Management of bacterial infection in the liver transplant candidate

Bacterial infection (BI) is a common cause of impairment of liver function in patients with cirrhosis, especially in the liver transplant candidates. These patients share an immunocompromised state and increased susceptibility to develop community and hospital-acquired infections. The changing epidemiology of BI, with an increase of multidrug resistant strains, especially in healthcare-associated settings, represents a critical issue both in the waiting list and in the post-operative management. This review focused on the role played by BI in patients awaiting liver transplantation, evaluating the risk of drop-out from the waiting list, the possibility to undergo liver transplantation after recovery from infection or during a controlled infection

Non-Invasive Estimation of Right Atrial Pressure Using a Semi-Automated Echocardiographic Tool for Inferior Vena Cava Edge-Tracking

: The non-invasive estimation of right atrial pressure (RAP) would be a key advancement in several clinical scenarios, in which the knowledge of central venous filling pressure is vital for patients’ management. The echocardiographic estimation of RAP proposed by Guidelines, based on inferior vena cava (IVC) size and respirophasic collapsibility, is exposed to operator and patient dependent variability. We propose novel methods, based on semi-automated edge-tracking of IVC size and cardiac collapsibility (cardiac caval index—CCI), tested in a monocentric retrospective cohort of patients undergoing echocardiography and right heart catheterization (RHC) within 24 h in condition of clinical and therapeutic stability (170 patients, age 64 ± 14, male 45%, with pulmonary arterial hypertension, heart failure, valvular heart disease, dyspnea, or other pathologies). IVC size and CCI were integrated with other standard echocardiographic features, selected by backward feature selection and included in a linear model (LM) and a support vector machine (SVM), which were cross-validated. Three RAP classes (low < 5 mmHg, intermediate 5−10 mmHg and high > 10 mmHg) were generated and RHC values used as comparator. LM and SVM showed a higher accuracy than Guidelines (63%, 71%, and 61% for LM, SVM, and Guidelines, respectively), promoting the integration of IVC and echocardiographic features for an improved non-invasive estimation of RAP

271 AUTOMATED REAL TIME ECHOCARDIOGRAPHIC TOOL FOR EDGE TRACKING OF INFERIOR VENA CAVA AND NON-INVASIVE ESTIMATION OF RIGHT ATRIAL PRESSURE

The non-invasive estimation of right atrial pressure (RAP) would be a key advancement in several clinical scenarios, in which the knowledge of central venous filling pressure is vital for patients’ management. The echocardiographic estimation of RAP proposed by Guidelines, based on inferior vena cava (IVC) size and respirophasic collapsibility, is exposed to operator and patient dependent variability. We introduce an automated real time method to process ultrasound scans of IVC and to measure pulsatility indexes, which are then used, together with other non-invasive measurements, to estimate RAP. Specifically, our method is based on the cardiac collapsibility (cardiac caval index - CCI), tested in a monocentric retrospective cohort of patients undergoing echocardiography and right heart catheterization (RHC) within 24 hour in condition of clinical and therapeutic stability (170 patients, age 64±14, male 45%, with pulmonary arterial hypertension, heart failure, valvular heart disease, dyspnea or other pathologies). IVC size and CCI were integrated with other standard echocardiographic features using machine-learning approaches. Three RAP classes (low 10 mmHg) were generated and RHC values used as comparator. Our classifications showed a higher accuracy than Guidelines (71% and 61% for our machine-learning method and Guidelines, respectively), promoting the integration of IVC and echocardiographic features for an improved non-invasive estimation of RAP

Machine Learning for Early Diagnosis of ATTRv Amyloidosis in Non-Endemic Areas: A Multicenter Study from Italy

Background: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv) is an adult-onset multisystemic disease, affecting the peripheral nerves, heart, gastrointestinal tract, eyes, and kidneys. Nowadays, several treatment options are available; thus, avoiding misdiagnosis is crucial to starting therapy in early disease stages. However, clinical diagnosis may be difficult, as the disease may present with unspecific symptoms and signs. We hypothesize that the diagnostic process may benefit from the use of machine learning (ML). Methods: 397 patients referring to neuromuscular clinics in 4 centers from the south of Italy with neuropathy and at least 1 more red flag, as well as undergoing genetic testing for ATTRv, were considered. Then, only probands were considered for analysis. Hence, a cohort of 184 patients, 93 with positive and 91 (age- and sex-matched) with negative genetics, was considered for the classification task. The XGBoost (XGB) algorithm was trained to classify positive and negative TTR mutation patients. The SHAP method was used as an explainable artificial intelligence algorithm to interpret the model findings. Results: diabetes, gender, unexplained weight loss, cardiomyopathy, bilateral carpal tunnel syndrome (CTS), ocular symptoms, autonomic symptoms, ataxia, renal dysfunction, lumbar canal stenosis, and history of autoimmunity were used for the model training. The XGB model showed an accuracy of 0.707 ± 0.101, a sensitivity of 0.712 ± 0.147, a specificity of 0.704 ± 0.150, and an AUC-ROC of 0.752 ± 0.107. Using the SHAP explanation, it was confirmed that unexplained weight loss, gastrointestinal symptoms, and cardiomyopathy showed a significant association with the genetic diagnosis of ATTRv, while bilateral CTS, diabetes, autoimmunity, and ocular and renal involvement were associated with a negative genetic test. Conclusions: Our data show that ML might potentially be a useful instrument to identify patients with neuropathy that should undergo genetic testing for ATTRv. Unexplained weight loss and cardiomyopathy are relevant red flags in ATTRv in the south of Italy. Further studies are needed to confirm these findings

MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma

Background: A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes. Methods: Primary objective of our study was to define miRs whose deregulation is predictive of CKD in patients treated with RN. Ribonucleic acid from formalin-fixed paraffin embedded renal parenchyma (cortex and medulla isolated separately) situated >3 cm from the matching RCC was tested for miR expression using nCounter NanoString technology in 71 consecutive patients treated with RN for RCC. Validation was performed by RT–PCR and in situ hybridisation. End point was post-RN CKD measured 12 months post-operatively. Multivariable logistic regression and decision curve analysis were used to test the statistical and clinical impact of predictors of CKD. Results: The overexpression of miR-193b-3p was associated with high risk of developing CKD in patients undergoing RN for RCC and emerged as an independent predictor of CKD. The addition of miR-193b-3p to a predictive model based on clinical variables (including sex and estimated glomerular filtration rate) increased the sensitivity of the predictive model from 81 to 88%. In situ hybridisation showed that miR-193b-3p overexpression was associated with tubule-interstitial inflammation and fibrosis in patients with no clinical or biochemical evidence of pre-RN nephropathy. Conclusions: miR-193b-3p might represent a useful biomarker to tailor and implement surveillance strategies for patients at high risk of developing CKD following RN

Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. We analysed PKD1 and PKD2, in a large cohort of 440 unrelated Italian patients with ADPKD and 203 relatives by direct sequencing and MLPA. Molecular and detailed phenotypic data have been collected and submitted to the PKD1/PKD2 LOVD database. This is the first large retrospective study in Italian patients, describing 701 variants, 249 (35.5%) already associated with ADPKD and 452 (64.5%) novel. According to the criteria adopted, the overall detection rate was 80% (352/440). Novel variants with uncertain significance were found in 14% of patients. Among patients with pathogenic variants, in 301 (85.5%) the disease is associated with PKD1, 196 (55.7%) truncating, 81 (23%) non truncating, 24 (6.8%) IF indels, and in 51 (14.5%) with PKD2. Our results outline the high allelic heterogeneity of variants, complicated by the presence of variants of uncertain significance as well as of multiple variants in the same subject. Classification of novel variants may be particularly cumbersome having an important impact on the genetic counselling. Our study confirms the importance to improve the assessment of variant pathogenicity for ADPKD; to this point databasing of both clinical and molecular data is crucial

Valutazione cardiorespiratoria e bioumorale in pazienti con scompenso cardiaco in terapia con sacubitril-valsartan

