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Objective: This study aims to know the surgical treatment of electrical injuries, perineum, and scrotum. Case(s) Presentation: A 55-year-old male sustained electric burns to the back, perineum and scrotum. The patient failed to void following removal of the catheter 6 weeks later, hence the patient was referred to the urology department for further management. was counselled for a two-phase urethral surgery. Discussion: In our case, the patient had sustained perineal and scrotal burns when he sat over a live wire. This led to the loss of skin and soft tissues, needing massive musculoskeletal and skin grafts. Our patient underwent a number of revision surgeries leading to repeated scarring of the perineal tissues and skin. Conclusion: Electrical injuries to the perinium and genitalia are rare. Hence the surgical strategy of electrical injuries requires a step-wise approach. Initially, conservative debridement needs to performed so as to preserve any tissue of questionable viability and ensure subsequent adequate soft-tissue coverage. The reconstructive surgical procedures bring about satisfactory outcomes. Keywords: Electrical injury, perineum, scrotum, surgical strategy.

Vascular complications after renal transplantation are rare, however, they are serious surgical complications. Intimal tears in the renal arteries can result from iatrogenic injuries. These injuries can occur due to crushing injuries of the intima secondary to the use of improper vascular clamps, mishandling of the vessels, and use of traumatic infusion/perfusion needles or devices. It is important to recognize these intimal injuries so that corrective measures can be undertaken immediately and avoid vascular complications. We report a case of renal artery thrombosis secondary to intimal injury leading to intraoperative poor blood flow across the anastomosis which was promptly recognized and corrected leading to successful salvage of the transplanted kidney.

Introduction: There is a high number of isoniazid-resistant tuberculosis (TB) in India; estimates imply that over 25% of TB patients there are isoniazid-resistant. Hence, the study aimed to evaluate the effectiveness of therapy for patients with isoniazid-mono-resistant TB and the negative effects of the H-mono-resistant TB Regime. Materials and Methods: It was a hospital-based prospective observational study from September 2021 to August 2022. Hence, 100 patients diagnosed with isoniazid mono-resistance TB enrolled in this study. After obtaining the prior informed consent of all patients willing to approve the collection and publication of their data, including extensive clinical history and radiological, microbiological, and biochemical investigations, this study included all diagnosed cases of isoniazid mono-resistant TB. A descriptive statistical analysis was done for continuous and categorical variables. Differences in characteristics between participants were tested with logistic regression and cross-tabulation. P

Abstract Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. A patient with metastatic medullary thyroid carcinoma (MTC) harboring a RET activation loop D898_E901del mutation was treated with selpercatinib. Molecular alterations were monitored with tissue biopsies and cfDNA during the treatment. The selpercatinib-responsive MTC progressed with an acquired ETV6::NTRK3 fusion, which was controlled by selpercatinib plus the NTRK inhibitor larotrectinib. Subsequently, tumor progressed with an acquired EML4::ALK fusion. Combination of selpercatinib with the dual NTRK/ALK inhibitor entrectinib reduced the tumor burden, which was followed by appearance of NTRK3 solvent-front G623R mutation. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.

Skin cancer is a significant health risk that requires early detection for effective treatment. This paper discusses two automated techniques, Artificial Neural Network (ANN) and Convolutional Neural Network (CNN), which make use of deep learning techniques for skin cancer detection. Through evaluation of research on skin cancer detection using ANN and CNN, the effectiveness and performance of these techniques in early and efficient diagnosis of skin cancer were established. The study found that ANN and CNN were successful in early detection of skin cancer using different data sets and hybrid models, demonstrating the potential for these technologies to improve accuracy in skin cancer detection. The paper highlights the novelty of using deep learning techniques for skin cancer detection and emphasises the critical need for an automated system for skin lesion recognition to reduce effort and time in the diagnosis process. The possible applications of this study include the development of more efficient and accurate skin cancer detection systems that can lead to earlier diagnosis and improved treatment outcomes. Overall, this research underscores the importance of using advanced technologies, such as ANN and CNN, in the fight against skin cancer and highlights the potential impact of these techniques in improving patient outcomes.

Patients with relapsed acute myeloid leukemia (rAML) experience dismal outcomes. We performed a comprehensive analysis of patients with rAML to determine the genetic dynamics and survival predictive factors. We analyzed 875 patients with newly diagnosed AML who received intensive treatment (IT) or low-intensity treatment (LIT). Of these patients, 197 experienced subsequent rAML. Data was available for 164 patients, with a median time from CR/CRi to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation (alloSCT). At relapse mutations in genes involved in pathway signaling tended to disappear, whereas clonal hematopoiesis-related mutations or TP53 tended to persist. Patients with normal karyotypes tended to acquire cytogenetic abnormalities at relapse. Patients treated with IT had a higher emergence rate of TP53 mutations (16%), compared to patients treated with LIT (1%, P = 0.009). The overall response rates were 38% and 35% for patients treated with salvage IT or LIT, respectively. Seventeen patients (10%) underwent alloSCT after salvage therapy. The median overall survival (OS) duration after relapse was 5.3 months, with a 1-year OS rate of 17.6%. Complex karyotype (hazard ratio [HR] = 2.14, P < 0.001), a KMT2A rearrangement (HR = 3.52, P = 0.011), time in remission < 12 months (HR = 1.71, P = 0.011), and an elevated white blood cell count at relapse (HR = 2.38, P = 0.005) were independent risk factors for OS duration. More effective frontline and maintenance therapies are warranted to prevent rAML.

Background. Metabolic dysfunction-associated steatohepatitis (MASH) has become the leading cause of chronic liver disease, but there has been no approved pharmacotherapy to date. Methods. We used a network analysis approach to delineate protein-protein interactions that contribute to the transition from steatosis to MASH, in order to identify and target this transition as a potential pharmacotherapeutic strategy. Acyl-CoA thioesterase 1 (ACOT1) was identified as a critical node in the protein-protein interaction (PPI) network of the transition from steatosis to MASH in patient samples. ACOT1 overexpression and silencing effects were tested in vivo on C57BL/6 mice exposed to high-fat diet (HFD) and inoculated with an adenoviral system to modulate ACOT1 expression. Transcriptomic and untargeted lipidomic profiles were performed on the mouse livers. Results. ACOT1 expression was 3-fold higher in MASH as compared to steatosis. In patient samples, ACOT1 was significantly correlated with the severity of MASH as reflected by the nonalcoholic fatty liver disease score. Experimental validation showed that downregulation of ACOT1 resulted in decreased lipid accumulation and prevention of MASH in vivo. Conversely, upregulation of ACOT1 via an adenoviral vector resulted in development of MASH, whereas control mice only developed steatosis. Lipidomic analysis revealed glycerophospholipids to be especially abundant in MASH accelerated by ACOT1 upregulation. Conclusion. These results suggest that ACOT1 contributes to the transition from steatosis to MASH through modulation of glycerophospholipid accumulation and its potential as a novel therapeutic target in MASH. This trial is registered with NCT02148471.

