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Aim Bariatric surgery has been shown to effectively improve glycaemic control in morbidly obese subjects. However, the molecular bases of this association are still elusive and may act independently of weight loss. Here, our retrospective study has investigated the inflammatory molecule osteopontin (OPN) as a potential predictor of type 2 diabetes mellitus (T2DM) remission. Methods Baseline serum levels of OPN were analyzed in 41 T2DM patients who underwent bariatric surgery. Anthropometric measures and biochemical variables, including insulin sensitivity indices (HOMA2), were assessed at baseline and at 1 and 3 years after surgery. Results At baseline, patients who experienced T2DM remission had increased waist circumference, body weight and BMI, and higher serum OPN, compared with non-remitters. Patients with and without T2DM remission improved their lipid and glucose profiles, although insulin resistance indices were only improved in the T2DM remission group. In the overall cohort of both T2DM remission and non-remission patients, baseline circulating levels of OPN significantly correlated with reductions of body weight and BMI over time, and insulin sensitivity improved as well. However, only the HOMA2-%S remained independently associated with serum OPN on multivariate linear regression analysis (B: 0.227, 95% CI: 0.067–0.387, β = 0.831; P = 0.010). Baseline values of OPN predicted 3-year T2DM remission independently of body weight loss, lower BMI and duration of diabetes (OR: 1.046, 95% CI: 1.004–1.090; P = 0.033). Conclusion Although larger studies are still needed to confirm our preliminary results, pre-operative OPN serum levels might be useful for predicting 3-year T2DM remission independently of weight loss in patients undergoing bariatric surgery.

Background: The incidence of trocar site hernia (TSH) in single-port laparoscopic cholecystectomy (SPC) is still a debated issue. Aim of this retrospective study was to compare the inciden...

This paper presents detailed information about national credit support programs, including guarantees for bank loans, implemented in the context of COVID-19 fiscal policy in 2020 in the largest national economies of the European Union and in the United Kingdom. The information was collected through thorough examination of published material and extended exchanges with national authorities and financial sector participants. It helps us understand (1) how countries positioned themselves on the many trade-offs that emerged in designing and implementing the programs; and (2) what explains differences in usage across countries and its leveling off everywhere in the second half of 2020.

Mini abstractWe tested usability, safety, and ability to manage elective surgery flow of a multidisciplinary pathway adopting the SWALIS-2020 model in an interhospital setting during the COVID-19 pandemic. This pilot included 295 adults. The pathway prioritized, monitored and scheduled surgery in an 840.000-inhabitants area. Using the COVID-19-GOA-Sur-MDT-SWALIS-2020 model may be warranted.Structured abstractThe COVID-19 outbreak burdens non-COVID elective surgery patients with figures similar to the SARS-Cov-2, by creating an overwhelming demand, increasing waiting times and costs. New tools are urgently needed to manage elective access. The study assesses the “SWALIS-2020” model’s ability to prioritize and optimize access to surgery during the pandemic.A 2020 March - May feasibility-pilot study, tested a software-aided, inter-hospital, multidisciplinary pathway. All specialties patients in the Genoa Departments referred for urgent elective surgery were included in a multidisciplinary pathway adopting a modified Surgical Waiting List InfoSystem (SWALIS) cumulative prioritization method (PAT-2020) based on waiting time and clinical urgency, in three subcategories: A1-15 days (certain rapid disease progression), A2-21 days (probable progression), and A3-30 days (potential progression).Following the feasibility study (N=55 patients), 240 referrals were evaluated in 4 weeks without major criticalities (M/F=73/167, Age=68.7±14.0). Waiting lists were prioritized and monitored, and theatres allocated based on demand. The SWALIS-2020 score (% of waited-against-maximum time) at operation was 88.7±45.2 at week 1 and then persistently over 100% (efficiency), over a controlled variation (equity), with a difference between A3 (153.29±103.52) vs. A1 (97.24 ± 107.93) (p The pathway has selected the very few patients with the greatest need, optimizing access even with +30% capacity weekly modifications. We will use the pathway to manage active, backlog, and hidden waiting lists throughout the further pandemic phases, and are looking for collaboration for multi-center research.https://www.isrctn.com/ISRCTN11384058.

Background: Surgical capacity is reduced due to COVID-19; and actions are required to optimise access, as the waiting patients’ needs dramatically exceed the available resources. The Italian Liguria Regional Health Trust (ALiSa) commissioned a pathway for all cancer/urgent cases from the metropolitan area of Genoa (840,000 inhabitants). Methods: The 6-week single-cohort feasibility-pilot of a software-aided, inter-hospital, collaborative multidisciplinary pathway covering all specialities in the Genoa Departments of Surgery. It modifies the Surgical Waiting List InfoSystem (SWALIS 2020) prioritisation model based on waiting time and clinical urgency by implicit criteria. We have introduced three new urgent subcategories: A1-15 days (certain rapid disease progression), A2-21 days (probable progression), and A3-30 days (potential progression). Findings: 295 referrals were evaluated in 6 weeks without major criticalities from 12 Surgical Units. Waiting lists were weekly monitored, and theatres allocated based on the existing demand. Their urgency category frequencies differed between week 3 and week 4 (p = 0·031). The SWALIS priority score (% of the waited against maximum time) in the operated patients was 88•7 ± 45•2 at week 1 and then persistently over 100% (efficiency), spread over a controlled variation (equity), with a difference between the A3 (153•29 ± 103•52) vs. A1 (97•24 ± 107•93) (p

