Correction to: PANLAR consensus statement on biosimilars.

The two co-authors of the mentioned above article were incorrect. The correct are authors should have been "P. A. Beltrán" instead of "P. A. B. Roa" and "J. F. Diaz-Coto" instead of "L. Diaz Soto".

PANLAR consensus statement on biosimilars.

INTRODUCTION: Biologics have improved the treatment of rheumatic diseases, resulting in better outcomes. However, their high cost limits access for many patients in both North America and Latin America. Following patent expiration for biologicals, the availability of biosimilars, which typically are less expensive due to lower development costs, provides additional treatment options for patients with rheumatic diseases. The availability of biosimilars in North American and Latin American countries is evolving, with differing regulations and clinical indications. OBJECTIVE: The objective of the study was to present the consensus statement on biosimilars in rheumatology developed by Pan American League of Associations for Rheumatology (PANLAR). METHODS: Using a modified Delphi process approach, the following topics were addressed: regulation, efficacy and safety, extrapolation of indications, interchangeability, automatic substitution, pharmacovigilance, risk management, naming, traceability, registries, economic aspects, and biomimics. Consensus was achieved when there was agreement among 80% or more of the panel members. Three Delphi rounds were conducted to reach consensus. Questionnaires were sent electronically to panel members and comments about each question were solicited. RESULTS: Eight recommendations were formulated regarding regulation, pharmacovigilance, risk management, naming, traceability, registries, economic aspects, and biomimics. CONCLUSION: The recommendations highlighted that, after receiving regulatory approval, pharmacovigilance is a fundamental strategy to ensure safety of all medications. Registries should be employed to monitor use of biosimilars and to identify potential adverse effects. The price of biosimilars should be significantly lower than that of reference products to enhance patient access. Biomimics are not biosimilars and, if they are to be marketed, they must first be evaluated and approved according to established regulatory pathways for novel biopharmaceuticals. KEY POINTS: • Biologics have improved the treatment of rheumatic diseases. • Their high cost limits access for many patients in both North America and Latin America. • Biosimilars typically are less expensive, providing additional treatment options for patients with rheumatic diseases. • PANLAR presents its consensus on biosimilars in rheumatology.

Computing of temporal information in spiking neural networks with ReRAM synapses.

Resistive switching random-access memory (ReRAM) is a two-terminal device based on ion migration to induce resistance switching between a high resistance state (HRS) and a low resistance state (LRS). ReRAM is considered one of the most promising technologies for artificial synapses in brain-inspired neuromorphic computing systems. However, there is still a lack of general understanding about how to develop such a gestalt system to imitate and compete with the brain's functionality and efficiency. Spiking neural networks (SNNs) are well suited to describe the complex spatiotemporal processing inside the brain, where the energy efficiency of computation mostly relies on the spike carrying information about both space (which neuron fires) and time (when a neuron fires). This work addresses the methodology and implementation of a neuromorphic SNN system to compute the temporal information among neural spikes using ReRAM synapses capable of spike-timing dependent plasticity (STDP). The learning and recognition of spatiotemporal spike sequences are experimentally demonstrated. Our simulation study shows that it is possible to construct a multi-layer spatiotemporal computing network. Spatiotemporal computing also enables learning and detection of the trace of moving objects and mimicking of the hierarchy structure of the biological visual cortex adopting temporal-coding for fast recognition.

Publisher Correction: Memristive neural network for on-line learning and tracking with brain-inspired spike timing dependent plasticity.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Memristive neural network for on-line learning and tracking with brain-inspired spike timing dependent plasticity.