Objective: In this paper we report our experience in the use of buccal mucosal grafts in the reconstruction of difficult upper ureteric and uretero-pelvic junction strictures. Material & Methods: We retrospectively looked at our hospital inpatient and outpatient records of all patients who underwent surgical treatment for benign upper ureteric strictures and ureteropelvic junction strictures. Results: During the study period a total of 22 patients with a mean age of 326.07 years underwent buccal mucosal graft repair. The mean length of the narrowing/stricture was 6.40 1.44 cm. Conclusion: Buccal mucosal onlay graft ureteroplasty is a suitable treatment option for long, complicated benign upper ureteric and select ureteropelvic junction stric­tures. It is technically simple and capable of providing optimum patency of ureter with good urinary drainage. It is safe and effective. Keywords: Buccal mucosa, ureteric stricture, ureteropelvic junction stricture, graft, ureteroplasty

Despite advances in posttransplant care, long-term outcomes for liver transplant recipients remain unchanged. Approximately 25% of recipients will advance to graft cirrhosis and require retransplantation. Graft fibrosis progresses in the context of de novo or recurrent disease. Recurrent hepatitis C virus infection was previously the most important cause of graft failure but is now curable in the majority of patients. However, with an increasing prevalence of obesity and diabetes and nonalcoholic fatty liver disease as the most rapidly increasing indication for liver transplantation, metabolic dysfunction-associated liver injury is anticipated to become an important cause of graft fibrosis alongside alloimmune hepatitis and alcoholic liver disease. To better understand the landscape of the graft fibrosis literature, we summarize the associated epidemiology, cause, potential mechanisms, diagnosis, and complications. We additionally highlight the need for better noninvasive methods to ameliorate the management of graft fibrosis. Some examples include leveraging the microbiome, genetic, and machine learning methods to address these limitations. Overall, graft fibrosis is routinely seen by transplant clinicians, but it requires a better understanding of its underlying biology and contributors that can help inform diagnostic and therapeutic practices.

ABSTRACT Objective: This study aims to describe the reconstruction of long ureteric strictures using buccal mucosal patch grafts and to report the short term outcome. Material & Methods: We retrospectively looked at our hospital inpatient and outpatient records of all patients who underwent surgical treatment for benign ureteric strictures. Imaging records and films, histopathological reports were reanalysed. The short term outcomes were also noted. Results: During this 10 years’ study period 8 patients (six Males and two Females) underwent 10 buccal mucosal grafts procedures. The mean age of the patients was 36.25 years and the mean length of the stricture was 7.13.41 cm. There were intraoperative complications noted and none of the patients needed either intra or post-operative blood transfusions. Serum creatinine remained stable at 6 and 12 weeks after surgery. Radioisotope renograms done 12-16 weeks after surgery showed improvement in function on the affected sides in all patients with adequate drainage. Conclusions: Buccal mucosal patch grafting and omental wrapping is feasible, effective, less complicated and associated with good outcomes at short term follow-up. Keywords: Reconstruction, ureteric stricture, buccal mucosa.

Background: To compare and correlate the relationship between body mass index (BMI) and blood and salivary glucose (mean values) in patients with diabetes and non-diabetic control group patients. Materials and Methods: In the study, 100 patients were included, 50 patients each-patients with diabetes and non-diabetic control group. Each patient had their BMI measured as well as unstimulated whole saliva collected and blood drawn. Results: When compared to BMI, blood glucose (mean), and salivary glucose (mean) in healthy controls, BMI, blood glucose, and salivary glucose values in diabetic patients were considerably higher. Conclusion: Patients who have a higher BMI are more likely to develop diabetes.

INTRODUCTION: The complications of benign prostatic hyperplasia (BPH) among others include bladder stones. The prevalence of vesical calculus is eight times higher in men having BPH (3.4%) as compared with men without BPH (0.4%). The guidelines suggest that BPH obstruction should be managed along with removal of bladder stones. The objective of the study was to study the outcome of surgery in patients with BPH and bladder calculi. MATERIALS AND METHODS: This prospective study included all patients undergoing surgical treatment for BPH with vesical calculi. Outcomes were measured in terms of blood loss, operating time, days of hospitalization, postoperative urinary flow, postvoid residual, and complications. RESULTS: Five (13.51%) patients underwent perurethral cystolitholapaxy, 17 (45.94%) underwent percutaneous suprapubic cystolitholapaxy, and the remaining 15 (40.54%) underwent open cystolithotomy for bladder stones. The prostate (BPH) was managed by monopolar transurethral resection of prostate (TURP) in 14 (37.83%), bipolar TURP in 12 (32.43%), and laser prostatectomy (Holmium enucleation) in the remaining 11 (29.72%). At the time of discharge, all patients were free of bladder stones and voided well. At 3-month follow-up, the mean Q-max was 18.65 mL/s. CONCLUSIONS: Simultaneous management of BPH and bladder stones is safe and effective. The procedure chosen for managing bladder stones depends on the size, number, and experience of the surgeon. Smaller stones can be easily managed by minimally invasive procedures such as perurethral cystolitholapaxy and percutaneous cystolitholapaxy.

Abstract While the clinical impact of mutations in the ABL1 gene on response to therapy in chronic phase chronic myeloid leukemia (CP-CML) is well established, less is known about how other mutations affect prognosis. In a retrospective analysis, we identified 115 patients with CML (71 chronic, 15 accelerated and 29 blast phase) where targeted next-generation sequencing of genes recurrently mutated in myeloid leukemias was performed. ASXL1 was the most frequently mutated gene in the chronic (14%) and accelerated phase (40%) CML patients, whereas RUNX1 (20%) was the most common mutation in blast phase. Compared with wild-type ASXL1, CP-CML with mutant ASXL1 was associated with worse event-free survival (EFS) (median of 32.8 vs 88.3 months; P = 0.002) and failure-free survival (median of 13.8 vs 57.8 months; P = 0.04). In a multivariate analysis, ASXL1 mutation was the only independent risk factor associated with worse EFS in chronic phase CML with a hazard ratio of 4.25 (95% CI 1.59–11.35, P = 0.004). In conclusion, mutations in ASXL1 are associated with worse outcomes when detected in chronic phase CML.