ObjectiveTo estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descriptive epidemiology and to provide a molecular characterization of the described patient cohort.MethodsWe enrolled all patients with a neuroradiologically confirmed diagnosis of JS who resided in Italy in 2018 and calculated age and sex prevalence, assuming a Poisson distribution. We also investigated the correlation between proband chronological age and age at diagnosis and performed next-generation sequencing (NGS) analysis on probands' DNA when available.ResultsWe identified 284 patients with JS: the overall, female- and male-specific population-based prevalence rates were 0.47 (95% confidence interval [CI] 0.41–0.53), 0.41 (95% CI 0.32–0.49), and 0.53 (95% CI 0.45–0.61) per 100,000 population, respectively. When we considered only patients in the age range from 0 to 19 years, the corresponding population-based prevalence rates rose to 1.7 (95% CI 1.49–1.97), 1.62 (95% CI 1.31–1.99), and 1.80 (95% CI 1.49–2.18) per 100,000 population. NGS analysis allowed identifying the genetic cause in 131 of 219 screened probands. Age at diagnosis was available for 223 probands, with a mean of 6.67 ± 8.10 years, and showed a statistically significant linear relationship with chronological age (r2 = 0.79; p < 0.001).ConclusionsWe estimated for the first time the age and sex prevalence of JS in Italy and investigated the patients’ genetic profile. The obtained population-based prevalence rate was ≈10 times higher than that available in literature for children population.

Dietary treatment is the cornerstone of therapy for phenylketonuria (PKU), but adherence to low- phenylalanine diet progressively decreases after adolescence. We designed a survey to characterize the dietary habits of Italian adult PKU patients and to identify psychological factors influencing disease perception and adherence to diet. Participants to the survey (n = 111; response rate 94%) were asked to complete a structured questionnaire. Patients appeared to have an altered perception and awareness of the disease. About 40% of them did not consider PKU a disease and, despite declaring regular monitoring of phenylalanine levels (85%), nearly half of them reported a high plasma value over the last 6 months (>600 μmol/L, 48%) or were unable to specify it (31%). Adherence to PKU diet was unsatisfactory, with increased consumption of natural protein sources and reduced daily use of amino-acid supplements (

Alkaptonuria (AKU) is a rare disorder characterized by the deficiency of the enzyme homogentisate 1,2-dioxygenase and consequent homogentisate accumulation, which leads to progressive and severe osteoarthopathy starting from the second decade of life. Thus, in AKU patients, bone involvement represents an important clinical issue, which we investigated. Serum levels of receptor activator of NF-κB ligand (RANKL), osteoprotegerin, sclerostin, Dickkopf-1, and bone remodeling markers were measured in nine AKU patients (two children and seven adults) and 22 controls, together with lumbar spine bone mineral density (LS-BMD) and femoral-BMD. In the two AKU children, the average of LS-BMD and femoral-BMD Z-scores were within the normal range, but reduced with respect to the controls. Otherwise, in the adult AKU patients, LS-BMD T-score was inside the normal range, but femoral-BMD T-score reached osteopenic levels. Consistently, in AKU adults, higher RANKL and C-terminal telopeptide of collagen type 1 and lower osteoprotegerin levels were observed than in controls. Otherwise, spontaneous osteoclastogenesis was already evident in peripheral blood mononuclear cell cultures from AKU children, together with a high percentage of circulating osteoclast precursors. Osteoclastogenesis was sustained by the high levels of tumor necrosis factor-α, RANK, RANKL, and LIGHT. In conclusion, the altered osteoclastogenesis was observed already in AKU children, despite the absence of evident injury. Thus, a preventive approach in young patients, targeting osteoclast activity, may prevent the macroscopic bone disease that appears in adult AKU.

Background and aims Severe hypercholesterolemia associated or not with xanthomas in a child may suggest the diagnosis of homozygous autosomal dominant hypercholesterolemia (ADH), autosomal recessive hypercholesterolemia (ARH) or sitosterolemia, depending on the transmission of hypercholesterolemia in the patient's family. Sitosterolemia is a recessive disorder characterized by high plasma levels of cholesterol and plant sterols due to mutations in the ABCG5 or the ABCG8 gene leading to a loss of function of the ATP-binding cassette (ABC) heterodimer transporter G5-G8. Methods We aimed to perform the molecular characterization of two children with severe primary hypercholesterolemia. Results Case #1 was a 2 year-old girl with high LDL-cholesterol (690 mg/dl) and tuberous and intertriginous xanthomas. Case #2 was a 7 year-old boy with elevated LDL-C (432 mg/dl) but no xanthomas. In both cases, at least one parent had elevated LDL-cholesterol level. For molecular diagnosis, we applied targeted next generation sequencing (NGS), which unexpectedly revealed that both patients were compound heterozygous for nonsense mutations: Case #1 in ABCG5 gene [p.(Gln251*)/p.(Arg446*) ] and Case #2 in ABCG8 gene [p.(Ser107*)/p.(Trp361*)]. Both children had extremely high serum sitosterol and campesterol levels, thus confirming the diagnosis of sisterolemia. A low-fat/low-sterol diet was promptly adopted with and without the addition of ezetimibe for Case #1 and Case #2, respectively. In both patients, serum total and LDL-cholesterol decreased dramatically in two months and progressively normalized. Conclusions Targeted NGS allows the rapid diagnosis of sitosterolemia in children with severe hypercholesterolemia, even though their family history does not unequivocally suggest a recessive transmission of hypercholesterolemia. A timely diagnosis is crucial to avoid delays in treatment.

Background and aims Several studies demonstrated that surgery can improve inflammation parameters, such as C-reactive protein (CRP). Few biomarkers have been investigated to potentially predict type 2 diabetes mellitus (T2DM) remission. We aimed at determining whether pre-surgery serum CRP levels could predict T2DM remission after 3 years in patients undergoing bariatric surgery, especially biliopancreatic diversion (BPD). Methods and results This study was conducted from 2007 to 2009 at the Surgical Department of the University of Genoa, Italy. Forty-four patients with T2DM undergoing BPD (n = 38) or Roux-en-Y gastric bypass (n = 6) were enrolled. The primary endpoint was to evaluate whether pre-surgery CRP levels could predict T2DM partial remission at 3-year follow-up. Secondary endpoints were to assess whether glycaemic, lipid, and inflammatory parameters modified during the follow-up. At baseline, patients with T2DM ranged from overweight to morbid obesity, had mild dyslipidaemia, and a low-grade inflammation. Bariatric surgery improved body weight, lipid and glycaemic profile both at 1- and 3-year follow-up. Pre-surgery CRP levels progressively decreased at 1- and 3-year follow-up. Among inflammatory pre-surgery parameters, only high CRP levels were shown to predict T2DM partial remission after 3 years. Multivariate analysis confirmed the predictive value of pre-surgery CRP levels independently of age, gender, type of surgery, and body mass index. Conclusion Bariatric surgery, in particular BPD, improved both metabolic and inflammatory biomarkers at 1- and 3-year follow-up. Pre-surgery high CRP levels predicted 3-year T2DM partial remission, indicating a promising target population to be especially treated with BPD.

