A different perspective on sofosbuvir-ledipasvir treatment of patients with HCV genotype 1b cirrhosis: The ital-c network study.

The effectiveness of a 12-week course of sofosbuvir-ledipasvir in treatment-experienced HCV genotype 1b-infected patients with cirrhosis is still under debate. Our primary endpoint was to compare the sustained virological response at post-treatment week 12 (SVR12) of sofosbuvir-ledipasvir in combination with ribavirin for 12 weeks, and sofosbuvir-ledipasvir alone for 24 weeks. This was a prospective observational study that enrolled 424 (195 naive, 229 experienced; 164 treated for 12 weeks with Ribavirin and 260 with sofosbuvir-ledipasvir alone for 24 weeks) consecutive HCV genotype 1b-infected patients with cirrhosis. The SVR12 rates were 93.9% and 99.2% in patients treated for 12 and 24 weeks, respectively (P = .002). The baseline characteristics of patients treated for 12 weeks were significantly different from those treated for 24 weeks as regards their younger age (P = .002), prevalence of Child-Pugh class A (P = .002), lower MELD scores (P = .001) and smaller number of nonresponders (P = .04). The shorter treatment was significantly associated with a lower SVR12 in univariate and multivariate analyses (P = .007 and P = .008, respectively). The SVR rate was unaffected by age, gender, BMI, Child-Pugh class, MELD score or previous antiviral treatment. Patients receiving ribavirin experienced more episodes of ascites and headache but less recurrence of hepatocellular carcinoma (HCC), and were prescribed more diuretics and cardiopulmonary drugs. No patient discontinued treatment. The therapeutic regimen of sofosbuvir-ledipasvir plus ribavirin administered for 12 weeks was less effective than sofosbuvir-ledipasvir alone given for 24 weeks. At odds with European guidelines, the recommended 12-week treatment with sofosbuvir-ledipasvir alone might be suboptimal for this setting of patients.

Multiple rare genetic variants co-segregating with familial IgA nephropathy all act within a single immune-related network.

BACKGROUND: IgA nephropathy (IgAN) is a common complex disease with a strong genetic involvement. We aimed to identify novel, rare, highly penetrant risk variants combining family-based linkage analysis with whole-exome sequencing (WES). METHODS: Linkage analysis of 16 kindreds of South Italian ancestry was performed using an 'affected-only' strategy. Eight most informative trios composed of two familial cases and an intrafamilial control were selected for WES. High-priority variants in linked regions were identified and validated using Sanger sequencing. Custom TaqMan assays were designed and carried out in the 16 kindreds and an independent cohort of 240 IgAN patients and 113 control subjects. RESULTS: We found suggestive linkage signals in 12 loci. After sequential filtering and validation of WES data, we identified 24 private or extremely rare (MAF <0.0003) linked variants segregating with IgAN status. These were present within coding or regulatory regions of 23 genes that merged into a common functional network. The genes were interconnected by AKT, CTNNB1, NFKB, MYC and UBC, key modulators of WNT/ß-catenin and PI3K/Akt pathways, which are implicated in IgAN pathogenesis. Overlaying publicly available expression data, genes/proteins with expression notably altered in IgAN were included in this immune-related network. In particular, the network included the glucocorticoid receptor gene, NR3C1, which is the target of corticosteroid therapy routinely used in the treatment of IgAN. CONCLUSION: Our findings suggest that disease susceptibility could be influenced by multiple rare variants acting in a common network that could provide the starting point for the identification of potential drug targets for personalized therapy.

Patient classification and outcome prediction in IgA nephropathy.