Background:. Liver transplantation (LT) is frequently lifesaving for people living with primary sclerosing cholangitis (PSC). However, patients are waitlisted for LT according to the model for end-stage liver disease-sodium (MELD-Na) score, which may not accurately reflect the burden of living with PSC. We sought to describe and analyze the clinical trajectory for patients with PSC referred for LT, in a mixed deceased donor/living donor transplant program. Methods:. This was a retrospective cohort study from November 2012 to December 2019, including all patients with PSC referred for assessment at the University Health Network Liver Transplant Clinic. Patients who required multiorgan transplant or retransplantation were excluded. Liver symptoms, hepatobiliary malignancy, MELD-Na progression, and death were abstracted from chart review. Competing risk analysis was used for timing of LT, transplant type, and death. Results:. Of 172 PSC patients assessed, 84% (n = 144) were listed of whom 74% were transplanted. Mean age was 47.6 years, and 66% were male. Overall mortality was 18.2% at 2 years. During the follow-up, 16% (n = 23) were removed from the waitlist for infection, clinical deterioration, liver-related mortality or new cancer; 3 had clinical improvement. At listing, 82% (n = 118) had a potential living donor (pLD). Patients with pLD had significantly lower waitlist and liver-related waitlist mortality (HR 0.20, p

Summary: Background: Recurrent graft fibrosis after liver transplantation can threaten both graft and patient survival. Therefore, early detection of fibrosis is essential to avoid disease progression and the need for retransplantation. Non-invasive blood-based biomarkers of fibrosis are limited by moderate accuracy and high cost. We aimed to evaluate the accuracy of machine learning algorithms in detecting graft fibrosis using longitudinal clinical and laboratory data. Methods: In this retrospective, longitudinal study, we trained machine learning algorithms, including our novel weighted long short-term memory (LSTM) model, to predict the risk of significant fibrosis using follow-up data from 1893 adults who had a liver transplantation between Feb 1, 1987, and Dec 30, 2019, with at least one liver biopsy post transplantation. Liver biopsy samples with indefinitive fibrosis stage and those from patients with multiple transplantations were excluded. Longitudinal clinical variables were collected from transplantation to the date of last available liver biopsy. Deep learning models were trained on 70% of the patients as the training set and 30% of the patients as the test set. The algorithms were also separately tested on longitudinal data from patients in a subgroup of patients (n=149) who had transient elastography within 1 year before or after the date of liver biopsy. Weighted LSTM model performance for diagnosing significant fibrosis was compared against LSTM, other deep learning models (recurrent neural network and temporal convolutional network), and machine learning models (Random Forest, Support vector machines, Logistic regression, Lasso regression, and Ridge regression) and aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4), and transient elastography. Findings: 1893 people who had a liver transplantation (1261 [67%] men and 632 [33%] women) with at least one liver biopsy between Jan 1, 1992, and June 30, 2020, were included in the study (591 [31%] cases and 1302 [69%] controls). The median age at liver transplantation was 53·7 years (IQR 47·3–59·0) for cases and 55·3 years (48·0 to 61·2) for controls. The median time interval between transplant and liver biopsy was 21 months (5 to 71). The weighted LSTM model (area under the curve 0·798 [95% CI 0·790 to 0·810]) consistently outperformed other methods, including unweighted LSTM (0·761 [0·750 to 0·769]; p=0·031) Recurrent Neural Network (0·736 [0·721 to 0·744]), Temporal Convolutional Networks (0·700 [0·662 to 0·747], and Random Forest 0·679 [0·652 to 0·707]), FIB-4 (0·650 [0·636 to 0·663]) and APRI (0·682 [0·671 to 0·694]) when diagnosing F2 or worse stage fibrosis. In a subgroup of patients with transient elastography results, weighted LSTM was not significantly better at detecting fibrosis (≥F2; 0·705 [0·687 to 0·724]) than transient elastography (0·685 [0·662 to 0·704]). The top ten variables predictive for significant fibrosis were recipient age, primary indication for transplantation, donor age, and longitudinal data for creatinine, alanine aminotransferase, aspartate aminotransferase, total bilirubin, platelets, white blood cell count, and weight. Interpretation: Deep learning algorithms, particularly weighted LSTM, outperform other routinely used non-invasive modalities and could help with the earlier diagnosis of graft fibrosis using longitudinal clinical and laboratory variables. The list of most important predictive variables for the development of fibrosis will enable clinicians to modify their management accordingly to prevent onset of graft cirrhosis. Funding: Canadian Institute of Health Research, American Society of Transplantation, Toronto General and Western Hospital Foundation, and Paladin Labs.

Background & Aims: Fibroblast activity is a key feature of fibrosis progression and organ function loss, leading to liver-related complications and mortality. The fibrogenesis marker, PRO-C3, has been shown to have prognostic significance in relation to fibrosis progression and as a treatment efficacy marker. We investigated whether PRO-C3 was prognostic for clinical outcome and mortality in two distinct cohorts of compensated cirrhosis. Methods: Cohort 1 was a rapid fibrosis progression cohort including 104 patients with HCV and biopsy-proven Ishak fibrosis stage ≥3 without prior clinical events. Cohort 2 was a prospective cohort including 172 patients with compensated cirrhosis of mixed aetiology. Patients were assessed for clinical outcomes. PRO-C3 was assessed in serum at baseline in cohorts 1 and 2, and compared with model for end-stage liver disease and albumin–bilirubin (ALBI) scores. Results: In cohort 1, a 2-fold increase in PRO-C3 was associated with 2.7-fold increased hazard of liver-related events (95% CI 1.6–4.6), whereas a one unit increase in ALBI score was associated with a 6.5-fold increased hazard (95% CI 2.9–14.6). In cohort 2, a 2-fold increase in PRO-C3 was associated with a 2.7-fold increased hazard (95% CI 1.8–3.9), whereas a one unit increase in ALBI score was associated with a 6.3-fold increased hazard (95% CI 3.0–13.2). A multivariable Cox regression analysis identified PRO-C3 and ALBI as being independently associated with the hazard of liver-related outcomes. Conclusions: PRO-C3 and ALBI were independent prognostic factors for predicting liver-related clinical outcomes. Understanding the dynamic range of PRO-C3 might enhance its use for both drug development and clinical practice. Impact and Implications: We tested novel proteins of liver scarring (PRO-C3) in two groups of liver patients with advanced disease to see if they could predict clinical events. We found that this marker and an established test called ALBI were both independently associated with future liver-related clinical outcomes.

