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Background: As the demand for kidney transplants continues to increase globally, healthcare institutions face a challenge to bridge the gap between patients waitlisted for kidney transplants and the number of donors. A major factor influencing the donor's decision is the operative risk and potential complications of the surgery. Open surgical approaches have been vastly replaced with laparoscopic donor nephrectomies as the standard of practice. However, there is a growing body of evidence pointing towards its potential superiority over laparoscopic methods. In this study, we aim to present our experience on outcomes of Robotic-Assisted Live Donor Nephrectomies (RALDN), the first series of its kind in the United Arab Emirates (UAE). Methods: We retrospectively collected data from patients who underwent RALDN at Mediclinc City Hospital. Demographic data, laboratory investigations, and operative details were collected and analyzed. Results: Seven patients underwent RALDN between 2021 and April 2022 at our facility. Four donors were male while three were female. Median length of hospital stay was 4 days. In our study, one of the patients suffered from a Clavien-Dindo grade IV complication which necessitated prolonged admission. Conclusion: We conclude that RALDN is a safe method for donor kidney procurement, carrying a low risk of morbidity and mortality. This method could potentially evolve the number of kidney donors to address the issue of high kidney transplant demand.
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BACKGROUND: Methylmalonic acidemia (MMAemia) is characterized by accumulation of methylmalonic acid (MMA) in all body tissues. To minimize disease-related complications, isolated kidney (KTx), liver (LTx) or combined liver-kidney transplantation (LKTx) have been suggested. However, the impact of these different transplant strategies on outcome are unclear. METHODS: In this multicenter retrospective observational study, we compared plasma MMA levels and estimated glomerular filtration rate (eGFR) data of 83 patients. Sixty-eight patients (82%) had a mut0-type MMAemia, one patient had a mut--type MMAemia, and seven (7.3%) had an inherited defect in cobalamin metabolism (cblA- or cblB-type MMAemia). Median observation period was 3.7 years (0-15.1 years). RESULTS: Twenty-six (31%) patients underwent KTx, 24 (29%) LTx and 33 (40%) LKTx. Posttransplant, mean plasma MMA concentration significantly decreased in all three cohorts; but at month 12, plasma MMA in KTx (1372 ± 1101 µmol/L) was 7.8-fold higher than in LTx (176 ± 103 µmol/L; P < 0.001) and 6.4-fold higher than in LKTx (215 ± 110 µmol/L; P < 0.001). Comparable data were observed at month 24. At time of transplantation, mean eGFR in KTx was 18.1 ± 24.3 mL/min/1.73 m2, in LTx 99.8 ± 29.9 mL/min/1.73 m2, and in LKTx 31.5 ± 21.2 mL/min/1.73 m2. At month 12 posttransplant, mean eGFR in KTx (62.3 ± 30.3 mL/min/1.73 m2) was 33.4% lower than in LTx (93.5 ± 18.3 mL/min/1.73 m2; P = 0.0053) and 25.4% lower than in LKTx (83.5 ± 26.9 mL/min/1.73 m2; P = 0.0403). CONCLUSIONS: In patients with isolated MMAemia, LTx and LKTx lead to markedly lower plasma MMA levels during the first 2 years posttransplant than KTx and are associated with a better preservation of kidney function. LTx should therefore be part of the transplant strategy in MMAemia.