Brain-inspired computation can revolutionize information technology by introducing machines capable of recognizing patterns (images, speech, video) and interacting with the external world in a cognitive, humanlike way. Achieving this goal requires first to gain a detailed understanding of the brain operation, and second to identify a scalable microelectronic technology capable of reproducing some of the inherent functions of the human brain, such as the high synaptic connectivity (~104) and the peculiar time-dependent synaptic plasticity. Here we demonstrate unsupervised learning and tracking in a spiking neural network with memristive synapses, where synaptic weights are updated via brain-inspired spike timing dependent plasticity (STDP). The synaptic conductance is updated by the local time-dependent superposition of pre- and post-synaptic spikes within a hybrid one-transistor/one-resistor (1T1R) memristive synapse. Only 2 synaptic states, namely the low resistance state (LRS) and the high resistance state (HRS), are sufficient to learn and recognize patterns. Unsupervised learning of a static pattern and tracking of a dynamic pattern of up to 4 × 4 pixels are demonstrated, paving the way for intelligent hardware technology with up-scaled memristive neural networks.

[Laparoscopic incisional hernia repair as first therapeutic choice]. / L'approccio laparoscopico nella riparazione del laparocele quale prima scelta terapeutica.

AIM: Incisional hernias are one of the most frequent complications of open abdominal surgery. Historically, the best results have been obtained with the open rives-stoppa approach. This is done by fixing a large piece of prosthetic mesh behind the rectus muscle. Laparoscopic approach allows similar mesh placement with minimal dissection and lower recurrence rate compared to the open mesh repair. METHODS: Between October 2001 to September 2003, 75 consecutive patients were scheduled to undergo laparoscopic incisional hernia repair with ePTFE mesh (Gore-Tex Dualmesh Plus). Postoperative complications were recorded and analysed. RESULTS: Most were obese affected by multiple wall defects Conversion to open surgery was required in 1 case Postoperative complications occurred 13.3%. Recurrence occurred in one only case. CONCLUSIONS: The key to the success of this procedure is avoidance of complications. The laparoscopic approach is safe, effective and relatively complication-free option in the management of patients presenting with a first time or recurrent incisional hernia and recommended as the treatment of choice.

[Surgical treatment of carcinoma of the left colon and rectum as an emergency. A new method for assessing operative risk]. / Trattamento chirurgico del carcinoma del colon sinistro e del retto in emergenza. Un nuovo metodo per la valutazione del rischio operatorio.

BACKGROUND/AIMS: The surgical treatment of the left colon and rectal cancer emergencies is still controversial. In our opinion the choices to be based on the general health status of the patient. METHODOLOGY: The authors analysed a series of 63 patients submitted to immediate resection and anastomosis. RESULTS: Factors significantly related to short term results were chronic heart disease, low albumin serum levels, and colonic perforation. The presence of a diverting colostomy did not provide a protective factor against anastomotic dehiscence. We constructed a Colorectal Tumours Emergencies Score made of the identified four factors in which the score of each factor is the approximated odds ratio (chronic renal failure 7 points, low albumin serum levels 6 points, heart disease 5 points, colon perforation 4 points). Each patient was classified as Low Risk (CTES < 4), Moderate Risk (CTES 4-12), High Risk (CTES > 12), mortality and morbidity being 4% and 20%, 19.3% and 61.3%, 88.9% and 88.9% respectively. CONCLUSIONS: High risk patients may undergo a staged procedure. Moderate risk patients may be treated by immediate resection of the tumor, without anastomosis. Immediate resection and anastomosis may be reserved to low risk patients.

Transjugular intrahepatic portosystemic shunt versus endoscopic sclerotherapy for the prevention of variceal bleeding in cirrhosis: a randomized multicenter trial. Gruppo Italiano Studio TIPS (G.I.S.T.).