Abstract In older/unfit newly diagnosed patients with FLT3 mutated acute myeloid leukemia (AML), lower intensity chemotherapy (LIC) in combination with either a FLT3 inhibitor or with venetoclax results in poor overall survival (median 8 to 12.5 months). We performed a retrospective analysis of 87 newly diagnosed FLT3 mutated AML patients treated on triplet (LIC + FLT3 inhibitor + Venetoclax, [N = 27]) and doublet (LIC + FLT3 inhibitor, [N = 60]) regimens at our institution. Data were collected from prospective clinical trials in 75% (N = 65) and 25% (N = 22) who received the same treatment regimens outside of a clinical trial. Triplet therapy was associated with significantly higher rates of complete remission (CR) (67% versus 32%, P = 0.002), CR/CRi (93% versus 70%, P = 0.02), FLT3-PCR negativity (96% versus 54%, P 0.5 (40 versus 21 days, P = 0.15) and platelet > 50 K (29 versus 25 days, P = 0.6) among responders was numerically longer with triplets, but 60-day mortality was similar (7% v 10%). With a median follow-up of 24 months (median 12 months for triplet arm, and 63 months for doublet arm), patients receiving a triplet regimen had a longer median overall survival (not reached versus 9.5 months, P

In the present era, social media platforms such as Facebook, WhatsApp, Twitter, and Telegram are significant sources of information distribution, and people believe it without knowing their origin and genuineness. Social media has fascinated people worldwide in spreading fake news due to its easy availability, cost-effectiveness, and ease of information sharing. Fake news can be generated to mislead the community for personal or commercial gains. It can also be used for other personal benefits such as defaming eminent personalities, amendment of government policies, etc. Thus, to mitigate the awful consequences of fake news, several research types have been conducted for its detection with high accuracy to prevent its fatal outcome. Motivated by the aforementioned concerns, we present a comprehensive survey of the existing fake news identification techniques in this paper. Then, we select Machine Learning (ML) models such as Long-Short Term Memory (LSTM), Passive Aggressive Algorithm, Random Forest (RF), and Naive Bayes (NB) and train them to detect fake news articles on the self-aggregated dataset. Later, we implemented these models by hyper tuning various parameters such as smoothing, drop out factor, and batch size, which has shown promising results in accuracy and other evaluation metrics such as F1-score, recall, precision, and Area under the ROC Curve (AUC) score. The model is trained on 6335 news articles, with LSTM showing the highest accuracy of 92.34% in predicting fake news and NB were showing the highest recall. Based on these results, we propose a hybrid fake news detection technique using NB and LSTM. At last, challenges and open issues along with future research directions are discussed to facilitate the research in this domain further.

Abstract Acquired resistance to molecular targeted therapy is a significant challenge of the precision medicine era. The ability to understand these mechanisms of resistance may improve patient selection and allow for the development of rationally designed next-line or combination treatment strategies and improved patient outcomes. AKT is a critical effector of the phosphoinositide 3-kinase signaling cascade, one of the most commonly activated pathways in human cancer. Deregulation of signaling pathways, such as RAF/MEK/ERK are previously described mechanisms of resistance to AKT/PI3K inhibitors. Mutations in the mTOR gene, however, are exceedingly rare. We present a case of acquired mTOR resistance, following targeted AKT inhibition, and subsequent response to mTOR1/2 inhibitor in a patient with metastatic endometrial cancer, the first documented response to ATP-competitive mTOR inhibition in this setting. This case supports mTOR mutation as a mechanism of resistance, and underscores the importance of tumor molecular profiling, exemplifying precision medicine in action.

Abstract Reliable and available non-invasive methods for hepatic fibrosis assessment are important in chronic liver disease (CLD). Our aim was to compare stepwise algorithms combining standard ultrasound with serum markers and transient elastography (TE) for detecting advanced fibrosis (F3-4) and cirrhosis. Retrospective single center study between 2012 and 2018 of CLD patients with biopsy, TE, blood tests, and liver ultrasound parameters of surface nodularity (SN), lobar redistribution, and hepatic vein nodularity. Our cohort included 157 patients (51.6% males), mean age 47.6 years, predominantly non-alcoholic fatty liver disease and viral hepatitis (61%), with F3-4 prevalence of 60.5%. Area under the curve for F3-4 was 0.89 for TE ≥ 9.6 kPa and 0.80 for FIB-4 > 3.25. In multivariate modeling, TE ≥ 9.6 kPa (OR 21.78) and SN (OR 3.81) had independent association with F3-4; SN (OR 5.89) and TE ≥ 10.2 kPa (OR 15.73) were independently associated with cirrhosis. Two stepwise approaches included FIB-4 followed by SN or TE; sensitivity and specificity of stepwise SN were 0.65 and 1.00, and 0.89 and 0.33 for TE ≥ 9.6 kPa, respectively. Ultrasound SN and TE were independently predictive of F3-4 and cirrhosis in our cohort. FIB-4 followed by SN had high specificity for F3-4.

Summary: Background: Non-alcoholic steatohepatitis (NASH) is the second-leading indication for liver transplantation (LT) worldwide and is projected to become the leading indication. Our study aimed to determine clinical variables that predict post-LT survival in NASH. Methods: A systematic review and meta-analysis was performed. On June 18, 2020 and April 28, 2022, Ovid MEDLINE ALL, Ovid Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials were searched. No date limits were applied. Inclusion criteria specified the type of study and our study's population/comparison and outcome/timepoints. Pediatric, animal, retransplantation-only, and studies classifying cryptogenic cirrhosis patients with body mass index (BMI)

Context: To study the demographics and clinical profile of patients with acute pulmonary embolism (PE) and impact of management as per risk stratification on outcome of patients with acute PE. Materials and Methods: Prospective observational study of demographics, clinical profile, risk stratification, management, and outcome of patients presenting with acute PE from August 2016 to July 2017. Results: One hundred and fifty patients who were detected to have acute pulmonary thromboembolism with a mean age of 45.08 years, with 70% being males, were included in the study. There were 6 (4%) patients in high-risk group, 69 (46%) patients in intermediate-high subgroup, 39 (26%) patients in intermediate-low subgroup and 36 (24%) patients in low-risk group as per the ESC 2019 guidelines using sPESI score, shock/hypotension, right ventricle (RV) dysfunction and cardiac marker elevation. 72 patients (52%) had antecedent deep vein thrombosis (DVT) of which 60 patients has proximal, whereas 12 patients had distal DVT. One hundred and forty-seven patients (98%) had moderate-to-severe TR, 117 patients (78%) had evidence of right atrium/RV dysfunction and 27 patients (18%) had evidence of thrombus in the heart. Computed tomography pulmonary angiogram showed middle pulmonary artery thrombus/dilatation in 63 patients (42%), saddle thrombus in 18 patients (12%), partial thrombus in the left pulmonary artery (LPA) and right pulmonary artery (RPA) in 84 (56%) and 75 (50%) patients, respectively. Majority (86%) of patients with tenecteplase; 9 (10.3%) patients with streptokinase and 3 (3.4%) was thrmobolysed with alteplase. Conclusion: PE can present with unexplained dyspnea and atypical chest pain, among other signs and symptoms. Early diagnosis, risk stratification, and guideline-directed prompt management can lead to favorable outcome.