OBJECTIVE: IgA Nephropathy (IgAN) is a common kidney disease which may entail renal failure, known as End Stage Kidney Disease (ESKD). One of the major difficulties dealing with this disease is to predict the time of the long-term prognosis for a patient at the time of diagnosis. In fact, the progression of IgAN to ESKD depends on an intricate interrelationship between clinical and laboratory findings. Therefore, the objective of this work has been the selection of the best data mining tool to build a model able to predict (I) if a patient with a biopsy proven IgAN will reach ESKD and (II) if a patient will reach the ESKD before or after 5 years. MATERIAL AND METHODS: The largest available cohort study worldwide on IgAN has been used to design and compare several data-driven models. The complete dataset was composed of 1174 records collected from Italian, Norwegian, and Japanese IgAN patients, in the last 30 years. The data mining tools considered in this work were artificial neural networks (ANNs), neuro fuzzy systems (NFSs), support vector machines (SVMs), and decision trees (DTs). A 10-fold cross validation was used to evaluate unbiased performances for all the models. RESULTS: An extensive model comparison based on accuracy, precision, recall, and f-measure was provided. Overall, the results indicate that ANNs can provide superior performance compared to the other models. The ANN for time-to-ESKD prediction is characterized by accuracy, precision, recall, and f-measure greater than 90%. The ANN for ESKD prediction has accuracy greater than 90% as well as precision, recall, and f-measure for the class of patients not reaching ESKD, while precision, recall, and f-measure for the class of patients reaching ESKD are slightly lower. The obtained model has been implemented in a Web-based decision support system (DSS). CONCLUSIONS: The extraction of novel knowledge from clinical data and the definition of predictive models to support diagnosis, prognosis, and therapy is becoming an essential tool for researchers and clinical practitioners in medicine. The proposed comparative study of several data mining models for the outcome prediction in IgAN patients, using a large dataset of clinical records from three different countries, provides an insight into the relative prediction ability of the considered methods applied to such a disease.

Transient neonatal hyperinsulinemic hypoglycemia and neurological outcome: a case report.

Transient neonatal hyperinsulinemic hypoglycemia (TNHI) is a form of neonatal-onset hyperinsulinism which usually resolves completely in a few days or months. It is secondary to conditions such as maternal diabetes mellitus or intra-uterine growth retardation. Other rare causes of TNHI are perinatal asphyxia and gestational diabetes. Hyperinsulinemic hypoglycemia (HI) is also observed in association with rare metabolic or genetic conditions. It can also occur in newborns without risk factors. TNHI is usually a transient phenomenon. However, some newborns can have prolonged HI that requires treatment with diazoxide, persists for several months and then resolves spontaneously. Neonatal hyperinsulinemic hypoglycemia must be promptly and correctly diagnosed and treated in order to avoid neurological consequences. We describe a case of transient neonatal hyperinsulinemic hypoglycemia in a full-term born without perinatal complications and appropriate for gestational age with an unfavourable neurological outcome.

Inflammatory bowel disease in children and adolescents in Italy: data from the pediatric national IBD register (1996-2003).

BACKGROUND: The purpose was to assess in Italy the clinical features at diagnosis of inflammatory bowel disease (IBD) in children. METHODS: In 1996 an IBD register of disease onset was established on a national scale. RESULTS: Up to the end of 2003, 1576 cases of pediatric IBD were recorded: 810 (52%) ulcerative colitis (UC), 635 (40%) Crohn's disease (CD), and 131 (8%) indeterminate colitis (IC). In the period 1996-2003 an increase of IBD incidence from 0.89 to 1.39/10(5) inhabitants aged <18 years was observed. IBD was more frequent among children aged between 6 and 12 years (57%) but 20% of patients had onset of the disease under 6 years of age; 28 patients were <1 year of age. Overall, 11% had 1 or more family members with IBD. The mean interval between onset of symptoms and diagnosis was higher in CD (10.1 months) and IC (9 months) versus UC (5.8 months). Extended colitis was the most frequent form in UC and ileocolic involvement the most frequent in CD. Upper intestinal tract involvement was present in 11% of CD patients. IC locations were similar to those of UC. Bloody diarrhea and abdominal pain were the most frequent symptoms in UC and IC, and abdominal pain and diarrhea in CD. Extraintestinal symptoms were more frequent in CD than in UC. CONCLUSIONS: The IBD incidence in children and adolescents in Italy shows an increasing trend for all 3 pathologies. UC diagnoses exceeded CD.