The 12q14 microdeletion syndrome is a rare condition characterized by low birth weight, failure to thrive, short stature, learning disabilities, and osteopoikilosis. To date, 20 cases of 12q14 deletion have been reported in the literature, displaying both phenotypic than genetic variability. We report on three familial cases, a mother and two brothers, with severe short stature. The mother and elder brother presented with osteopoikilosis while the younger brother had severe short stature and developmental delay. SNP array analysis revealed a 1.9 Mb heterozygous 12q14.2q14.3 deletion in all three patients encompassing 14 genes and 3 miRNAs. In addition, the younger brother carried a paternal 11q13.4 duplication including the SHANK2 gene. This latter patient was investigated for developmental delay and did not show osteopoikilosis, confirming the role of age in the clinical presentation of this condition. To the best of our knowledge, this is the second family described with the syndrome. Comparing the clinical and molecular data of our patients with those previously reported we performed a detailed genotype-phenotype correlation confirming the association between growth retardation and osteopoikilosis when the rearrangement includes both LEMD3 and HMGA2 genes. In addition, we suggest the XPOT, TBK1, WIF1 genes as candidates for the clinical features observed in our patients and discuss for the first time the possible involvement of some microRNAs, when deleted, in the etiology of the phenotypes in 12q14 microdeletion syndrome patients. We expect the interpretation of our findings to be useful both from a molecular point of view and for genetic counseling.

Metabolic surgery is considered as a therapeutic option for obese patients with type 2 diabetes (T2D). In order to identify novel laboratory variables that could improve the selection of patients who might greatly benefit from a surgical approach, we focused on the neutrophil-to-lymphocyte ratio (NLR) as a predictor of long-term T2D remission following metabolic surgery. Thirty-one obese patients with T2D included in this pilot study underwent Roux-en-Y gastric bypass or biliopancreatic diversion (BPD) at the Surgical Department of Genoa University, IRCCS Ospedale Policlinico San Martino in Genoa (Italy). Before surgery, serum samples were collected to evaluate blood count, glycemic profile, and circulating neutrophil degranulation products. The median age was 56 years, median body mass index (BMI) was 32.37 kg/m2, and median glycated hemoglobin was 8.4%. White blood cell count was in a range of normality, with a median NLR of 1.97. By a receiver operating characteristic curve analysis, NLR has been found to be significantly associated with T2D remission at 1, 3, and 5 years and the best cutoff of ≤ 1.97 has been identified by Youden index. When comparing study groups according to NLR cutoff, those with NLR ≤ 1.97 were older and underwent more often BPD. By a logistic regression analysis, NLR ≤ 1.97 has been found to predict T2D remission across 5 years, irrespective of baseline BMI. A baseline low NLR is associated with long-term T2D remission in obese patients undergoing metabolic surgery, suggesting that circulating inflammatory cells (i.e., neutrophils) might negatively impact on T2D remission.

Purpose: The COVID-19 pandemic burdens non-covid elective surgical patients by reducing service capacity, forcing extreme selection of patients most in need. New tools are urgently required to prioritize operations and optimize the process sustainably. Our study assesses the SWALIS-2020 model ability to prioritize access to surgery during the highest viral outbreak peaks. Methods: A 2020 March - May feasibility-pilot study, tested a software-aided, inter-hospital, multidisciplinary pathway. All specialties patients in the Genoa Departments referred for urgent elective surgery were included in a multidisciplinary pathway adopting a modified Surgical Waiting List InfoSystem (SWALIS) cumulative prioritization method (PAT-2020) based on waiting time and clinical urgency, in three subcategories: A1-15 days (certain rapid disease progression), A2-21 days (probable progression), and A3-30 days (potential progression). We have studied the model applicability and its ability to prioritize patients by monitoring their waiting list and service performance. https://www.isrctn.com/ISRCTN11384058. Results: Following the feasibility study (N=55 patients), 240 referrals were evaluated in 4 weeks without major criticalities (M/F=73/167, Age=68.7 +/- 14.0). Waiting lists were prioritized and monitored. The SWALIS-2020 score (% of waited-against-maximum time) at operation was 88.7 +/- 45.2 at week 1 and then persistently over 100% (efficiency), over a controlled variation (equity), with a difference between A3 (153.29 +/- 103.52) vs. A1 (97.24 +/- 107.93) (p

Background: The COVID-19 outbreak is burdening non-COVID elective surgery patients with figures similar to the SARS-Cov-2, by creating an overwhelming demand, increasing waiting times and costs New tools are urgently needed Our feasibility-pilot single cohort study assesses a modified Surgical Waiting List InfoSystem (SWALIS-2020) model to prioritize and optimize access to elective surgery throughout and beyond the pandemic (https://www isrctn com/ISRCTN11384058) Materials and Methods: In March-May 2020 we tested a software-aided, inter-hospital, multidisciplinary pathway All specialties elective urgent surgery referrals in the Genoa Metropolitan area have been centralized in the SWALIS-2020 pathway adopting a cumulative linear prioritization method (PAT-2020) by waiting time and clinical urgency categories: A1-15 days (certain rapid disease progression), A2-21 days (probable progression), and A3-30 days (potential progression) Results: Following the feasibility phase (N=55 patients), 240 referrals were prioritized in 4 weeks without major criticalities (M/F=73/167, Age=68 7±14 0), waiting lists monitored, and theatres allocated based on the demand The SWALIS-2020 score (% of waited-against-maximum time) at operation was 88 7±45 2 at week 1, then persistently over 100% (efficiency), over a controlled variation (equity), with a difference between A3 (153 29±103 52) vs A1 (97 24±107 93) (p