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Errores Innatos del Metabolismo de los Aminoácidos , Trasplante de Riñón , Humanos , Ácido Metilmalónico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Riñón , HígadoRESUMEN
Antibody-mediated rejection is a common cause of early kidney allograft loss but the specifics of antibody measurement, therapies and endpoints have not been universally defined. In this retrospective study, we assessed the performance of risk stratification using systematic donor-specific antibody (DSA) monitoring. Included in the study were children who underwent kidney transplantation between January 1, 2010 and March 1, 2018 at Stanford, with at least 12-months follow-up. A total of 233 patients were included with a mean follow-up time of 45 (range, 9-108) months. Median age at transplant was 12.3 years, 46.8% were female, and 76% had a deceased donor transplant. Fifty-two (22%) formed C1q-binding de novo donor-specific antibodies (C1q-dnDSA). After a standardized augmented immunosuppressive protocol was implemented, C1q-dnDSA disappeared in 31 (58.5%). Graft failure occurred in 16 patients at a median of 54 (range, 5-83) months, of whom 14 formed dnDSA. The 14 patients who lost their graft due to rejection, all had persistent C1q-dnDSA. C1q-binding status improved the individual risk assessment, with persistent; C1q binding yielding the strongest independent association of graft failure (hazard ratio, 45.5; 95% confidence interval, 11.7-177.4). C1q-dnDSA is more useful than standard dnDSA as a noninvasive biomarker for identifying patients at the highest risk of graft failure.
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Complemento C1q , Trasplante de Riñón , Anticuerpos , Suero Antilinfocítico , Biomarcadores , Niño , Femenino , Rechazo de Injerto , Supervivencia de Injerto , Antígenos HLA , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Estudios Retrospectivos , Medición de RiesgoRESUMEN
Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of αß T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor. Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation. (Funded by the Kruzn for a Kure Foundation.).
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Trasplante de Células Madre Hematopoyéticas , Síndromes de Inmunodeficiencia , Trasplante de Riñón , Síndrome Nefrótico , Osteocondrodisplasias , Enfermedades de Inmunodeficiencia Primaria , Arteriosclerosis/genética , Arteriosclerosis/terapia , Rechazo de Injerto/prevención & control , Humanos , Síndromes de Inmunodeficiencia/terapia , Riñón/fisiología , Trasplante de Riñón/efectos adversos , Síndrome Nefrótico/genética , Síndrome Nefrótico/terapia , Osteocondrodisplasias/genética , Osteocondrodisplasias/terapia , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/terapia , Embolia Pulmonar/genética , Embolia Pulmonar/terapia , Acondicionamiento Pretrasplante/métodosRESUMEN
Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.
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Atlas como Asunto , Células , Especificidad de Órganos , Empalme del ARN , Análisis de la Célula Individual , Transcriptoma , Linfocitos B/metabolismo , Células/metabolismo , Humanos , Especificidad de Órganos/genética , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Currently, there is no consensus among pediatric kidney transplant centers regarding the use and regimen for immunosuppressive induction therapy. METHODS: In this single center, retrospective cohort study, pediatric kidney transplant recipients transplanted between 1 May 2013 and 1 May 2018 with rabbit antithymocyte globulin (rATG) induction were included. We stratified patients based on immunological risk, with high risk defined as those with repeat transplant, preformed donor specific antibody, current panel-reactive antibodies > 20%, 0 antigen match and/or African-American heritage. Outcome of interest was the incidence of biopsy proven acute rejection by 1 year. RESULTS: A total of 166 patients met inclusion criteria. Age of patients was 12 years (11 mo-21 y), (median, range), 21.5% received a living donor transplant and 50.6% were female. Low-immunologic-risk patients were divided into 2 groups, those who received the lower cumulative rATG dose of ≤ 3.5 mg/kg (n = 52) versus the higher cumulative dose of > 3.5 mg/kg (n = 47). The median total dose in the lower dose group was 3.1 (IQR 0.3) and 4.4 (IQR 0.8) in the higher dose group, P < 0.001. Rejection rate did not differ significantly between the 2 treatment groups (7/52 vs. 6/47). None in the lower dose group developed BK nephropathy versus 3 in the higher dose group. Graft loss due to BK nephropathy occurred in 1 patient in the higher dose group. Graft loss in the whole cohort at 12 months was a rare event (n = 1) with 99.5% graft survival and 100% patient survival. CONCLUSIONS: Reduced rATG dosing (≤ 3.5 mg/kg) when compared to higher dosing (> 3.5 mg/kg) is safe and effective in low-risk pediatric kidney transplant recipients without increasing risk of rejection. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Trasplante de Riñón , Suero Antilinfocítico/efectos adversos , Femenino , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/efectos adversos , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) are noninvasive surrogates for hepatic steatosis and fibrosis, respectively, and could help identify extended criteria donors in liver transplantation (LT). We aimed to determine the accuracy of CAP/LSM in deceased donors along with post-LT changes. METHODS: Accuracy of preprocurement CAP/LSM to grade/stage steatosis/fibrosis was determined using liver biopsy as reference. Transplant outcomes, including primary nonfunction (PNF) and early allograft dysfunction, were recorded. Recipients underwent CAP/LSM as outpatients. Areas under the receiver operating characteristic curve and regression models were constructed to analyze data. RESULTS: We prospectively evaluated 160 allografts (138 transplanted). Same-probe paired baseline/post-LT CAP was 231 dB/m (181-277)/225 (187-261) (P = 0.61), and LSM 7.6 kPa (6.3-10.8)/5.9 (4.6-8.7) (P = 0.002), respectively. CAP reading was affected by BMI and LSM by ALT, race and bilirubin. Although CAP did not correlate with steatosis from frozen sections (ρ = 0.08, P = 0.47), it correlated with steatosis from permanent sections (ρ = 0.32, P < 0.001) and with oil red O histomorphometry (ρ = 0.35, P = 0.001). CAP identified moderate-to-severe steatosis with an areas under the receiver operating characteristic curve curve of 0.79 (0.66-0.91), for a negative predictive value of 100% at a cutoff value of 230 dB/m. LSM correlated with fibrosis staging (ρ = 0.22, P = 0.007) and it identified discarded allografts with advanced fibrosis/cirrhosis. Patients with no to minimal fibrosis had an LSM of 7.6 (6-10.1) kPa. CONCLUSIONS: Our results are proof-of-concept of the utility of CAP/LSM during organ procurement. Establishing the precise role of these noninvasive tools in the organ allocation process mandates confirmatory studies.
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Diagnóstico por Imagen de Elasticidad , Trasplante de Hígado , Enfermedad del Hígado Graso no Alcohólico , Biopsia , Diagnóstico por Imagen de Elasticidad/métodos , Humanos , Hígado/diagnóstico por imagen , Hígado/patología , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/cirugía , Trasplante de Hígado/efectos adversos , Enfermedad del Hígado Graso no Alcohólico/patología , Curva ROCRESUMEN
Liver transplantation (LT) is definitive treatment for end-stage liver disease. This study evaluated factors predicting successful evaluation in patients transferred for urgent inpatient LT evaluation. Eighty-two patients with cirrhosis were transferred for urgent LT evaluation from January 2016 to December 2018. Alcohol-associated liver disease was the common etiology of liver disease (42/82). Of these 82 patients, 35 (43%) were declined for LT, 27 (33%) were wait-listed for LT, 5 (6%) improved, and 15 (18%) died. Psychosocial factors were the most common reasons for being declined for LT (49%). Predictors for listing and receiving LT on multivariate analysis included Hispanic race (odds ratio [OR], 1.89; P = 0.003), Asian race (OR, 1.52; P = 0.02), non-Hispanic ethnicity (OR, 1.49; P = 0.04), hyponatremia (OR, 1.38; P = 0.04), serum albumin (OR, 1.13; P = 0.01), and Model for End-Stage Liver Disease (MELD)-Na (OR, 1.02; P = 0.003). Public insurance (i.e., Medicaid) was a predictor of not being listed for LT on multivariate analysis (OR, 0.77; P = 0.02). Excluding patients declined for psychosocial reasons, predictors of being declined for LT on multivariate analysis included Chronic Liver Failure Consortium (CLIF-C) score >51.5 (OR, 1.26; P = 0.03), acute-on-chronic liver failure (ACLF) grade 3 (OR, 1.41; P = 0.01), hepatorenal syndrome (HRS) (OR, 1.38; P = 0.01), and respiratory failure (OR, 1.51; P = 0.01). Predictors of 3-month mortality included CLIF-C score >51.5 (hazard ratio [HR], 2.52; P = 0.04) and intensive care unit (HR, 8.25; P < 0.001). Conclusion: MELD-Na, albumin, hyponatremia, ACLF grade 3, HRS, respiratory failure, public insurance, Hispanic race, Asian race, and non-Hispanic ethnicity predicted liver transplant outcome. Lack of psychosocial support was a major reason for being declined for LT. The CLIF-C score predicted being declined for LT and mortality.