Summary: Background: Cirrhosis is the result of advanced scarring (or fibrosis) of the liver, and is often diagnosed once decompensation with associated complications has occurred. Current non-invasive tests to detect advanced liver fibrosis have limited performance, with many indeterminate classifications. We aimed to identify patients with advanced liver fibrosis of all-causes using machine learning algorithms (MLAs). Methods: In this retrospective study of routinely collected laboratory, clinical, and demographic data, we trained six MLAs (support vector machine, random forest classifier, gradient boosting classifier, logistic regression, artificial neural network, and an ensemble of all these algorithms) to detect advanced fibrosis using 1703 liver biopsies from patients seen at the Toronto Liver Clinic (TLC) between Jan 1, 2000, and Dec 20, 2014. Performance was validated using five datasets derived from patient data provided by the TLC (n=104 patients with a biopsy sample taken between March 24, 2014, and Dec 31, 2017) and McGill University Health Centre (MUHC; n=404). Patients with decompensated cirrhosis were excluded. Performance was benchmarked against aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4), non-alcoholic fatty liver disease fibrosis score (NFS), transient elastography, and an independent panel of five hepatology experts (MB, GS, HK, KP, and RSK). MLA performance was evaluated using the area under the receiver operating characteristic curve (AUROC) and the percentage of determinate classifications. Findings: The best MLA was an ensemble algorithm of support vector machine, random forest classifier, gradient boosting classifier, logistic regression, and neural network algorithms, which achieved 100% determinate classifications (95% CI 100·0–100·0), an AUROC score of 0·870 (95% CI 0·797–0·931) on the TLC validation set (fibrosis stages F0 and F1 vs F4), and an AUROC of 0·716 (95% CI 0·664–0·766) on the MUHC validation set (fibrosis stages F0, F1, and F2 vs F3 and F4). The ensemble MLA outperformed all routinely used biomarkers and achieved comparable performance to hepatologists as measured by AUROC and percentage of indeterminate classifications in both the TLC validation dataset (APRI AUROC score 0·719 [95% CI 0·611–0·820], 83·7% determinate [95% CI 76·0–90·4]; FIB-4 AUROC score 0·825 [95% CI 0·730–0·912], 72·1% determinate [95% CI 63·5–80·8]) and the MUHC validation dataset (APRI AUROC score 0·618 [95% CI 0·548–0·691], 75·5% determinate [95% CI 71·5–79·2]; FIB-4 AUROC score 0·717 (95% CI 0·652–0·776), 75·5% determinate [95% CI 0·713–0·797]), and achieving only slightly lower AUROC than transient elastography (0·773 [95% CI 0·699–0·834] vs 0·826 [95% CI 0·758–0·889]). Interpretation: We have shown that an ensemble MLA outperforms non-imaging-based methods in detecting advanced fibrosis across different causes of liver disease. Our MLA was superior to APRI, FIB-4, and NFS with no indeterminate classifications, while achieving performance comparable to an independent panel of experts. MLAs using routinely collected data could identify patients at high-risk of advanced hepatic fibrosis and cirrhosis among patients with chronic liver disease, allowing intervention before onset of decompensation. Funding: Toronto General Hospital Foundation.

With the advancements in machine and deep learning algorithms, the envision of various critical real-life applications in computer vision becomes possible. One of the applications is facial sentiment analysis. Deep learning has made facial expression recognition the most trending research fields in computer vision area. Recently, deep learning-based FER models have suffered from various technological issues like under-fitting or over-fitting. It is due to either insufficient training and expression data. Motivated from the above facts, this paper presents a systematic and comprehensive survey on current state-of-art Artificial Intelligence techniques (datasets and algorithms) that provide a solution to the aforementioned issues. It also presents a taxonomy of existing facial sentiment analysis strategies in brief. Then, this paper reviews the existing novel machine and deep learning networks proposed by researchers that are specifically designed for facial expression recognition based on static images and present their merits and demerits and summarized their approach. Finally, this paper also presents the open issues and research challenges for the design of a robust facial expression recognition system.

Background Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide. Cardiovascular disease (CVD) is the leading cause of mortality among patients with NAFLD. The aim of our study was to develop a machine learning algorithm integrating clinical, lifestyle, and genetic risk factors to identify CVD in patients with NAFLD. Methods and Results We created a cohort of patients with NAFLD from the UK Biobank, diagnosed according to proton density fat fraction from magnetic resonance imaging data sets. A total of 400 patients with NAFLD with subclinical atherosclerosis or clinical CVD, defined by disease codes, constituted cases and 446 NAFLD cases with no CVD constituted controls. We evaluated 7 different supervised machine learning approaches on clinical, lifestyle, and genetic variables for identifying CVD in patients with NAFLD. The most significant clinical and lifestyle variables observed by the predictive modeling were age (59 years [54.00–63.00 years]), hypertension (145 mm Hg [134.0–156.0 mm Hg] and 85 mm Hg [79.00–93.00 mm Hg]), waist circumference (98 cm [95.00–105.00 cm]), and sedentary lifestyle, defined as time spent watching TV >4 h/d. In the genetic data, single‐nucleotide polymorphisms in IL16 and ANKLE1 gene were most significant. Our proposed ensemble‐based integrative machine learning model achieved an area under the curve of 0.849 using the random forest modeling for CVD prediction. Conclusions We propose a machine learning algorithm that identifies CVD in patients with NAFLD through integration of significant clinical, lifestyle, and genetic risk factors. These patients with NAFLD at higher risk of CVD should be flagged for screening and aggressive treatment of their cardiometabolic risk factors to prevent cardiovascular morbidity and mortality.