In this study, we investigated the bone cell activity in patients with osteogenesis imperfecta (OI) treated and untreated with neridronate. We demonstrated the key role of Dickkopf-1 (DKK1), receptor activator of nuclear factor-κB ligand (RANKL), and tumor necrosis factor alpha (TNF-α) in regulating bone cell of untreated and treated OI subjects. These cytokines could represent new pharmacological targets for OI. Bisphosphonates are widely used in the treatment of children with osteogenesis imperfecta (OI) with the objective of reducing the risk of fractures. Although bisphosphonates increase bone mineral density in OI subjects, the effects on fracture incidence are conflicting. The aim of this study was to investigate the mechanisms underlying bone cell activity in subjects with mild untreated forms of OI and in a group of subjects with severe OI treated with cycles of intravenous neridronate. Sclerostin, DKK1, TNF-α, RANKL, osteoprotegerin (OPG), and bone turnover markers were quantified in serum of 18 OI patients (12 females, mean age 8.86 ± 3.90), 8 of which were receiving cyclic intravenous neridronate, and 21 sex- and age-matched controls. The effects on osteoblastogenesis and OPG expression of media conditioned by the serum of OI patients and anti-DKK1 neutralizing antibody were evaluated. Osteoclastogenesis was assessed in cultures from patients and controls. DKK1 and RANKL levels were significantly increased both in untreated and in treated OI subjects with respect to controls. The serum from patients with high DKK1 levels inhibited both osteoblast differentiation and OPG expression in vitro. High RANKL and low OPG messenger RNA (mRNA) levels were found in lymphomonocytes from patients. High amounts of TNF-α were expressed by monocytes, and an elevated percentage of circulating CD11b-CD51/CD61+ osteoclast precursors was observed in patients. Our study demonstrated the key role of DKK1, RANKL, and TNF-α in regulating bone cell activity of subjects with OI untreated and treated with bisphosphonates. These cytokines could represent new pharmacological targets for OI patients.

Bariatric surgery has been shown to be effective in severely obese patients with type 2 diabetes mellitus (T2DM).Evaluate the long-term efficacy of biliopancreatic diversion (BPD) for the treatment of T2DM depending on the preoperative duration of T2DM.University Hospital.Retrospective analysis investigating 2 subsets of severely obese patients who had undergone BPD from 1984 to 1995. The first included 52 patients with a preoperative T2DM duration of ~1 year (SD group - 49 on oral agents and 3 on insulin), and the second included 68 patients who had been diabetic for5 years before BPD (LD group - 52 on oral agents and 16 on insulin). Postoperatively, T2DM was regarded as in remission when fasting serum glucose (FSG) was lower than 100 mg/dL on regular diet and without antidiabetic therapy.In the SD patients, the number of individuals without T2DM remission were lower both at 5-10 (0/31, 0% of patients, versus 8/54, 15% of patients, p.04) and at15 years (1/28, 3% of patients, versus 10/41, 24% of patients, p.0012). Furthermore, after BPD, the number of patients with dyslipidemia strongly reduced (p.001) in both groups, values at 5-10 years remaining very similar to those observed at15 years.These results indicate that severely obese patients with longer T2DM duration have a worse metabolic outcome maintained at long and very long term following BPD.

We report on a patient with psychomotor deficits, language delay, dyspraxia, skeletal anomalies, and facial dysmorphisms (hirsutism, right palpebral ptosis, a bulbous nasal tip with enlarged and anteverted nares, and a mild prominent antihelix stem). Using high-resolution SNP array analysis, we identified a 0.49-Mb microduplication in chromosome 6q26 inherited from the mother involving the PARK2 gene: arr[hg19] 6q26(162,672,821-163,163,143)×3 mat. To the best of our knowledge, this is the third patient to date described in whom a 6q26 microduplication encompassing only the PARK2 gene has been reported in medical literature. The PARK2 gene is a neurodevelopmental gene that was initially discovered as one of the causes of autosomal recessive juvenile Parkinson disease and subsequently reported to be linked to autism spectrum disorders and attention-deficit hyperactivity disorders. We provide an overview of the literature on PARK2 microduplications and further delineate the associated phenotype. Taken together, our findings confirm the involvement of this gene in neurodevelopmental disorders and are useful to strengthen the hypothesis that, although with variable expressivity and incomplete penetrance, the PARK2 microduplication is associated with a new emerging neurodevelopmental delay syndrome. However, clinical and molecular evaluations of more patients with the microduplication are needed for full delineation of this syndrome.

Background and objectives The purpose of the investigation was to compare clinical results and diagnostic accuracy for conventional multiport laparoscopic lymph node biopsy (MPLB) and single-port laparoscopic lymph node biopsy (SPLB) operations at a single institution. Methods A set of 20 SPLB patients operated on from October 2016 to May 2019 were compared to an historical series of 35 MPLB patients. Primary endpoints were the time of surgery, estimated blood loss, surgical conversion, length of stay and morbidity. The secondary endpoint was the diagnostic accuracy of the technique. Results SPLB was completed laparoscopically in all cases. Two MPLB patients (5.7%) experienced a surgical conversion due to intraoperative difficulties. Duration of surgery was similar in SPLB and MPLB groups respectively (84 ± 31.7 min vs. 81.1 ± 22.2; P = .455). A shorter duration of hospital stay was shown for patients operated on by SPLB compared to the MPLB group (1.7 ± 0.9 days vs. 2.1 ± 1.2 days; P = .133). The postoperative course was uneventful in both groups. In 95% of the SPLB and 97.1% of the MPLB cases respectively, LLB achieved the necessary information for the diagnosis. Conclusion SPLB has shown good procedural and postoperative outcomes as well as a high diagnostic yield, comparable to traditional MPLB. Therefore, our results show that this approach is safe and effective and can be an equally valid option to MPLB to obtain a diagnosis or to follow the progression of a lymphoproliferative disease. Further studies are necessary to support these results before its widespread adoption.