Stato dell’arte e razionale: Lo scompenso cardiaco (SC) è una sindrome clinica complessa, cronica e progressiva, gravata da un alto tasso di mortalità. La comprensione dei determinanti fisiopatologici dello SC ha consentito, negli ultimi quarant’anni, di dotarsi di strumenti terapeutici razionali ed in grado di migliorare significativamente la prognosi dei pazienti. Accanto alla modulazione del sistema nervoso simpatico (SNS) e del sistema renina-angiotensina-aldosterone (RAAS), da tempo cardini del trattamento dello SC, negli ultimi anni la ricerca si è focalizzata sul potenziamento degli effetti controregolatori del sistema dei peptidi natriuretici. Il primo farmaco con questo razionale approvato nel 2015 dalle autorità regolatorie è l’associazione sacubitril-valsartan, a seguito dei risultati dello studio di fase III PARADIGM-HF; a dispetto di precedenti tentativi con molecole quali candoxatril e omapatrilat, falliti per inefficacia o eccesso di effetti avversi, questo farmaco ha infatti dimostrato superiorità prognostica rispetto ad enalapril senza significativo incremento dell’incidenza di effetti avversi. Questo positivo risultato ha portato alla revisione delle linee guida internazionali per la diagnosi e terapia dello SC che, a partire dal 2016, raccomandano l’utilizzo di sacubitril-valsartan in pazienti con ridotta frazione di eiezione (<35%) e sintomatici nonostante terapia medica ottimale con β-bloccanti, ACE-inibitori o sartani ed antialdosteronici. Tuttavia, le modalità attraverso cui si manifesta il beneficio clinico non sono del tutto spiegate dai meccanismi d’azione noti del farmaco, né lo è il suo effetto su vari biomarcatori di attività neuro-ormonale o cardiorespiratoria. Scopo della tesi: Lo studio, monocentrico, longitudinale e in aperto, caratterizza gli effetti bioumorali della terapia con sacubitril-valsartan sul RAAS, sul SNS, sul danno miocardico, sull’infiammazione e sulla fibrosi, e valuta le variazioni del profilo aritmico, di tolleranza allo sforzo e della funzione cardiorespiratoria. Materiali e metodi: In questo studio sono stati arruolati per il trattamento con sacubitril-valsartan ventiquattro pazienti con SC cronico a ridotta frazione di eiezione (età media 67.5 anni, frazione di eiezione ventricolare sinistra media 28%, deviazione standard DS 6). I pazienti sono stati sottoposti, prima dell’inizio della terapia e ad uno, tre e sei mesi, ad indagini bioumorali comprendenti il dosaggio di renina attiva, aldosterone, catecolamine plasmatiche, sodio, potassio, creatinina, troponina T ad alta sensibilità, sST2, GDF-15, Gal-3; alla valutazione basale e dopo sei mesi di trattamento i pazienti hanno eseguito un ecocolor-Doppler cardiaco, test da sforzo cardiopolmonare (CPET), elettrocardiogramma dinamico secondo Holter (hECG) e monitoraggio cardiorespiratorio nelle ventiquattro ore (CRM). Risultati: Dei 24 pazienti arruolati, 14 (58%, responders) hanno mostrato una risposta positiva a sacubitril-valsartan definita come riduzione dei valori di NT-proBNP superiore al 30% dopo sei mesi di trattamento; 10 pazienti (42%, non-responders) al contrario, nonostante l’introduzione del farmaco, non hanno mostrato significativa riduzione del NT-proBNP, ed in alcuni casi anche un aumento dei valori durante il follow-up. I responders alla valutazione basale risultavano tendenzialmente meno sintomatici, presentavano valori pressori diastolici più elevati (p=0.033), un maggior diametro telediastolico ventricolare sinistro (p=0.042) ed assumevano dosi inferiori di diuretico (p=0.022) rispetto ai non-responders, i quali presentavano una condizione di iperaldosteronismo iper-reninemico ed una capacità di esercizio significativamente inferiore (p=0.003). In corso di terapia i livelli di renina attiva si sono innalzati (p=0.001) e l’aldosterone è diminuito (p=0.034) solo nei responders, mentre i non-responders presentavano valori estremamente elevati già basalmente. Il sistema nervoso simpatico non appariva significativamente coinvolto in nessuno dei due gruppi. I valori di BNP hanno subito un lieve aumento nei responders, mentre si sono elevati significativamente (p=0.050) nei non-responders. I livelli di troponina circolante sono rimasti stabilmente elevati nei non-responders mentre si sono ridotti fino a rientrare nei limiti di normalità tra i responders (p=0.009). Il rapporto NT-proBNP/BNP, associato in altri studi ad un miglior outcome, si è ridotto nella popolazione complessiva (p=0.002) e nel gruppo dei responders (p=0.009). Il GDF-15 si è innalzato nei non-responders (p=0.019) con un trend consensuale del sST2; nei responders i marcatori di infiammazione e fibrosi sono rimasti stabili. Non si sono documentati effetti positivi della terapia con sacubitril-valsartan sulla funzione sisto-diastolica, sul profilo aritmico o sulla capacità all’esercizio. I non-responders sono andati incontro a dilatazione atriale (p=0.050), riduzione del TAPSE (p=0.05) e peggioramento dell’insufficienza mitralica (p=0.034). Nel gruppo dei responders il trattamento ha prodotto una riduzione significativa dell’AHI (p=0.016). Conclusioni: Sacubitril-valsartan modula efficacemente il RAAS e porta in circa 2/3 dei pazienti trattati ad una riduzione del NT-proBNP, della troponina circolante e dell’incidenza di apnee in pazienti affetti da HFrEF. Un sottogruppo di pazienti, probabilmente con un quadro clinico più avanzato, non ha tratto beneficio dalla terapia con ARNI. Ulteriori studi saranno necessari per meglio identificare predittori di risposta ed approfondire l’effetto sulle apnee

Post-COVID-19 Lymphocytopenia and Opportunistic Pathogens Infection in a Thalassemia Major Patient

Transfusion-dependent thalassemia patients undergo transfusion immunomodulating effects, which result in a general immune response depression and, consequently, an increase in the frequency of infectious episodes and neoplastic events due to a reduction in phagocytic function. Altered natural killer functions and IL-2-mediated lymphocytic response, defects in antigen presentation due to monocyte–macrophage cells, and decreases in bone marrow precursors and HLA II+ cells all play key roles in immunodepression in thalassemia major. SARS-CoV-2 infection presents marked lymphopenia, occurring in 96.1% of severe cases. COVID-19-related lymphopenia is due to various mechanisms, which lead to an increase in lymphocytic apoptosis. Post-COVID-19 lymphocytic quantitative and functional disorders may compromise immune response and promote the onset of infections via opportunistic pathogens. Herein, we report a case of a thalassemia major patient who developed severe post-COVID-19 lymphocytopenia, which may have facilitated the onset of a severe Klebsiella Pneumoniae infection