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Enfermedad Hepática en Estado Terminal/cirugía , Trasplante de Hígado/estadística & datos numéricos , Selección de Paciente , Derivación y Consulta/estadística & datos numéricos , Índice de Severidad de la Enfermedad , Anciano , Enfermedad Hepática en Estado Terminal/psicología , Femenino , Humanos , Trasplante de Hígado/psicología , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Psicología , Estudios Retrospectivos , Estados Unidos , Listas de EsperaRESUMEN
Combined heart-liver transplant is an emerging option for patients with indications for heart transplantation and otherwise prohibitive hepatic dysfunction. Heart-liver transplantation is particularly relevant for patients with single ventricle physiology who often develop Fontan-associated liver disease and fibrosis. Although only performed at a limited number of centers, several approaches to combined heart-liver transplantation have been described. The en bloc technique offers several potential advantages over the traditional sequential technique. Specifically, en bloc heart-liver transplantation may allow improved hemodynamics, decreased bleeding, reduced liver allograft ischemic time, and may result in reduced rates of graft dysfunction. Here we describe our center's en bloc heart-liver procurement technique in detail, with the aim of allowing broader use and standardization of this technique.
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Trasplante de Corazón , Trasplante de Hígado , Obtención de Tejidos y Órganos , Trasplante de Corazón/métodos , Humanos , Hígado , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/métodos , Estudios RetrospectivosRESUMEN
BACKGROUND: Indications for a heartâliver transplantation (HLT) for Fontan recipients are not well defined. We compared listing characteristics, post-operative complications, and post-transplant outcomes of Fontan recipients who underwent HLT with those of patients who underwent heart-only transplantation (HT). We hypothesized that patients who underwent HLT have increased post-operative complications but superior survival outcomes compared with patients who underwent HT. METHODS: We performed a retrospective review of Fontan recipients who underwent HLT or HT at a single institution. Characteristics at the time of listing, including the extent of liver disease determined by laboratory, imaging, and biopsy data, were compared. Post-operative complications were assessed, and the KaplanâMeier survival method was used to compare post-transplant survival. Univariate regression analyses were performed to identify the risk factors for increased mortality and morbidity among patients who underwent HT. RESULTS: A total of 47 patients (9 for HLT, 38 for HT) were included. Patients who underwent HLT were older, were more likely to be on dual inotrope therapy, and had evidence of worse liver disease. Whereas ischemic time was longer for the group who underwent HLT, post-operative complications were similar. Over a median post-transplant follow-up of 17 (interquartile range: 5-52) months, overall mortality for the cohort was 17%; only 1 patient who underwent HLT died (11%) vs 7 patients who underwent HT (18%) (pâ¯=â¯0.64). Among patients who underwent HT, cirrhosis on pre-transplant imaging was associated with worse outcomes. CONCLUSIONS: Despite greater inotrope need and more severe liver disease at the time of listing, Fontan recipients undergoing HLT have post-transplant outcomes comparable with those of patients undergoing HT. HLT may offer a survival benefit for Fontan recipients with liver disease.