In severely obese patients with type 2 diabetes (T2DM), the metabolic benefits after biliopancreatic diversion (BPD) are due to mechanisms independent of weight loss. Therefore, the anti-diabetic effect of BPD in overweight or mildly obese T2DM patients was investigated. Ninety T2DM patients with BMI 25–35 underwent BPD and were evaluated 1 and 5 years after the operation (follow-up rate 100 and 83%, respectively). T2DM control (Hb1Ac

Fundamental questions about the optimal set-up for central banks are examined in this book. In particular, we ask whether the model of an independent central bank devoted to price stability,1 which affirmed itself in most advanced economies at the turn of the last century, is the final resting point of a long and complex development that started centuries ago. We dissect the hypothesis that the Great Recession has prompted a reassessment and a possible revision of that model....

The central banking model prevailing before the Great Recession suffered six hits during the crisis. First, new financial stability responsibilities created dilemmas in the use of the interest rate. Second, quantitative easing blurred the borders between monetary and fiscal policy. Third, the action to support banks and, in the euro-area, peripheral sovereigns created moral hazard. Fourth, the ECB had to take on itself the task of preserving the euro. Fifth, the ECB had to participate in the so-called troika. Sixth, both the Fed and the ECB had to adopt a more global perspective. This chapter concludes that these hits have not basically jeopardized the pre-crisis central bank model. Still, four of the six hits to the pre-crisis central bank model identified above have a good probability of requiring changes in the pre-crisis model, thus some incremental adaptations to that model are proposed.

Monetary policy before the Great Recession rested on three unacknowledged assumptions: first, the central bank could effectively control a short-term rate; second, this short-term rate had a stable relationship with longer/riskier rates; third, the central bank could move the short-term rate up or down as needed. In one or the other phase of the Great Recession one or more of these assumptions no longer held. The Fed and the ECB reacted to these difficulties, adding balance sheet management to their weaponry. After the failure of Lehman Brothers, measures of financial stress exploded and the banking sector was affected by an acute lack of liquidity, large losses, a disproportion between diminished capital and a riskier balance sheet, low profitability, enhanced competition of shadow banks, deleveraging, and difficulties in raising new capital. The Fed and the ECB could address some, but not all, of these problems.

The chapter describes the historical process as well as the analytical and empirical factors that, at the end of the twentieth century, led to the dominance, in advanced economies, of a central bank model based on an independent institution devoted to price stability as its overriding objective. The central bank pre-crisis model was elegant, performing, and efficient. However, it could not easily accommodate the pursuit of a traditionally important central bank objective: financial stability. Indeed, since central banks have, in essence, just one tool, that is, the interest rate, the pursuit of a financial stability objective in addition to a price stability objective could create dilemma situations. In the two decades between the mid-1980s and the mid-2000s, the economies of advanced economies were very stable, and this period was thus identified as Great Moderation. However, subsequent experience showed that, in this period, the crisis was incubating.

Obesity is associated with NAFLD, and bariatric surgery has significant impact on this liver disease, with reported improvement in hepatic fibrosis. To investigate the effects of bariatric surgery on long-term liver disease-related outcome in obese patients with nonalcoholic fatty liver disease (NAFLD) and significant liver damage. This study included 56 NAFLD patients who underwent bilio-pancreatic diversion for morbid obesity and who had significant fibrosis at intraoperative liver biopsy. Data were analyzed at 1, 3, and 5 years of follow-up, and at the latest available visit in patients who had longer follow-up. We assessed the incidence of clinically relevant liver events (ascites, hepatic encephalopathy, portal hypertension-related bleeding, and jaundice) as well as modifications of a validated biochemical index such as the NAFLD score. During a median follow-up of 78 months, median weight decreased from 119 to 78 kg (P

Background Data regarding management of former bariatric operations after onset of a malignancy are still lacking and there is no consensus whether bariatric surgery negatively influences the oncologic management of patients. Objectives To investigate the strategy by which patients previously submitted to bariatric surgery were managed after diagnosis of malignancy of the digestive apparatus, whether a revision was performed or not, to assess the incidence of nutritional complications, and the effect of revision versus no revision of bariatric surgery on the outcome of cancer treatment. Setting University Hospital, Italy. Methods Occurrence of a malignancy of the digestive apparatus in patients submitted to biliopancreatic diversion was investigated retrospectively. Patients' data were collected preoperatively, at 2 and 3 years after the operation, at oncologic diagnosis, and at the longest available postoncologic follow-up. Results From May 1976 to January 2017, 3341 morbidly obese patients were submitted to biliopancreatic diversion. Sixteen patients were diagnosed with a malignancy involving the digestive apparatus 5 to 28 years after bariatric surgery. Of 10 patients diagnosed with colorectal cancer, 6 were revised. At 2 years after biliopancreatic diversion, body mass index, hemoglobin, and iron levels were significantly lower than preoperatively. Serum transferrin and total protein were unchanged. There was no difference between body mass index, hemoglobin, transferrin, and total protein levels at 2 years and at oncologic diagnosis, or between revised and unrevised patients. Conclusion Revision of a preexisting bariatric operation after digestive cancer surgery is common, although selected, unrevised cases do not seem to be associated with worse outcome.