Transjugular intrahepatic portosystemic shunt (TIPS), a new technique for the treatment of portal hypertension, has been successful in preliminary studies to treat acute variceal hemorrhage and to prevent variceal rebleeding. The purpose of this multicenter, randomized controlled trial is to compare the efficacy of TIPS with that of endoscopic sclerotherapy in the prevention of variceal rebleeding in cirrhosis. Eighty-one cirrhotic patients, with endoscopically proven variceal bleeding, were randomized to either TIPS (38 patients) or endoscopic sclerotherapy (43 patients). Randomization was stratified according to the following: if bleeding occurred < 1 week (stratum I); if bleeding occurred 1 to 6 weeks (stratum II); and if bleeding occurred 6 weeks to 6 months (stratum III) before enrollment. Follow-up included clinical, biochemical, Doppler Ultrasound, and endoscopic examinations every 6 months. During a mean follow-up of 17.7 months, 51% of the patients treated with sclerotherapy and 24% of those treated with TIPS rebled (P = .011). Mortality was 19% in sclerotherapy patients and 24% in TIPS patients (P = .50). Hepatic encephalopathy (HE) developed in 26% and 55%, respectively (P = .006). A separate analysis of the three strata showed that TIPS was significantly more effective than sclerotherapy (P = .026) in preventing rebleeding only in stratum I patients. TIPS is significantly better than sclerotherapy in preventing rebleeding only when it is performed shortly after a variceal bleed; however, TIPS does not improve survival and is associated with a significantly higher incidence of HE. The overall performance of TIPS does not seem to justify the adoption of this technique as a first-choice treatment to prevent rebleeding from esophageal varices in cirrhotic patients.

Is the tantalum Strecker stent suitable for TIPS creation? Short- and mid-term results in 20 consecutive patients.

PURPOSE: To assess the suitability of tantalum Strecker stents for transjugular intrahepatic portosystemic shunt (TIPS) creation. METHODS: TIPS was performed with Strecker balloon-expandable stents in the first 20 patients of our series. A total of 26 prostheses were utilized (average 1.3 per patient). RESULTS: Immediate technical success was achieved in all 20 cases. Nine patients (45%) died during follow-up. The overall average follow-up period was 18.9 months; the 11 survivors were followed for a mean period of 29.8 months. In 4 patients (20%) the stent dislodged towards the hepatic vein during withdrawal of the balloon catheter, and difficulties in recatheterizing the shunt for routine control portal phlebography were frequently encountered. Rebleeding occurred in 5 cases and aggravation of pre-existing encephalopathy occurred in 2 cases. Shunt occlusions or stenosis required further intervention in 4 and 9 patients, respectively. CONCLUSION: In our opinion the tantalum Strecker stent is not particularly suitable for TIPS. Although it has evident advantages, such as high radiopacity and minimal shortening after deployment, the tendency of the device to dislodge and the difficulty in recatheterization during portal phlebography were important drawbacks. Furthermore, the atraumatic ends of the device did not seem to reduce shunt-related complications, which were comparable to those occurring with other types of stent.

Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Incidence and risk factors.

Forty-seven consecutive patients were prospectively evaluated to study the incidence of hepatic encephalopathy as well as modifications in the PSE index after TIPS. Various clinical, laboratory, and angiographic parameters were also recorded to identify risk factors for the development of post-TIPS hepatic encephalopathy (HE). Mean follow-up was 17 +/- 7 months. During follow-up, six patients died and one underwent transplantation. All other patients were followed for at least a year. Fifteen patients (32%) experienced 20 acute episodes of precipitated HE (hospitalization was necessary in 10 instances), and five patients (11%) presented a continuous alteration in mental status with frequent spontaneous exacerbation during follow-up. Both precipitated and spontaneous HE occurred more frequently during the first three months of follow-up. Moreover the PSE index was significantly worse than basal values one month after TIPS, thereafter returning to near basal values. HE was successfully treated in all patients but one who required a reduction in the stent/shunt diameter. Increasing age (>65 years) and low portacaval gradient (<10 mm Hg) were predictors of HE after TIPS. A gradual dilation of the stent/shunt should be performed to obtain a portacaval gradient >10 mm Hg to avoid an unacceptable rate of HE after TIPS.

TIPS (transjugular intrahepatic portosystemic shunt): state of art and personal experience.