Background & Aims: A recent consensus document has defined metabolic dysfunction-associated fatty liver disease (MAFLD) as hepatic steatosis together with overweight, diabetes, and/or a combination of other metabolic risk factors. The clinical relevance of this novel diagnosis is unknown among patients with chronic hepatitis B (CHB). We studied the association between MAFLD (with or without steatohepatitis) and adverse clinical outcomes in patients with CHB. Methods: We performed a retrospective long-term follow-up cohort study at 2 tertiary hospitals in patients with CHB who underwent liver biopsy. Biopsies were reassessed for steatosis, degree of fibrosis, and presence of steatohepatitis. Associations with event-free hepatocellular carcinoma (HCC)-free and transplant-free survival were explored. Results: In our cohort, 1076 patients were included, median follow-up was 9.8 years (25th–75th percentile: 6.6−14.0), and 107 events occurred in 78 patients, comprising death (n = 43), HCC (n = 36), liver decompensation (n = 21), and/or liver transplantation (n = 7). MAFLD was present in 296 (27.5%) patients and was associated with reduced event-free (adjusted hazard ratio [aHR] 2.00, 95% CI 1.26–3.19), HCC-free (aHR 1.93, 95% CI 1.17–3.21), and transplant-free survival (aHR 1.80, 95% CI 0.98–3.29) in multivariable analysis. Among patients with MAFLD, the presence of steatohepatitis (p = 0.95, log-rank test) was not associated with adverse outcomes. Conclusions: The presence of MAFLD in patients with CHB was associated with an increased risk for liver-related clinical events and death. Among patients with MAFLD, steatohepatitis did not increase the risk of adverse outcomes. Our findings highlight the importance of metabolic dysfunction in patients with CHB. Lay summary: Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) has been defined as fatty liver disease with signs of metabolic dysfunction. Among patients with chronic hepatitis B, MAFLD was associated with liver-related events and death. Metabolic health assessment should be encouraged among patients with chronic hepatitis B, especially in those with fatty liver disease.

An organization’s success depends on its employees, and an employee’s performance decides whether the organization is successful. Employee performance enhances the productivity and output of organizations, i.e., the performance of an employee paves the way for the organization’s success. Hence, analyzing employee performance and giving performance ratings to employees is essential for companies nowadays. It is evident that different people have different skill sets and behavior, so data should be gathered from all parts of an employee’s life. This paper aims to provide the performance rating of an employee based on various factors. First, we compare various AI-based algorithms, such as random forest, artificial neural network, decision tree, and XGBoost. Then, we propose an ensemble approach, RanKer, combining all the above approaches. The empirical results illustrate that the efficacy of the proposed model compared to traditional models such as random forest, artificial neural network, decision tree, and XGBoost is high in terms of precision, recall, F1-score, and accuracy.

Background: The global COVID-19 pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted the need for rapid, accurate, and accessible diagnostics to enable timely treatment and outbreak control. However, current diagnostic tests based on RT-qPCR are insufficient to meet the global testing demand because of their high cost and complexity and supply chain shortages. Reverse transcription loop-mediated isothermal amplification (RT-LAMP) is a promising alternative to RT-qPCR because of its sensitivity, speed, and robustness to sample inhibitors. Here, we describe the development and optimisation of a sample-to-answer workflow, including a simple lysis and inactivation protocol that provides results in

Despite the promising result with FLT3 inhibitors in AML, the emergence of resistance poses a significant challenge, leading to a shorter response duration and inferior survival. This is frequently driven by on-target or parallel prosurvival mutations. The emergence of BCR–ABL1 as a mechanism of possible clonal evolution in relapsed AML has rarely been reported. Here we report our experience with three patients who had emergent BCR–ABL1 fusion at relapse after FLT3 inhibitors–based therapies. The first patient was refractory to multiple lines of therapies, including FLT3 inhibitors–based therapy. Patients 2 and 3 showed some response to combined FLT3-inhibitor and BCR–ABL targeted therapy (gilteritinib and ponatinib). The availability of effective targeted therapies for BCR–ABL1 makes this an important aberration to proactively identify and possibly target at relapse post–FLT3-inhibitor therapies.

The prognostics implications of patients with acute myeloid leukemia harboring non-canonical FLT3 is unknown. The use of tyrosine kinase inhibitors in this patient population has not been previously reported. We report successful targeted therapy against non-ITD, non-D835 driver FLT3 alterations in two patient case studies with acute myeloid leukemia.

Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.

Summary: The diagnostic assessment of liver injury is an important step in the management of patients with chronic liver disease (CLD). Although liver biopsy is the reference standard for the assessment of necroinflammation and fibrosis, the inherent limitations of an invasive procedure, and need for repeat sampling, have led to the development of several non-invasive tests (NITs) as alternatives to liver biopsy. Such non-invasive approaches mostly include biological (serum biomarker algorithms) or physical (imaging assessment of tissue stiffness) assessments. However, currently available NITs have several limitations, such as variability, inadequate accuracy and risk factors for error, while the development of a newer generation of biomarkers for fibrosis may be limited by the sampling error inherent to the reference standard. Many of the current NITs were initially developed to diagnose significant fibrosis in chronic hepatitis C, subsequently refined for the diagnosis of advanced fibrosis in patients with non-alcoholic fatty liver disease, and further adapted for prognostication in CLD. An important consideration is that despite their increased use in clinical practice, these NITs were not designed to reflect the dynamic process of fibrogenesis, differentiate between adjacent disease stages, diagnose non-alcoholic steatohepatitis, or follow longitudinal changes in fibrosis or disease activity caused by natural history or therapeutic intervention. Understanding the strengths and limitations of these NITs will allow for more judicious interpretation in the clinical context, where NITs should be viewed as complementary to, rather than as a replacement for, liver biopsy. Keywords: Liver biopsy, Biomarkers, Elastography, Viral hepatitis, Non-alcoholic fatty liver disease

The severity of hepatic fibrosis is the primary predictor of liver‐related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD). Unfortunately, noninvasive serum biomarkers for NAFLD‐associated fibrosis are limited. We analyzed baseline serum samples for 24 cytokines of 97 patients with biopsy‐proven NAFLD. These patients were prospectively enrolled in a clinical study (ClinicalTrials.gov NCT00794716) to identify cytokines associated with liver fibrosis in patients with nonalcoholic steatohepatitis. Patients were stratified according to severity of hepatic fibrosis (mild, stage 0‐1, n = 37; moderate, stage 2, n = 40; and advanced, stage 3‐4, n = 20) while controlling for age, race, sex, body mass index, and diabetes mellitus. Interleukin‐8 (IL‐8), osteopontin (OPN), and monocyte chemoattractant protein 1 (MCP1) were associated with liver fibrosis (P

Mixed phenotype acute leukemia (MPAL) is a rare leukemia that presents both myeloid and lymphoid markers on blasts. Here the authors perform genomic analysis to show MPAL involves genetic and epigenetic heterogeneity and is genetically distinct from AML, B-ALL, and T-ALL.