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Procedimiento de Fontan , Cardiopatías Congénitas/cirugía , Trasplante de Corazón/métodos , Trasplante de Hígado/métodos , Complicaciones Posoperatorias/epidemiología , Adolescente , California/epidemiología , Niño , Femenino , Estudios de Seguimiento , Supervivencia de Injerto , Cardiopatías Congénitas/mortalidad , Humanos , Incidencia , Masculino , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia/tendencias , Adulto JovenRESUMEN
The accuracy of liver biopsy to stage fibrosis due to Fontan-associated liver disease (FALD) remains unclear. We compared the results of biopsy pre-combined heart and liver transplantation (CHLT) to the results of whole liver explant. Liver biopsy and explants from 15 Fontan patients (ages 16-49, median 28 years) were retrospectively reviewed. Staging was as follows: stage 0: no fibrosis, stage 1: pericellular fibrosis, stage 2: bridging fibrosis, and stage 3: regenerative nodules. There is no stage 4. Clinical characteristics including Model of End-stage Liver Disease eXcluding INR and Varices, Ascites, Splenomegaly, and Thrombocytopenia (VAST) scores were collected, and descriptive statistics and Mann-Whitney U tests were used to analyze the data. All patients had biopsies with at least bridging fibrosis, and all had nodularity on explant; transjugular biopsy never overestimated fibrosis. Explant showed higher-grade fibrosis (stage 3) than pre-CHLT biopsy (stage 2) in 6 of 15 patients and equal grade of fibrosis (stage 3) in 9 of 15 patients. Though clinical characteristics varied significantly, VAST score was ≥2 in all but two patients. Transjugular liver biopsy does not overestimate and can underestimate fibrosis in Fontan patients undergoing CHLT, likely due to the patchy nature of fibrosis in FALD.
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Procedimiento de Fontan , Cardiopatías Congénitas , Hepatopatías , Trasplante de Hígado , Adolescente , Adulto , Biopsia , Fibrosis , Procedimiento de Fontan/efectos adversos , Cardiopatías Congénitas/etiología , Cardiopatías Congénitas/patología , Cardiopatías Congénitas/cirugía , Humanos , Hígado/patología , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Hepatopatías/patología , Trasplante de Hígado/efectos adversos , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Acute kidney injury (AKI) is characterized by rapid failure of renal function and has no curative therapies. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) are known to carry therapeutic factors, which have shown promise in regenerative medicine applications, including AKI. However, there remains an unmet need to optimize their therapeutic effect. One potential avenue of optimization lies in pulsed focused ultrasound (pFUS), where tissues-of-interest are treated with sound waves. pFUS has been shown to enhance MSC therapy via increased cell homing, but its effects on cell-free EV therapy remain largely unexplored. METHODS: We combine pFUS pretreatment of the kidney with MSC-derived EV therapy in a mouse model of cisplatin-induced AKI. RESULTS: EVs significantly improved kidney function, reduced injury markers, mediated increased proliferation, and reduced inflammation and apoptosis. While pFUS did not enhance EV homing to the kidney, the combined treatment resulted in a superior therapeutic effect compared to either treatment alone. We identified several molecular mechanisms underlying this synergistic therapeutic effect, including upregulation of proliferative signaling (MAPK/ERK, PI3K/Akt) and regenerative pathways (eNOS, SIRT3), as well as suppression of inflammation. CONCLUSION: Taken together, pFUS may be a strategy for enhancing the therapeutic efficacy of MSC-derived EV treatment for the treatment of AKI.
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Lesión Renal Aguda , Vesículas Extracelulares , Células Madre Mesenquimatosas , Ondas Ultrasónicas , Lesión Renal Aguda/terapia , Animales , Tratamiento Basado en Trasplante de Células y Tejidos , RatonesRESUMEN
Although it is known that children undergoing heart transplantation are at increased risk for both AKI and CKD, renal function following CHLT remains understudied. All pediatric CHLT patients from 2006 to 2019 were included. The prevalence of AKI in the first 7 post-operative days, renal recovery at 30 post-operative days, and CKD were ascertained. AKI was defined as an increase in creatinine greater than 1.5 times baseline, and CKD, as an eCrCl less than 90 mL/min/1.73 m2 . The need for RRT was also analyzed. 10 patients were included, with an average age of 20 years and an average listing time of 130 days. Preoperatively, the median eCrCl was 91.12 mL/min/m2 (IQR 70.51, 127.75 min/mL/m2 ). 5 (50%) patients had CKD, with 4 at stage 2 and 1 at stage 3. AKI occurred post-operatively in 3 of 9 (33%) patients: 2 at stage 1 and 1 at stage 2. 2 (67%) resolved by 7 days. Of the 5 patients who reached their 1-year follow-up, 1 (20%) had stage 3 CKD. Among 2 patients, neither had CKD at 5 years. One patient required RRT 2 weeks after CHLT. Despite an increased prevalence of preoperative CKD, patients undergoing CHLT have a lower AKI prevalence than those receiving an isolated heart or liver transplant. Of those with AKI, early renal recovery is common, although at 1 year CKD remains present in 20%. Among long-term survivors, normal renal function is achievable.
