appreciated is that B cells are also integral in securing self-tolerance; this has led to interest in their therapeutic application to downregulate unwanted immune responses, such as transplant rejection. In this study, we found that PMA- and ionomycin-activated mouse B cells acquire regulatory properties following stimulation through TLR4/TLR9 receptors (Bregs-TLR). Bregs-TLR efficiently inhibited T cell proliferation in vitro and prevented allograft rejection. Unlike most reported Breg activities, the inhibition of alloimmune responses by Bregs-TLR relied on the expression of TGF-ß and not IL-10. In vivo, Bregs-TLR interrupted donor-specific T cell expansion and induced Tregs in a TGF-ß-dependent manner. RNA-Seq analyses corroborated the involvement of TGF-ß pathways in Breg-TLR function, identified potential gene pathways implicated in preventing graft rejection, and suggested targets to foster Breg regulation.
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Linfocitos B Reguladores , Aloinjertos , Animales , Linfocitos B Reguladores/metabolismo , Activación de Linfocitos , Ratones , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Importance: Despite high prevalence of elevated blood pressure (BP) among medical inpatients, BP management guidelines are lacking for this population. The outcomes associated with intensifying BP treatment in the hospital are poorly studied. Objectives: To characterize clinician response to BP in the hospital and at discharge and to compare short- and long-term outcomes associated with antihypertensive treatment intensification. Design, Setting, and Participants: This cohort study took place from January 1 to December 31, 2017, with 1 year of follow-up at 10 hospitals within the Cleveland Clinic Hospitals health care system. All adults admitted to a medicine service in 2017 were evaluated for inclusion. Patients with cardiovascular diagnoses were excluded. Demographic and BP characteristics were used for propensity matching. Exposures: Acute hypertension treatment, defined as administration of an intravenous antihypertensive medication or a new class of an oral antihypertensive treatment. Main Outcomes and Measures: The association between acute hypertension treatment and subsequent inpatient acute kidney injury, myocardial injury, and stroke was measured. Postdischarge outcomes included stroke and myocardial infarction within 30 days and BP control up to 1 year. Results: Among 22â¯834 adults hospitalized for noncardiovascular diagnoses (mean [SD] age, 65.6 [17.9] years; 12 993 women [56.9%]; 15 963 White patients [69.9%]), 17 821 (78%) had at least 1 hypertensive BP recorded during their admission. Of these patients, 5904 (33.1%) were treated. A total of 8692 of 106 097 cases (8.2%) of hypertensive systolic BPs were treated; of these, 5747 (66%) were treated with oral medications. In a propensity-matched sample controlling for patient and BP characteristics, treated patients had higher rates of subsequent acute kidney injury (466 of 4520 [10.3%] vs 357 of 4520 [7.9%]; P < .001) and myocardial injury (53 of 4520 [1.2%] vs 26 of 4520 [0.6%]; P = .003). There was no BP interval in which treated patients had better outcomes than untreated patients. A total of 1645 of 17 821 patients (9%) with hypertension were discharged with an intensified antihypertensive regimen. Medication intensification at discharge was not associated with better BP control in the following year. Conclusions and Relevance: In this cohort study, hypertension was common among medical inpatients, but antihypertensive treatment intensification was not. Intensification of therapy without signs of end-organ damage was associated with worse outcomes.
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Antihipertensivos/efectos adversos , Hipertensión/epidemiología , Pacientes Internos/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Femenino , Médicos Hospitalarios/psicología , Humanos , Hipertensión/tratamiento farmacológico , Hallazgos Incidentales , Masculino , Persona de Mediana Edad , Ohio/epidemiología , Prevalencia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Through multiple mechanisms, regulatory B cells (Breg) have been shown to play an important role in the development of allograft tolerance. However, a careful understanding of the role of antigen-specificity in Breg-mediated allograft tolerance has remained elusive. In experimental models of islet and cardiac transplantation, it has been established that Bregs can be induced in vivo by anti-CD45RB ± anti-TIM1antibody treatment, resulting in prolonged, Breg-dependent allograft tolerance. The importance of Breg antigen recognition has been suggested but not confirmed through adoptive transfer experiments, using tolerant WT C57BL/6 animals challenged with either BALB/c or C3H grafts. However, the importance of receptor-specificity has not been formally tested. Here, we utilize the novel ovalbumin-specific B cell receptor transnuclear (OBI) mice in multiple primary tolerance and adoptive transfer experiments to establish that Breg-dependent allograft tolerance relies on antigen recognition by B cells. Additionally, we identify that this Breg-dependent tolerance relies on the function of transforming growth factor-ß. Together, these experiments mark important progress toward understanding how best to improve Breg-mediated allograft tolerance.