Impact of the endorectal ultrasound probe on uroflow parameters in males.

OBJECTIVES: The aim of this study was to test the null hypothesis that the presence in the rectum of an endorectal ultrasound probe during transrectal voiding ultrasonography (TRVUS) would have no significant effect on uroflowmetry parameters. PATIENTS AND METHODS: We studied 43 randomly selected men undergoing TRVUS of the prostate for non-neurogenic lower urinary tract symptoms. Uroflowmetry was performed immediately before and during the TRVUS. Results were compared with a paired Student's t test; the null hypothesis was confirmed by p values >0.05. RESULTS: Forty patients were able to void with the endorectal probe inserted, and 95% described this micturition as representative of their usual voiding behavior. No significant statistical difference was found between uroflowmetry parameters before and during TRVUS, confirming our null hypothesis. CONCLUSION: Our data suggest that uroflowmetry in combination with TRVUS can be a reliable tool for evaluating disorders of micturition in males, at least in selected cases.

Association of peripheral multifocal choroiditis with sarcoidosis: a study of thirty-seven patients.

OBJECTIVE: To assess the clinical spectrum of peripheral multifocal choroiditis (PMC) and its association with sarcoidosis. METHODS: Thirty-seven patients examined between November 1997 and November 2001 who met all diagnostic criteria for PMC were included in this retrospective study. Patients were assessed for the following signs of sarcoidosis: typical changes on chest radiography or computed tomography; predominantly CD4 lymphocytosis in bronchoalveolar lavage fluid; elevated serum angiotensin-converting enzyme levels; elevated gallium uptake; and noncaseating granuloma on biopsy. RESULTS: Most of the patients were female (30 of 37; 81%) and white (30 of 37; 81%). Mean +/- SD age at onset was 57.5 +/- 18.7 years. Seven (19%) of the 37 patients had biopsy-proven sarcoidosis and 18 patients (49%) with presumed sarcoidosis met at least 2 of the above-mentioned criteria for sarcoidosis but had normal biopsy results. Twelve patients (32%) had an indeterminate diagnosis. Patients with presumed sarcoidosis did not differ from those with proven sarcoidosis as regards the above-mentioned criteria, except for noncaseating granuloma, implying that more than two-thirds of patients (predominantly whites) had underlying sarcoidosis. Most patients with positive gallium scintigraphy had increased mediastinal uptake, as described in sarcoidosis. Patients with underlying sarcoidosis had more severe visual impairment due to cystoid macular edema (CME). Weekly methotrexate (0.3 mg/kg) seemed to control CME. CONCLUSION: White patients with PMC should be considered to have sarcoidosis. The identification of sarcoidosis in patients with severe ocular disease can help with therapeutic choices.

Prevalence of urinary incontinence among institutionalized patients: a cross-sectional epidemiologic study in a midsized city in northern Italy.

OBJECTIVES: To determine the prevalence of urinary incontinence among institutionalized elderly people. METHODS: A cross-sectional study was conducted on 839 subjects, resident in 14 residential or nursing homes. A questionnaire was administered to the study population and their clinical records were reviewed. RESULTS: The overall prevalence of urinary incontinence was 54.5%, higher in women (59.8%) than in men (39.2%). The prevalence increased significantly with age, from 26.5% in subjects 65 years old or younger to 73.7% in subjects 95 years old or older; with worsening of mental status, from 36.2% in well-oriented subjects to 76.7% in poorly oriented subjects; and with worsening of mobility, from 23.8% in self-sufficient subjects to 82.1% in bedridden patients. The prevalence was significantly associated with parity, from 54.1% in nulliparous women to 65.4% in multiparous women. Urinary incontinence was also associated with urinary tract infection, constipation, and fecal incontinence. CONCLUSIONS: The results of our study are in accordance with other similar studies. That more than one half of the elderly residents of nursing and residential homes have urinary incontinence shows the relevance of this condition. We believe that urinary incontinence in institutionalized elderly people can be managed essentially by measures of tertiary prevention, aimed at reducing the handicapping conditions and at slowing down the process of self-sufficiency impairment.