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Lesión Renal Aguda/etiología , Cardiopatías Congénitas/cirugía , Trasplante de Corazón/efectos adversos , Trasplante de Hígado/efectos adversos , Complicaciones Posoperatorias , Insuficiencia Renal Crónica/etiología , Lesión Renal Aguda/sangre , Lesión Renal Aguda/fisiopatología , Adolescente , Biomarcadores/sangre , Niño , Creatinina/sangre , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Masculino , Pronóstico , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/fisiopatología , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Ecological momentary assessment (EMA) enables individuals to self-report their subjective momentary physical and emotional states. However, certain conditions, including routine observable behaviors (eg, moods, medication adherence) as well as behaviors that may suggest declines in physical or mental health (eg, memory losses, compulsive disorders) cannot be easily and reliably measured via self-reports. OBJECTIVE: This study aims to examine a method complementary to EMA, denoted as peer-ceived momentary assessment (PeerMA), which enables the involvement of peers (eg, family members, friends) to report their perception of the individual's subjective physical and emotional states. In this paper, we aim to report the feasibility results and identified human factors influencing the acceptance and reliability of the PeerMA. METHODS: We conducted two studies of 4 weeks each, collecting self-reports from 20 participants about their stress, fatigue, anxiety, and well-being, in addition to collecting peer-reported perceptions from 27 of their peers. RESULTS: Preliminary results showed that some of the peers reported daily assessments for stress, fatigue, anxiety, and well-being statistically equal to those reported by the participant. We also showed how pairing assessments of participants and peers in time enables a qualitative and quantitative exploration of unique research questions not possible with EMA-only based assessments. We reported on the usability and implementation aspects based on the participants' experience to guide the use of the PeerMA to complement the information obtained via self-reports for observable behaviors and physical and emotional states among healthy individuals. CONCLUSIONS: It is possible to leverage the PeerMA method as a complement to EMA to assess constructs that fall in the realm of observable behaviors and states in healthy individuals.
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Proyectos de Investigación , Adolescente , Adulto , Evaluación Ecológica Momentánea , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Autoinforme , Envío de Mensajes de Texto , Adulto JovenRESUMEN
BACKGROUND: Mortality and complications are not well defined nationally for emergency general surgery (EGS) patients presenting with underlying all-cause liver disease (LD). STUDY DESIGN: We analyzed the 2012-2014 National Inpatient Sample for adults (aged ≥ 18 years) with a primary EGS diagnosis. Underlying LD included International Classification of Diseases, Ninth Revision, Clinical Modification codes for alcoholic and viral hepatitis, malignancy, congenital etiologies, and cirrhosis. The primary outcome was mortality; secondary outcomes included complications, operative intervention, and costs. RESULTS: Of the 6.8 million EGS patients, 358 766 (5.3%) had underlying LD. 59.1% had cirrhosis, 6.7% had portal hypertension, and 13.7% had ascites. Compared with other EGS patients, EGS-LD patients had higher mean costs ($12 847 vs $10 234, P < .001). EGS-LD patients were less likely to have surgery (26.1% vs 37.0%, P < .001) but for those who did, mortality was higher (4.8% vs 1.8%, P < .001). Risk factors for mortality included ascites (adjusted odds ratio [aOR] = 2.68, P < .001), dialysis (aOR = 3.44, P < .001), sepsis (aOR = 8.97, P < .001), and respiratory failure requiring intubation (aOR = 10.40, P < .001). Odds of death increased in both surgical (aOR = 4.93, P < .001) and non-surgical EGS-LD patients (aOR = 2.56, P < .001). CONCLUSIONS: Underlying all-cause LD among EGS patients is associated with increased in-hospital mortality, even in the absence of surgical intervention.