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Linfocitos B Reguladores , Tolerancia al Trasplante , Animales , Tolerancia Inmunológica , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Linfocitos T ReguladoresRESUMEN
BACKGROUND: DBA/2J kidney allografts, but not heart allografts, are spontaneously accepted indefinitely in C57BL/6 (B6) mice, through regulatory tolerance mechanism dependent on Foxp3 cells. In contrast, B6 kidneys are rejected within a week in DBA/2J recipients. We hypothesized that the tolerogenic difference of the kidneys might be due to differences in number or function of plasmacytoid dendritic cells (pDCs), because these cells are potent inducers of Foxp3 cells. METHODS: pDCs from murine bone marrow, native kidneys, and spontaneously accepted kidney allografts were analyzed using flow cytometry and immunohistochemical staining. Naive T cells were cocultured with pDCs in specific strain combinations and analyzed for FoxP3 induction and functionality. MEK/ERK and NFκB inhibitors were used to assess the regulatory T-cell induction pathways. pDCs and T-cell cultures were adoptively transferred before heterotopic heart transplantation to assess allograft survival. RESULTS: DBA/2J pDCs were more potent in inducing Foxp3 in B6 T cells than the reverse combination, correlating with survival of the kidney allografts. Foxp3 induction by pDCs in vitro was dependent on pDC viability, immaturity, and class II MHC mismatch and blocked by MEK/ERK and NFκB inhibition. pDC-induced Foxp3 T cells suppressed proliferation of B6 T cells in vitro, and adoptive transfer into B6 recipients 2 weeks before heterotopic DBA/2J heart transplantation resulted in prolonged allograft survival. CONCLUSIONS: These data suggest that pDC-induced regulatory T cells are dependent on downstream signaling effects and on strain-dependent, MHC class II disparity with naive T cells, which may explain organ- and strain-specific differences in spontaneous tolerance.
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Células Dendríticas/inmunología , Supervivencia de Injerto/inmunología , Tolerancia Inmunológica , Trasplante de Riñón/efectos adversos , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Aloinjertos/inmunología , Animales , Comunicación Celular/inmunología , Separación Celular , Modelos Animales de Enfermedad , Citometría de Flujo , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Rechazo de Injerto/inmunología , Trasplante de Corazón , Humanos , Riñón/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Linfocitos T Reguladores/metabolismo , Trasplante HomólogoRESUMEN
Epstein-Barr virus-related lymphoproliferative disease (EBV-LPD) rarely occurs in patients with acute lymphoblastic leukemia (ALL), who have not received hematopoietic transplantation. We describe EBV-LPD manifesting as facial lesions in two children with ALL in remission. One patient was a 16-year-old male with T-cell ALL with an EBV-positive angiocentric polymorphous lip lesion presenting as right-sided facial swelling. The other patient was a 12-year-old male with B-cell ALL with an EBV-positive polymorphous lymphoplasmacytic infiltrate presenting as bilateral dacryoadenitis. Neither patient had known primary immunodeficiencies. Both cases improved with immunosuppressant de-escalation. These cases suggest that immunosuppression induced by maintenance chemotherapy is sufficient to promote EBV-LPD.
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Dacriocistitis/etiología , Infecciones por Virus de Epstein-Barr/complicaciones , Trastornos Linfoproliferativos/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Adolescente , Niño , Humanos , MasculinoRESUMEN
The airway epithelium develops into a tree-like structure via branching morphogenesis. Here, we show a critical role for localized differentiation of airway smooth muscle during epithelial bifurcation in the embryonic mouse lung. We found that during terminal bifurcation, changes in the geometry of nascent buds coincided with patterned smooth muscle differentiation. Evaluating spatiotemporal dynamics of α-smooth muscle actin (αSMA) in reporter mice revealed that αSMA-expressing cells appear at the basal surface of the future epithelial cleft prior to bifurcation and then increase in density as they wrap around the bifurcating bud. Disrupting this stereotyped pattern of smooth muscle differentiation prevents terminal bifurcation. Our results reveal stereotyped differentiation of airway smooth muscle adjacent to nascent epithelial buds and suggest that localized smooth muscle wrapping at the cleft site is required for terminal bifurcation during airway branching morphogenesis.