Pancreatitis caused by duodenal duplication.

The authors present the investigations and surgical treatment of two cases of duodenal cystic duplication. Abdominal pain and gastroesophageal reflux were the most important symptoms and signs associated with an history of recurrent acute pancreatitis. Computed tomography scan, ultrasound examination, and cholangiography confirmed preoperatively the diagnosis, and a transduodenal surgical approach was carried out in both children. A simple marsupialization of the cyst was performed in the former, and a sphincterotomy with papillosphincteroplasty was associated in the latter. The diagnosis was confirmed by microscopy, and both the children are asymptomatic after a 14 and 18 months of follow-up. This report focuses on the importance of the cholangiopancreatography for every child presenting with recurrent, unexplained bouts of acute pancreatitis, and underlines the technical surgical aspects on the basis of the anatomic identification of the malformation.

Pancreatitis caused by duodenal duplication.

Two cases of recurrent pancreatitis, due to duodenal duplication, are reported. The aim of this paper is to emphasise the role of endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) in the detection of associated pancreaticobiliary anomalies and in the planning of the correct surgical approach. The order of imaging in a child with recurrent pancreatitis should be US, barium meal and PTC. ERCP is often difficult to perform in children.

Voiding dysfunction in patients with spinal cord lesions at the thoracolumbar vertebral junction.

Neurogenic voiding dysfunction invariably follows a complete spinal cord lesion. With spinal shock urodynamic investigation will show an areflexic bladder if the sacral spinal cord has been damaged, otherwise, if the lesion involves the suprasacral cord, an overactive bladder will result. There are some exceptions to this rule, particularly in those with lesions of the thoracolumbar vertebral junction, where the sacral cord is located, it may be difficult to predict urodynamic dysfunction merely on the basis of the vertebral body involved. 46 patients with a complete SCI neurological lesion at the thoraco-lumbar vertebral junction underwent a neurourological evaluation including multi-channel urodynamic studies. Overall in 20 to 36% of the patients the urodynamic pattern was different from what one would have expected considering the anatomical level of the vertebral body involved. Urodynamic study is confirmed as an essential tool in the correct diagnostic and therapeutic approach to the voiding dysfunction in these type of patients.

Endoscopic ballistic lithotripsy in the treatment of bladder calculi in patients with neurogenic voiding dysfunction.

Bladder stones represent a troublesome complication in patients suffering from neurogenic voiding dysfunction, in whom prompt and effective therapy is required. A variety of endoscopic lithotripsy methods are available; however, current devices can be tedious to use. We have treated 17 patients affected by bladder calculi and spinal cord injury or multiple sclerosis by means of the ballistic lithotripter EMS Swiss Lithoclast. The mean diameter of the stones was 2.7 cm. The mean operative time was 27 minutes. There were five intraoperative complications, including crises of autonomic dysreflexia (three patients) and light hematuria (two patients). There was no malfunction of the lithotripter and no long-term complications. All the patients were stone free at 6 months postoperatively. In conclusion, endoscopic lithotripsy with the ballistic lithotripter proved to be a very effective, rapid, and safe method for treating bladder calculi in patients with neurogenic bladders.

Continuous (6 hour) urodynamic monitoring in children with neuropathic bladder.