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Servicio de Urgencia en Hospital , Tratamiento de Urgencia , Cirugía General/estadística & datos numéricos , Hepatopatías/mortalidad , Adolescente , Adulto , Anciano , Servicio de Urgencia en Hospital/economía , Servicio de Urgencia en Hospital/estadística & datos numéricos , Tratamiento de Urgencia/economía , Tratamiento de Urgencia/estadística & datos numéricos , Femenino , Humanos , Hepatopatías/economía , Hepatopatías/cirugía , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Complicaciones Posoperatorias/etiologíaRESUMEN
Acute kidney injury (AKI) is the abrupt loss of renal function, for which only supportive therapies exist. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) have been shown to be therapeutically effective in treating AKI by spurring endogenous cell proliferation and survival while suppressing inflammation. Pre-treating kidneys with pulsed focused ultrasound (pFUS) has also been shown to enhance MSC therapy for AKI, but its role in MSC-derived EV therapy remains unexplored. Using a mouse model of cisplatin-induced AKI, we show that combination therapy with pFUS and EVs restores physiological and molecular markers of kidney function, more so than either alone. Both pFUS and EVs downregulate heat shock protein 70 (HSP70), the NLRP3 inflammasome, and its downstream pro-inflammatory cytokines IL-1ß and IL-18, all of which are highly upregulated in AKI. In vitro knockdown studies suggest that HSP70 is a positive regulator of the NLRP3 inflammasome. Our study therefore demonstrates the ability of pFUS to enhance EV therapy for AKI and provides further mechanistic understanding of their anti-inflammatory and regenerative effects.
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Lesión Renal Aguda/metabolismo , Vesículas Extracelulares/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/patología , Lesión Renal Aguda/terapia , Animales , Terapia Combinada , Modelos Animales de Enfermedad , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Ratones , Medicina Regenerativa , Terapia por UltrasonidoRESUMEN
Acute kidney injury (AKI) is characterized by a sudden failure of renal function, but despite increasing worldwide prevalence, current treatments are largely supportive, with no curative therapies. Mesenchymal stromal cell (MSC) therapy has been shown to have a promising regenerative effect in AKI but is limited by the ability of cells to home to damaged tissue. Pulsed focused ultrasound (pFUS), wherein target tissues are sonicated by short bursts of sound waves, has been reported to enhance MSC homing by upregulating local homing signals. However, the exact mechanism by which pFUS enhances MSC therapy remains insufficiently explored. In this study, we studied the effect of bone marrow-derived MSCs (BM-MSCs), in conjunction with pFUS, in a mouse model of cisplatin-induced AKI. Here, BM-MSCs improved kidney function, reduced histological markers of kidney injury, decreased inflammation and apoptosis, and promoted cellular proliferation. Surprisingly, whereas pFUS did not upregulate local cytokine expression or improve BM-MSC homing, it did potentiate the effect of MSC treatment in AKI. Further analysis linked this effect to the upregulation of heat shock protein (HSP)20/HSP40 and subsequent phosphatidylinositol 3-kinase (PI3K)/Akt signaling. In summary, our results suggest that pFUS and BM-MSCs have independent as well as synergistic therapeutic effects in the context of AKI.