After a brief historical view, we describe the basic technique currently used to create percutaneous portosystemic shunt. Between September 1992 and March 1995, TIPS was achieved in 50 out of 52 patients; main indications included bleeding from esophageal or gastric varices and refractory ascites. The mean portal pressure reduction was 14.9 mmHg and the mean residual portosystemic gradient was 10.5 mmHg. The average follow-up time was 11.8 months; in this period the overall mortality rate was 28%, while rebleeding occurred in 8 patients and new onsets of encephalopathy occurred in 4 cases. The major problems were due to shunt related complications observed in 46% of the patients; close follow-up and reintervention are required to keep the shunt previous. TIPS, developed ad an alternative to surgery and endoscopic sclerotherapy, is an effective and relatively safe procedure for the treatment of symptomatic portal hypertensive patient.

Octreotide versus terlypressin in acute variceal hemorrhage in liver cirrhosis. Emergency control and prevention of early rebleeding.

Sixty patients with endoscopically confirmed active variceal bleeding entered a randomized controlled clinical trial aimed at comparing the efficacy of octreotide vs. terlypressin in the control of acute variceal hemorrhage (period I, 24 h) and in the prevention of early rebleeding (period II, 6 days). Of the sixty 30 received octreotide (period I, 100 micrograms bolus followed by continuous intravenous infusion at 25 micrograms/h; period II, 100 micrograms t.i.d. subcutaneously), and 30 received terlypressin (period I, 2 mg intravenous bolus every 4 h; period II, 2nd day, 2 mg every 6 h; from 3th to 7th days, 1 mg every 6 h). Control of bleeding was achieved in 23 (76.6%) patients receiving octreotide and in 16 (53%) treated with terlypressin (NS); none of these patients suffered rebleeding during treatment. No significant difference in mortality was observed between the two groups during the hospitalization period. Complications due to therapy were lower with octreotide than with terlypressin (P < 0.01). Under the same effectiveness conditions the cost/benefit ratio must be taken into account.

Oral isosorbide-5-mononitrate reduces the rebleeding rate during the course of injection sclerotherapy for esophageal varices.

A double-blind, multicenter trial was carried out to assess the effectiveness of isosorbide-5-mononitrate in preventing recurrent variceal hemorrhage during the course of endoscopic sclerotherapy. Seventy-six patients with their first bleeding episode from esophageal varices were randomly allocated, after initial control of hemorrhage, to groups receiving either 50 mg/day oral isosorbide-5-mononitrate retard (37 patients) or an identical placebo (39 patients) until variceal eradication. Sclerotherapy was performed at weekly intervals, and varices were intra- and para-variceally injected with 1% polidocanol until eradication. If rebleeding occurred, additional sclerotherapy was performed. Four (10.8%) patients rebled in the isosorbide group, compared with 15 (38.4%) in the placebo group (p = 0.01). The total number of rebleeding episodes was also significantly lower in the isosorbide group (5 versus 19, p = 0.043), whereas comparison between major versus minor rebleedings was not significant. The median transfusion requirement per bleeding episode was not significantly different in the two groups, although the cumulative number of blood units transfused was over threefold greater (22 versus 70) in the placebo group. Two (5.4%) deaths occurred among isosorbide-treated patients and nine (17.9%) among placebo patients (NS). The number of sclerotherapy sessions and the time required to obtain variceal eradication were also comparable in the two groups. Finally, the nitrovasodilator was well tolerated, requiring withdrawal for severe headache in only one patient. In conclusion, isosorbide-5-mononitrate reduces the rebleeding rate and the number of rebleeding episodes before variceal eradication in patients treated with sclerotherapy.

Comparative analysis of torasemide and furosemide in liver cirrhosis.