OBJECTIVE In children with type 1 diabetes mellitus (T1DM), elevated levels of antitissue transglutaminase (anti-tTG) antibody may spontaneously normalize, despite continued consumption of gluten. We aimed to investigate the prevalence of spontaneous normalization of anti-tTG levels and the existence of factors predictive for this outcome. RESEARCH DESIGN AND METHODS All children referred from 2002 to 2012 were screened for celiac disease (CD) at diabetes onset and at specific intervals. In the presence of a high anti-tTG titer or clinical symptoms, children were offered endoscopy, and asymptomatic patients with a low anti-tTG titer were invited to a second serological test after 6 months of eating a gluten-containing diet. RESULTS The study included 446 children. Of these, 65 (14.5%) became positive for celiac serology: 38 (58%) had a persistently elevated anti-tTG titer and 27 (41%) fluctuating anti-tTG titer; 18 (28%) became negative. The prevalence of positive CD autoimmunity and overt CD was 14.3% (95% CI 11–17) and 8.5% (95% CI 5–10), 15- and 8-times higher than the general pediatric population, respectively. Asymptomatic children older than 9.1 years at T1DM onset had the lowest risk to develop CD. CONCLUSIONS Serum anti-tTG levels decreased spontaneously in 40% of children with T1DM and became negative in 20%, despite gluten consumption. This finding supports the hypothesis of a state of temporary positivity of celiac serology in children with diabetes. In absence of clinical symptoms or signs of CD, histological confirmation of the disease and the gluten-free diet should be postponed to avoid unnecessary procedures and reduce an additional psychological burden.

This article illustrates what would be the operational implications of a hypothetical demise of the euro. In order to do this, it examines what were the operational implications of establishing the euro and shows that the opposite endeavour would not just be its symmetric counterpart. The paper also looks at two developments that took place after the launch of the euro – the emergence of very large Target2 balances during the crisis that started in 2010 and the move towards financial integration – showing that they would add to the formidable operational complications that would be created by the demise of the euro. The paper concludes that the logistical difficulties considered here only look minor in comparison with the fundamental reasons that led governments and central banks to fight with determination the risk of a demise of the euro. In absolute terms, they are important enough to tilt the balance of costs and benefits in the direction of preserving the eurozone.

Insulin gene mutations, either dominant or recessive, can cause permanent neonatal diabetes mellitus (INS/PNDM), which is defined as diabetes with onset within 6 months of birth [1, 2]. More rarely, INS dominant mutations give rise to diabetes that presents during infancy [3]. In most patients with heterozygous, dominant INS mutations, C-peptide is in the normal-low range at diabetes outset, but over time declines to undetectable levels as a consequence of ongoing apoptosis of the pancreatic beta cells. This process is triggered by the sustained endoplasmic reticulum (ER) stress [2] induced by misfolding of mutant insulin trapped inside the beta cell. Thus, at least in principle, strategies aimed at relieving ER stress of beta cells may help to preserve endogenous insulin production from the normal allele. During the last 8 years, we identified a total of 16 cases with dominant INS gene mutations from 13 different Italian centers [2–4]. Thirteen were diagnosed with INS/PNDM (or with diabetes with onset during infancy) (2–4 and FB unpublished observations) before year 2010 and were treated with standard insulin therapy. Currently, all of them show undetectable C-peptide values. Instead, the three patients diagnosed with a dominant INS mutation after year 2010 were started on continuous subcutaneous insulin infusion (CSII) within a week after diagnosis. The three patients carried the novel INS mutation c.149A>G, p.Tyr50Cys (patient 1) and the already described c.94G>A p.Gly32Ser (patient 2) and c.314T>C p.Leu105Pro (patient 3). Diabetes onset was at 1 month of age for patient 1, 7 months for patient 2, and 5 months and a half for patient 3. In patient 1, CSII was integrated with continuous (i.e., 24 h a day) glucose monitoring (CGM). CGM was set with alarms for hypoglycemia, with a 2-h automatic interruption of insulin delivery by the pump if glucose sensor detected a value ≤4.44 mmol/l (80 mg/dl), and for hyperglycemia, with increased insulin infusion over basal level (“correction factor”) of 0.025 U for every 5.55 mmol/l (100 mg/dl) above the glucose value of 8.33 mmol/l (150 mg/dl), in order to obtain the narrowest plasma glucose fluctuations possible. Patient 1 was discharged from the hospital after 1 month, patient 2 after 18 days, and patient 3 after 12 days. Informed consent was obtained from parents of patients. C-peptide was evaluated in patients 1 and 2 by two-site chemiluminescent immunometric assay. Assay employed for patient 1 (Liaison C-peptide, Diasorin, Saluggia, Italy) has a reported limit of detection of 0.01 ng/ml (0.003 nmol/l) and functional sensitivity of 0.03 ng/ml (0.01 nmol/l); for patient 2, the assay (Immulite 2000 C-Peptide, Siemens) has a reported limit of detection and functional sensitivity of 0.08 ng/ml (0.03 nmol/l). Blood samples for C-peptide determination were drawn after an overnight fast, without suspension of basal insulin infusion. At follow-up as outpatients, no allergic reaction, lipo-atrophy, or -hypertrophy at the site of catheter insertion were observed; in addition, no episodes of ketosis or severe hypoglycemia requiring new hospitalization were reported for any patient. HbA1c is not a reliable method to evaluate metabolic control below the age of 6 months, because of the interfering effect of fetal hemoglobin: consequently, we do not report on patient 1’s glycated hemoglobin during the first semester of CSII. HbA1c values determined in patients 1 and 2 six months after diabetes onset were nevertheless comparable: 50 mmol/mol (6.7 %) for patient 1 (age 7 months) and 48 mmol/mol (6.5 %) for patient 2 (age 13 months) (Table 1). At follow-up, HbA1c values 12, 18, and 24 months after diabetes onset were declining in patient 1, while patient 2 showed a more irregular pattern (Table 1). Of note, insulin dose used for patient 2 was much lower for the entire period of CSII treatment (Table 1), suggesting that patient 2 may be more insulin-sensitive than patient 1. At strong variance with patients 1 and 2, patient 3 showed very high HbA1c from diabetes onset and never reached optimal metabolic control (Table 1). Table 1 Insulin dose and HbA1c in the three patients during 24-month period of treatment with CSII Interestingly, C-peptide was measurable at diabetes onset (1.04 ng/ml or 0.35 nmol/l), but became undetectable in patient 2 (CSII only) after 12 and 24 months from diabetes diagnosis, consistent with other reports showing this pattern in patients with INS proteotoxic mutations [2, 3]. In contrast, after the initial decrement recorded the first month after diabetes presentation, C-peptide of patient 1 (integrated system CSII/CGM) increased with a current value at 24 months of age of 0.26 nmol/l (Fig. 1). However, it has to be noticed that because of different sensitivities between C-peptide assays utilized, a direct comparison of these two patients cannot be easily made. Nevertheless, this was a surprising finding that has no easy explanation. From the clinical standpoint, the effect of the p.Tyr50Cys mutation seemed more pronounced than p.Gly32Ser, because patient 1 had an earlier diabetes presentation combined with a higher plasma glucose at onset (509 vs 293 mg/dl of patient 2). Interestingly, five patients previously described who bear INS/G23S mutation had diabetes onset at 6 months of age or beyond [1, 3]. On the other side of the token, patient 1 had no HbA1c fluctuations (Table 1), and it is tempting to speculate that the reduction in patient’s glycemic excursions obtained with CSII/CGM integrated system may have led to a substantial reduction in beta cell apoptosis consequent to the alleviation of endoplasmic reticulum crowding [5]. Fig. 1 C-peptide plasma level of patient 1 during the 24-month period of integrated CSII–CGM system. Numbers below each point are glucose values (mg/dl) at the time of blood drawing The results presented here indicate that CSII alone as well as sensor-augmented CSII is a feasible—and safe—therapeutic strategy for neonates or infants with diabetes, not only in the hospital setting, but at home. Moreover, CSII–CGM integrated system may be superior to CSII only, though we acknowledge that more cases must be studied to draw any robust conclusion. This may be probably obtained only through an international collaborative study, taking into consideration that PNDM is a rare condition (1:200,000 live births in countries with low rate of consanguineous marriages) [4].