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Diseases of the kidney contribute a significant morbidity and mortality burden on society. Localized delivery of therapeutics directly into the kidney, via its arterial blood supply, has the potential to enhance their therapeutic efficacy while limiting side effects associated with conventional systemic delivery. Targeted delivery in humans is feasible given that we can access the renal arterial blood supply using minimally invasive endovascular techniques and imaging guidance. However, there is currently no described way to reproduce or mimic this approach in a small animal model. Here, we develop in mice a reproducible microsurgical technique for the delivery of therapeutics directly into each kidney, via its arterial blood supply. Using our technique, intra-arterially (IA) injected tattoo dye homogenously stained both kidneys, without staining any other organ. Survival studies showed no resulting mortality or iatrogenic kidney injury. We demonstrate the therapeutic potential of our technique in a mouse model of cisplatin-induced acute kidney injury (AKI). IA injection of mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) successfully reversed AKI, with reduced physiological and molecular markers of kidney injury, attenuated inflammation, and restoration of proliferation and regeneration markers. This reproducible delivery technique will allow for further pre-clinical translational studies investigating other therapies for the treatment of renal pathologies.
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Lesión Renal Aguda/terapia , Vesículas Extracelulares/trasplante , Riñón/irrigación sanguínea , Lesión Renal Aguda/patología , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Riñón/patología , RatonesRESUMEN
Mesenchymal stromal cells (MSCs) have been a popular platform for cell-based therapy in regenerative medicine due to their propensity to home to damaged tissue and act as a repository of regenerative molecules that can promote tissue repair and exert immunomodulatory effects. Accordingly, a great deal of research has gone into optimizing MSC homing and increasing their secretion of therapeutic molecules. A variety of methods have been used to these ends, but one emerging technique gaining significant interest is the use of ultrasound. Sound waves exert mechanical pressure on cells, activating mechano-transduction pathways and altering gene expression. Ultrasound has been applied both to cultured MSCs to modulate self-renewal and differentiation, and to tissues-of-interest to make them a more attractive target for MSC homing. Here, we review the various applications of ultrasound to MSC-based therapies, including low-intensity pulsed ultrasound, pulsed focused ultrasound, and extracorporeal shockwave therapy, as well as the use of adjunctive therapies such as microbubbles. At a molecular level, it seems that ultrasound transiently generates a local gradient of cytokines, growth factors, and adhesion molecules that facilitate MSC homing. However, the molecular mechanisms underlying these methods are far from fully elucidated and may differ depending on the ultrasound parameters. We thus put forth minimal criteria for ultrasound parameter reporting, in order to ensure reproducibility of studies in the field. A deeper understanding of these mechanisms will enhance our ability to optimize this promising therapy to assist MSC-based approaches in regenerative medicine.
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Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Células Madre Mesenquimatosas/metabolismo , Ultrasonografía/métodos , Diferenciación Celular , Humanos , Células Madre Mesenquimatosas/citologíaRESUMEN
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal disorder characterized by progressive gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, skeletal myopathy, ophthalmoparesis, and ptosis. MNGIE stems from deficient thymidine phosphorylase activity (TP) leading to toxic elevations of plasma thymidine. Hematopoietic stem cell transplant (HSCT) restores TP activity and halts disease progression but has high transplant-related morbidity and mortality. Liver transplant (LT) was reported to restore TP activity in two adult MNGIE patients. We report successful LT in four additional MNGIE patients, including a pediatric patient. Our patients were diagnosed between ages 14 months and 36 years with elevated thymidine levels and biallelic pathogenic variants in TYMP. Two patients presented with progressive gastrointestinal dysmotility, and three demonstrated progressive peripheral neuropathy with two suffering limitations in ambulation. Two patients, including the child, had liver dysfunction and cirrhosis. Following LT, thymidine levels nearly normalized in all four patients and remained low for the duration of follow-up. Disease symptoms stabilized in all patients, with some manifesting improvements, including intestinal function. No patient died, and LT appeared to have a more favorable safety profile than HSCT, especially when liver disease is present. Follow-up studies will need to document the long-term impact of this new approach on disease outcome. Take Home Message: Liver transplantation is effective in stabilizing symptoms and nearly normalizing thymidine levels in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and may have an improved safety profile over hematopoietic stem cell transplant.