Abstract: Recent studies have revealed that clonal hematopoiesis of indeterminate potential (CHIP) is an important risk factor for therapy-related myeloid neoplasms (t-MNs). CHIP is currently defined as a clonal hematopoietic population carrying somatic point mutations in 1 of the leukemia-associated genes. Patients with t-MNs often present with chromosomal abnormalities in addition to somatic point mutations. It remains unclear whether chromosomal abnormalities can cooccur with point mutations as part of CHIP. Here we report that 3 of 14 patients with t-MNs had low amplitude but detectable chromosome arm-level copy number alterations (CNAs) in the peripheral blood samples that were taken at the time of their primary cancer diagnosis and before exposure to therapy. These CNAs were the same CNAs seen in t-MN bone marrow samples and affected the same allele, suggesting the same clonal origin. These data suggest that not only somatic point mutations but also chromosome arm-level CNAs are detectable as CHIP and preexist before patients' exposure to chemotherapy and/or radiation therapy. These data suggest that screening of both somatic point mutations and CNAs might allow more complete ascertainment of CHIP.

Abstract Treatment of cancer patients involves a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Traditionally, patients with metastatic disease are treated with combination chemotherapies or targeted agents. These cytotoxic agents have good response rates and achieve palliation; however, complete responses are rarely seen. The field of cancer immunology has made rapid advances in the past 20 years. Recently, a number of agents and vaccines, which modulate the immune system to allow it to detect and target cancer cells, are being developed. The benefit of these agents is twofold, it enhances the ability the body’s own immune system to fight cancer, thus has a lower incidence of side effects compared to conventional cytotoxic chemotherapy. Secondly, a small but substantial number of patients with metastatic disease are cured by immunotherapy or achieve durable responses lasting for a number of years. In this article, we review the FDA-approved immunotherapy agents in the field of genitourinary malignancies. We also summarize new immunotherapy agents being evaluated in clinical studies either as single agents or as a combination.

Background Food deserts (FDs), defined as low‐income communities with limited access to healthy food, are a growing public health concern. We evaluated the impact of living in FDs on incident cardiovascular events. Methods and Results We recruited 4944 subjects (age 64±12, 64% male) undergoing cardiac catheterization into the Emory Cardiovascular Biobank. Using the US Department of Agriculture definition of FD, we determined whether their residential addresses had (1) poor access to healthy food, (2) low income, or (3) both (=FD). Subjects were prospectively followed for a median of 3.2 years for myocardial infarction (MI) and death. Fine and Gray's subdistribution hazard models for MI and Cox proportional hazard models for death/MI were used to examine the association between area characteristics (FD, poor access, and low income) and the rates of adverse events after adjusting for traditional risk factors. A total of 981 (20%) lived in FDs and had a higher adjusted risk of MI (subdistribution hazard ratio, 1.44 [95% CI, 1.06–1.95]) than those living in non‐FDs. In a multivariate analysis including both food access and area income, only living in a low‐income area was associated with a higher adjusted risk of MI (subdistribution hazard ratio, 1.40 [1.06–1.85]) and death/MI (hazard ratio, 1.18 [1.02–1.35]) while living in a poor‐access area was not significantly associated with either (subdistribution hazard ratio, 1.05 [0.80–1.38] and hazard ratio, 0.99 [0.87–1.14], respectively). Conclusions Living in an FD is associated with a higher risk of adverse cardiovascular events in those with coronary artery disease. Specifically, low area income of FDs, not poor access to food, was significantly associated with worse outcomes.

Non-cirrhotic portal hypertension (NCPH) comprises a heterogeneous group of liver disorders causing portal hypertension without cirrhosis and carries a high risk of variceal bleeding. Recent guidelines, based largely on patients with viral cirrhosis, suggest low likelihood of high risk varices (HRV) in patients with a liver stiffness measurement (LSM) 150 × 109/L. In NCPH, LSM is often higher than healthy controls but lower than matched cirrhotic patients. The aim of this study was to assess whether LSM or other noninvasive assessments of portal hypertension could predict HRV in NCPH patients. Methods. Records of patients with NCPH seen at a single centre between 2007 and 2018 were reviewed retrospectively. Primary outcome measure was presence or absence of HRV at gastroscopy within 12 months of clinical assessment. Association of LSM or other clinical features of portal hypertension (spleen size, platelet count, platelet count/spleen length ratio (PSL), LSM-spleen length/platelet count ratio score (LSP)) with HRV and ability of these variables to predict HRV was analysed. Results. Of 44 patients with NCPH who met inclusion criteria, 34% (15/44) had HRV. In a multivariate model, spleen size and PSL correlated with HRV but platelet count, LSM, and LSP did not (spleen size: β = 0.35, p = 0.02; OR 1.42, 95% CI 1.06-1.92; PSL: β = -1.47, p = 0.02; OR 0.23, 95% CI 0.07-0.80). There was no significant difference between spleen size and PSL in predicting HRV (AUROC 0.81 (95% CI 0.66 – 0.91) versus 0.71 (95% CI 0.54 – 0.84), respectively, p = 0.400). Spleen size >17.2cm had sensitivity 78.6% and specificity 64.3% for prediction of HRV. Conclusions. In NCPH patients, spleen size may predict risk of HRV at gastroscopy within 12 months. LSM and platelet count are not useful to assess risk of HRV in NCPH.