In adults the development of modern equipment for ambulatory monitoring permits long-term evaluation of the lower urinary tract which is more accurate than standard urodynamics (SUD). In children continuous urodynamic monitoring (CUM) has been used infrequently and therefore standardisation of the method has not been previously achieved, nor have the techniques and difficulties of performing 24-hour monitoring been solved. The aim of this study was to identify a technical method of CUM in children which was feasible and to verify its usefulness. For this purpose, we reviewed our preliminary experiences of CUM in children with neuropathic bladder. From March to November 1995 we made an outpatient study of the neuropathic bladders of 11 myelodysplastic children aged 1 to 18 years (average age 10.2 years). 7 of them were males and 4 females. All underwent SUD. With the children resting in bed, a 6-hour CUM (Lectromed MPR-2) was performed using a 4 Fr. microtip intravesical catheter (suprapubic in 3 infants and transurethral in 8 children) and an intrarectal catheter. The parents and/or a nurse monitored the fluid intake and micturition events and recorded the data in a diary. Based on the CUM experience in infants with non-neurogenic bladder dysfunction, the 3 suprapubic studies were done after 12 hours of urethral drainage in order to prevent leakage of urine. In all of the patients we were able to study 2 to 4 bladder fillings during a period of 6 to 8 hours (average 6.5 hours) observation. In 9 of the 11 children the CUM pattern was comparable to the SUD one but in the 2 remaining patients CUM showed uninhibited contractions. Higher uninhibited voiding contraction pressures were recorded in hyper-reflexic bladders. Our preliminary results show that it is feasible to perform CUM in children and that it has advantages over standard cystometry in the investigation of children with neuropathic bladder even if it is carried out for short term (6 hours).

Intraepithelial gamma/delta-positive T lymphocytes and intestinal villous atrophy.

We have evaluated the expression of different molecular forms of T cell antigen receptor (TcR) in duodenal biopsies of pediatric patients with different forms of villous atrophy: celiac disease, autoimmune enteropathy, intractable diarrhea of unknown origin, and severe cow milk intolerance. A panel of monoclonal antibodies recognizing alpha/beta and gamma/delta TcR (and gamma/delta TcR subsets) was used for immunostaining. The results showed an increase of T cells with gamma/delta-type TcR in celiac patients and also in patients with other forms of villous atrophy with respect to normal controls. Amongst the gamma/delta TcR-positive cells, the subset expressing the molecular product of V delta 1 region was the most represented. The gamma/delta TcR-positive T cells were mainly located within the epithelium: few of them were observed in the lamina propria. On the basis of these results, we hypothesize that the increased homing of gamma/delta TcR-positive T lymphocytes in gut epithelium observed in celiac disease is, at least in part, related to villous atrophy per se.

Reliability of short-term esophageal pH monitoring versus 24-hour study.

The child's discomfort and the cost of overnight hospitalization are clear disadvantages of prolonged esophageal pH monitoring. The aim of this study was to verify the reliability of short recording versus 24-h testing in a pediatric series with symptoms suggestive of gastroesophageal reflux (GER) disease. A 24-h pH monitoring performed on 160 patients with either gastroenterological symptoms (n = 61), respiratory problems (n = 58), or emesis plus respiratory problems (n = 41) was reviewed. Regardless of clinical presentation, children were also classified according to age: < 12 months (n = 39), 12-71 months (n = 81), and 72-168 months (n = 40). A diurnal fraction of 6 h, including at least 2 h after a meal, was compared to the entire 24-h recording in all groups with respect to the reflux index (RI) (sum of the periods with pH < 3.9 expressed as percentage of time) and reflux/h. RIs of > 10% were considered positive in patients < 1 year of age, whereas RIs of > 5% were considered positive in other age groups. Negative predictive values of the short recording RI ranged from 71 to 90%. Positive predictive values ranged from 50 to 83%; it was unreliable for children < 12 mos (50%) and patients with emesis plus respiratory problems (64%), who were, significantly, the youngest. Reflux/h values were not in agreement for the same groups. Absence of agreement was found if the absolute value of RI was considered.(ABSTRACT TRUNCATED AT 250 WORDS)