This review concerns studies of the comparative efficacy and safety of torasemide and furosemide in patients with cirrhosis of the liver complicated by ascites and oedema. The short-term trials reviewed indicated that in patients who had failed to respond with adequate diuresis and loss of body weight and ascites to bed rest, restricted salt and water intake and spironolactone, torasemide had a longer duration of action than furosemide and resulted in a greater urinary excretion of salt and water and greater loss of body weight. Torasemide also had less effect than furosemide on urinary potassium excretion and unlike furosemide did not increase the fractional excretion of magnesium or phosphate or the blood ammonia concentration. Two longer term trials in similar patients with decompensated hepatic cirrhosis confirm the results of the shorter term studies. These studies, albeit each in relatively small numbers of patients, confirm the ability of torasemide to enhance diuresis, free water clearance and fractional excretion of sodium and chloride, resulting in loss of body weight and mobilization of ascites in patients with decompensated hepatic cirrhosis. In these patients, the relatively small increase in urinary excretion of potassium, induced by torasemide without any marked effect on renal function or on the plasma neurohormonal profile, enhances its potential safety.

Torasemide versus furosemide in cirrhosis: a long-term, double-blind, randomized clinical study.

The effects of long-term therapy (70 days) with torasemide (20 mg/day), a new loop diuretic, were compared with those of furosemide (50 mg/day) in a randomized double-blind trial. Both drugs were administered in association with spironolactone (200 mg/day) in 28 nonazotemic cirrhotic patients with controlled ascites. The treatments did not modify creatinine clearance and exhibited a similar effect on body weight, urinary volume, and fractional excretion of uric acid, sodium, and chloride. The effect of torasemide on fractional potassium excretion was lower than that of furosemide. Torasemide showed higher sparing effect than furosemide on calcium, inorganic phosphate, and magnesium excretion and stronger action on free water clearance. No changes in serum parameters were induced by either treatment. Two episodes of hepatic encephalopathy occurred in the torasemide group. In view of its effects on sodium and water excretion and on other urinary parameters, torasemide can represent an alternative tool for the long-term treatment of ascites.

[The value of ultrasonography in benign breast diseases]. / Utilità dell'ecografia nella patologia mammaria benigna.

In recent years breast scans have been widely used for the precise diagnosis of breast cancer. However, the value of this diagnostic tool is debatable in comparison to mammography in women of a childbearing age who often present a dense youthful breast. The role of clinical examination as a screening process is also examined. In the light of these findings the Authors evaluated the role played by ultrasonography in breast cancer, and in particular benign breast tumours, in a group of outpatients attending the clinic. The technique used was relatively simple: the scan in the department used for gynecological and obstetrical ultrasonography was fitted with a 5 MHz probe and was used to perform all the scans. In addition, a Kiteco space maintainer was used for ultrasonography of soft tissue. Scans were performed at a distance of 0.5 cm. The Authors examined 107 patients with benign breast tumours using ultrasonography. They evaluated the morphology, dimensions, edges and internal echo-structure of pathological formations and adjacent areas. The value of breast ultrasonography emerges from an analysis of the results both in the study of the glandular structure and in the differentiation between cystic and solid type lesions which are not always diagnosed during clinical examination. A total of 59 fibroadenoma, 44 cysts, 2 lipoma and 2 phylloids were diagnosed. Fibroadenomas had smooth edges in 98.4% of cases and were lobulate in 1.6%. In 100% of cases the fibroadenomas diagnosed presented fine internal homogeneous echoes with a lower echogenicity than that of surrounding glandular tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

[Spontaneous bacterial peritonitis during liver cirrhosis: the clinical findings and therapeutic considerations]. / Peritonite batterica spontanea in corso di cirrosi epatica: rilievi clinici e considerazioni terapeutiche.

Among 1211 consecutive patients admitted to hospital for liver cirrhosis, 625 (51.6%) had ascites. Forty-four of them (7%) had ascitic infection. Thirty-four cases (5.4%) of spontaneous bacterial peritonitis (SBP) and 10 cases (1.6%) of culture-negative neutrocytic ascites (CNNA) were diagnosed. The infecting organism was most likely Gram-negative of enteric origin (80%), CNNA mortality (30%) was lower than that of SBP (47%). High mortality suggests to treat patients affected by either SBP or CNNA with antibiotics.