Objective: The present study was planned to investigate, by means of quantitative FDG-PET, how bariatric surgery (BS) modifies the metabolic pattern of the whole body and different tissues in slightly obese patients with type 2 diabetes mellitus (T2DM). Design and Methods: Before, 1 and 4 months after BS, 21 consecutive slightly obese T2DM patients underwent blood sampling to estimate plasma levels of glucose, insulin, glycosylated hemoglobin. At the same time points, these patients underwent a dynamic 18F-FDG PET study of thorax and upper abdomen in fasting state and after washout of T2DM therapy. Gjedde-Patlak analysis was applied to estimate glucose uptake in the whole body and in different tissues (myocardium, skeletal back muscle, adipose tissue, and liver). Results: Surgical intervention quickly lowered levels of both insulin and glucose documenting an amelioration of glucose tolerance. Similarly, skeletal muscle and myocardial glucose uptake significantly increased soon after surgery (P < 0.001 and P < 0.01 at 1 month versus baseline, respectively) and remained substantially stable thereafter. By contrast, glucose uptake slightly decreased from its baseline values in the liver (P < 0.01 at 4 months) while no response could be documented over time in the adipose tissue. Conclusions: These findings document that BS-induced modification of glucose homeostasis in slightly obese T2DM patients is mostly due to an increase in muscle glucose consumption. The surgically modified metabolic pattern of these patients might be of interest as a new model to investigate mechanism underlying insulin resistance.

WOS: 000373180700001, PubMed ID: 27030250, Background: Isovaleric aciduria (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonaemia arising partly from secondary deficiency of N-acetylglutamate (NAG) synthase. Rapid reduction in plasma ammonia is required to prevent neurological complications. This retrospective, multicentre, open-label, uncontrolled, phase IIIb study evaluated the efficacy and safety of carglumic acid, a synthetic structural analogue of NAG, for treating hyperammonaemia during OA decompensation. Methods: Eligible patients had confirmed OA and hyperammonaemia (plasma NH3 > 60 mu mol/L) in >= 1 decompensation episode treated with carglumic acid (dose discretionary, mean (SD) first dose 96.3 (73.8) mg/kg). The primary outcome was change in plasma ammonia from baseline to endpoint (last available ammonia measurement at = 1 dose of study drug and had post-baseline measurements) comprised 41 patients (MMA: 21, PA: 16, IVA: 4) with 48 decompensation episodes (MMA: 25, PA: 19, IVA: 4). Mean baseline plasma ammonia concentration was 468.3 (+/- 365.3) mu mol/ L in neonates (29 episodes) and 171.3 (+/- 75.7) mu mol/L in non-neonates (19 episodes). At endpoint the mean plasma NH3 concentration was 60.7 (+/- 36.5) mu mol/L in neonates and 55.2 (+/- 21.8) mu mol/ L in non-neonates. Median time to normalise ammonaemia was 38.4 hours in neonates vs 28.3 hours in non-neonates and was similar between OA subgroups (MMA: 37.5 hours, PA: 36.0 hours, IVA: 40.5 hours). Median time to ammonia normalisation was 1.5 and 1.6 days in patients receiving and not receiving concomitant scavenger therapy, respectively. Although patients receiving carglumic acid with scavengers had a greater reduction in plasma ammonia, the endpoint ammonia levels were similar with or without scavenger therapy. Clinical symptoms improved with therapy. Twenty-five of 57 patients in the safety population (67 episodes) experienced AEs, most of which were not drug-related. Overall, carglumic acid seems to have a good safety profile for treating hyperammonaemia during OA decompensation. Conclusion: Carglumic acid when used with or without ammonia scavengers, is an effective treatment for restoration of normal plasma ammonia concentrations in hyperammonaemic episodes in OA patients., Orphan Europe; Orphan Europe SARL, This study was sponsored by Orphan Europe. The study sponsor was involved in the conception and design of the study, collection and interpretation of data, in manuscript preparation and in the decision to submit the manuscript for publication. We thank Brigitte Chabrol, Rita Fischetto, Gemma Ginovart, Elisabetta Pasquini and Carlo Dionisi-Vici for their valuable insights during data analysis. We also thank Dr Silke Geb and Dr Helene Ogier de Baulny for their contributions to the study. Medical writing assistance was provided by apothecom scopemedical ltd, funded by Orphan Europe SARL.