BackgroundThe associations between high‐sensitivity troponin I (hsTnI) levels and coronary artery disease (CAD) severity and progression remain unclear. We investigated whether there is an association between hsTnI and angiographic severity and progression of CAD and whether the predictive value of hsTnI level for incident cardiovascular outcomes is independent of CAD severity. Methods and ResultsIn 3087 patients (aged 63±12 years, 64% men) undergoing cardiac catheterization without evidence of acute myocardial infarction, the severity of CAD was calculated by the number of major coronary arteries with ≥50% stenosis and the Gensini score. CAD progression was assessed in a subset of 717 patients who had undergone ≥2 coronary angiograms >3 months before enrollment. Patients were followed up for incident all‐cause mortality and incident cardiovascular events. Of the total population, 11% had normal angiograms, 23% had nonobstructive CAD, 20% had 1‐vessel CAD, 20% had 2‐vessel CAD, and 26% had 3‐vessel CAD. After adjusting for age, sex, race, body mass index, smoking, hypertension, diabetes mellitus history, and renal function, hsTnI levels were independently associated with the severity of CAD measured by the Gensini score (log 2 ß=0.31; 95% confidence interval, 0.18–0.44; P

BackgroundBeing unmarried is associated with decreased survival in the general population. Whether married, divorced, separated, widowed, or never‐married status affects outcomes in patients with cardiovascular disease has not been well characterized. Methods and ResultsA prospective cohort (inception period 2003–2015) of 6051 patients (mean age 63 years, 64% male, 23% black) undergoing cardiac catheterization for suspected or confirmed coronary artery disease was followed for a median of 3.7 years (interquartile range: 1.7–6.7 years). Marital status was stratified as married (n=4088) versus unmarried (n=1963), which included those who were never married (n=451), divorced or separated (n=842), or widowed (n=670). The relationship between marital status and primary outcome of cardiovascular death and myocardial infarction was examined using Cox regression models adjusted for clinical characteristics. There were 1085 (18%) deaths from all causes, 688 (11%) cardiovascular‐related deaths, and 272 (4.5%) incident myocardial infarction events. Compared with married participants, being unmarried was associated with higher risk of all‐cause mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI], 1.06–1.47), cardiovascular death (HR: 1.45; 95% CI, 1.18–1.78), and cardiovascular death or myocardial infarction (HR: 1.52; 95% CI, 1.27–1.83). Compared with married participants, the increase in cardiovascular death or myocardial infarction was similar for the participants who were divorced or separated (HR: 1.41; 95% CI, 1.10–1.81), widowed (HR: 1.71; 95% CI, 1.32–2.20), or never married (HR: 1.40; 95% CI, 0.97–2.03). The findings persisted after adjustment for medications and other socioeconomic factors. ConclusionsMarital status is independently associated with cardiovascular outcomes in patients with or at high risk of cardiovascular disease, with higher mortality in the unmarried population. The mechanisms responsible for this increased risk require further study.

Vosaroxin is an anti-cancer quinolone-derived DNA topoisomerase II inhibitor. We investigated vosaroxin with decitabine in patients ≥60 years of age with newly diagnosed acute myeloid leukemia (n=58) or myelodysplastic syndrome (≥10% blasts) (n=7) in a phase II non-randomized trial. The initial 22 patients received vosaroxin 90 mg/m2 on days 1 and 4 with decitabine 20 mg/m2 on days 1–5 every 4–6 weeks for up to seven cycles. Due to a high incidence of mucositis the subsequent 43 patients were given vosaroxin 70 mg/m2 on days 1 and 4. These 65 patients, with a median age of 69 years (range, 60–78), some of whom with secondary leukemia (22%), adverse karyotype (35%), or TP53 mutation (20%), are evaluable. The overall response rate was 74% including complete remission in 31 (48%), complete remission with incomplete platelet recovery in 11 (17%), and complete remission with incomplete count recovery in six (9%). The median number of cycles to response was one (range, 1–4). Grade 3/4 mucositis was noted in 17% of all patients. The 70 mg/m2 induction dose of vosaroxin was associated with similar rates of overall response (74% versus 73%) and complete remission (51% versus 41%, P=0.44), reduced incidence of mucositis (30% versus 59%, P=0.02), reduced 8-week mortality (9% versus 23%; P=0.14), and improved median overall survival (14.6 months versus 5.5 months, P=0.007). Minimal residual disease-negative status by multiparametric flow-cytometry at response (± 3 months) was achieved in 21 of 39 (54%) evaluable responders and was associated with better median overall survival (34.0 months versus 8.3 months, P=0.023). In conclusion, the combination of vosaroxin with decitabine is effective and well tolerated at a dose of 70 mg/m2 and warrants randomized prospective evaluation. ClinicalTrials.gov: NCT01893320

Our aim was to improve outcome prediction after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia by combining cytogenetic and molecular data at diagnosis with minimal residual disease assessment by multicolor flow-cytometry at transplantation. Patients with acute myeloid leukemia in first complete remission in whom minimal residual disease was assessed at transplantation were included and categorized according to the European LeukemiaNet classification. The primary outcome was 1-year relapse incidence after transplantation. Of 152 patients eligible, 48 had minimal residual disease at the time of their transplant. Minimal residual disease-positive patients were older, required more therapy to achieve first remission, were more likely to have incomplete recovery of blood counts and had more adverse risk features by cytogenetics. Relapse incidence at 1 year was higher in patients with minimal residual disease (32.6% versus 14.4%, P=0.002). Leukemia-free survival (43.6% versus 64%, P=0.007) and overall survival (48.8% versus 66.9%, P=0.008) rates were also inferior in patients with minimal residual disease. In multivariable analysis, minimal residual disease status at transplantation independently predicted 1-year relapse incidence, identifying a subgroup of intermediate-risk patients, according to the European LeukemiaNet classification, with a particularly poor outcome. Assessment of minimal residual disease at transplantation in combination with cytogenetic and molecular findings provides powerful independent prognostic information in acute myeloid leukemia, lending support to the incorporation of minimal residual disease detection to refine risk stratification and develop a more individualized approach during hematopoietic stem cell transplantation.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and encompasses a spectrum from simple steatosis to steatohepatitis (NASH). There is currently no approved pharmacologic therapy against NASH, partly due to an incomplete understanding of its molecular basis. The goal of this study was to determine the key differentially expressed genes (DEGs), as well as those genes and pathways central to its pathogenesis. We performed an integrative computational analysis of publicly available gene expression data in NASH from GEO (GSE17470, GSE24807, GSE37031, GSE89632). The DEGs were identified using GEOquery, and only the genes present in at least three of the studies, to a total of 190 DEGs, were considered for further analyses. The pathways, networks, molecular interactions, functional analyses were generated through the use of Ingenuity Pathway Analysis (IPA). For selected networks, we computed the centrality using igraph package in R. Among the statistically significant predicted networks (p-val < 0.05), three were of most biological interest: the first is involved in antimicrobial response, inflammatory response and immunological disease, the second in cancer, organismal injury and development and the third in metabolic diseases. We discovered that HNF4A is the central gene in the network of NASH connected to metabolic diseases and that it regulates HNF1A, an additional transcription regulator also involved in lipid metabolism. Therefore, we show, for the first time to our knowledge, that HNF4A is central to the pathogenesis of NASH. This adds to previous literature demonstrating that HNF4A regulates the transcription of genes involved in the progression of NAFLD, and that HNF4A genetic variants play a potential role in NASH progression.