Obesity surgery has been proposed as a treatment option for diabetic patients with body mass index (BMI)35 kg/m(2), but the efficacy of metabolic surgery has not been conclusively determined.To evaluate the long-term metabolic outcome of non-morbidly obese (NMO) patients with type 2 diabetes (T2D) after biliopancreatic diversion (BPD).Two groups of T2D patients with different degree of obesity (NMO, 17 cases, BMI 25-35 kg/m(2); and morbidly obese [MO], 13 cases, BMI35 kg/m(2)) were studied before and at 1 and 5 years after BPD in a university hospital setting. Insulin secretion was assessed by acute insulin response (AIR) to intravenous glucose and by insulinogenic index (IGI).In all MO patients, T2D was remitted or controlled (1 case) at 1 year and results were maintained at 5 years; AIR (μU/mL) and IGI (μU/mg) improved (P.001) at 1 year (from .1±3.1 to 18.52±21.9, and from 6.0±8.5 to 9.1±22.8, respectively) with a further increase (to 24.8±25.5 and to 14.3±13.8, respectively) at 5 years. Within the NMO group, T2D was remitted in 1/17 and controlled in 14/17 patients at 1 year, and in 2/17 and in 4/17 patients at 5 years, respectively; AIR (μU/mL) and IGI (μU/mg) remained unchanged throughout the postoperative period (from .31±9.26 to 1.5±2.8 at 1 yr and to .4±3.29 at 5 yr for AIR, and from 2.2±4.9 to 1.3±9.0 at 1 yr and to 2.3±3.3 at 5 yr for IGI).After BPD, restoration of β-cell secretion/production plays a pivotal role in determining postoperative T2D remission.

Roux-en-Y gastric bypass (RYGBP) and biliopancreatic diversion (BPD) are highly beneficial operations for type 2 diabetes mellitus (T2DM) in obese patients, leading to complete T2DM resolution in 75-90 and 97-99% of cases, respectively. In both RYGBP and BPD, the foregut is excluded from the food stream and the distal small bowel receives the food stimulation, while following BPD fat intestinal absorption is also extremely limited. This study was carried out to identify clinical features that could give insight on the different mechanisms of action on diabetes resolution.The files of 443 severely obese patients with T2DM undergoing BPD from May 1976 to May 2007 were examined, and the presence of T2DM (fasting serum glucose125 mg/ml) at 1-2 months, at 1 year, at 10 years, and ator =20 years following the operation was recorded.The percentage of patients cured (fasting serum glucose reduced toor =110 mg/dl, on free diet and with no therapy) was 74% at 1 month, 97% at 1 and 10 years, and 91% ator =20 years, the 26% of uncured patients at 1 month being those with most severe preoperative T2DM.As the early results after BPD resemble those reported after RYGBP, it can be hypothesized that the duodenal exclusion and the distal small bowel stimulation are the first mechanisms acting in BPD, immediately after the operation, that only subsequently the myocellular fat depletion, which cannot be immediate, takes over, and that the minimal fat absorption is the mechanism accounting for the long-term results of BPD.

Because of the rearrangement of the gastrointestinal tract, biliopancreatic diversion (BPD) could lead to an increased risk of colorectal cancer caused by possible carcinogenetic action of the unabsorbed food and bile acid on colonic mucosa.The incidence of colorectal cancer in 1,898 obese subjects submitted to BPD from May 76 to July 2002 with a minimum follow-up of 5 years was retrospectively evaluated.Among 28,811 person-years, seven cases of colorectal cancer were detected, for an overall incidence of 29.4 per 100,000, which is not different from that observed in the general Italian population, and lower than that reported for obese and type 2 diabetes patients. Logistic regression model suggests that occurrence of colorectal cancer is positively related to the time elapsed from BPD.This study indicates that BPD does not carry any increased risk for colorectal cancer. The complete postoperative restoration of insulin sensibility could exert a valuable protective action.

Background The benefits of bariatric surgery in adult obese patients are well known, but data are lacking regarding the outcome of the surgery in adolescents. The aim of this study was to retrospectively assess the operative morbidity and mortality, percentage of loss of initial excess weight, and the incidence of long-term complications and reoperations in a cohort of obese patients who underwent biliopancreatic diversion (BPD) before their 18th birthday. Methods A total of 76 adolescent subjects underwent BPD between 1976 and 2005. Of these 78 patients, 7 had Prader-Willi syndrome and 1 had Turner syndrome and were excluded from the study. Results The patient population comprised 52 girls and 16 boys. Their mean age was 16.8 years, mean body weight at operation was 125 kg (mean body mass index 46 kg/m 2 ). Operative mortality was nil. The mean follow-up was 11 years (range 2–23). The mean percentage of loss of initial excess weight at each patient's longest follow-up was 78%. Before surgery, 33 patients were hypertensive (49%), 11 were dyslipidemic (16%), 3 were hyperglycemic, and 2 had type 2 diabetes. At the longest follow-up period after surgery, only 6 patients were hypertensive, and none were dyslipidemic or diabetic. A total of 19 reoperations were performed in 14 patients (20%), including 7 revisions. Eleven patients developed protein malnutrition 1–10 years after BPD. The long-term mortality rate was 4%. At 4 to 23 years after BPD, 18 of the women had given birth to 28 healthy babies. Three women had had a complicated pregnancy. Conclusion Adolescents can undergo malabsorptive bariatric surgery with excellent long-term weight loss results and an incidence of long-term complications similar to that observed during the 30-year evolution of BPD in our experience.