PRELIMINARY RESULTS OF A PHASE I / II STUDY WITH PERIODIC CYCLES OF A LOW-PROTEIN AND ONLY MODERATELY LOW-CALORIE DIET IN PATIENTS WITH COGNITIVE IMPAIRMENT

Aim of the study: several preclinical studies have shown that calorie restriction has a protective effect against aging, oxidative stress and neurodegenerative diseases. Moreover, cycles of a diet designed to recreate the metabolic consequences of fasting (Fasting-Miming Diet, DMD) produced neuro-regenerative effects in mouse models of Alzheimer's disease (AD). In consideration of the above results, a randomized, single-blind, multi-centric phase I / II clinical trial of low-protein and low-calorie DMD (ProlonADTM) was conducted in patients diagnosed with mild AD or with amnestic Mild Cognitive Impairment (aMCI). Methods: The clinical study involves the enrollment of 40 patients in good nutritional status at the San Martino Polyclinic Hospital in Genoa and at the Perugia Hospital. Once eligibility is ascertained, patients are randomly assigned to the experimental arm, in which 12 monthly cycles of ProlonADTM for 5 consecutive days and a series of dietary supplements known to have neuro-protective properties are administered, or to the placebo arm, which involves 12 cycles of a placebo diet. Both diets are produced and provided free of charge by L-Nutra. The feasibility of ProlonADTM is assessed by monitoring the percentage of patients able to follow the assigned diet, while the safety assessment is linked to the estimate of grade ≥ 3 adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Secondary objectives include assessing the impact of DMD on patients' cognitive and functional status, quality of life, mood, nutritional status, body composition, caregiver burden and inflammatory, oxidative stress and of neuronal damage. Results: The enrollment of 40 patients ended in July 2022. For ProlonADTM, 8 patients (40%) completed the 12 cycles, while 5 patients (25%) were on treatment. For the placebo diet, 10 patients (50%) completed the 12 cycles, while 2 patients (10%) were on treatment. The dropout results in a similar number of patients in the two groups: in particular for ProlonADTM at the moment there are 7 patients (35%), while for the placebo diet 8 (40%). Regarding the adverse events, they mainly occurred in the treatment group in 12 patients (60%), but they are all mild or moderate (G1-2). The nutritional data show a similar trend of the two groups in the first six months as regards body composition. There is a reduction in weight in the treatment group compared to placebo, but when analyzing the odds ratios adjusted for the number of assessments and sex, there are no differences attributable to the assignment group. Finally, evaluating the neuropsychological data, a worsening on the cognitive level of the placebo group is highlighted, not evident in the treatment group. Conclusions: Overall, the data collected so far indicate a fair safety and feasibility of ProlonADTM, with a possible protective effect of the latter on cognitive decline. The above data will be confirmed at the end of the study and with further phase III clinical studies

Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models

The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer's disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls. Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients. These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain

Twelve Variants Polygenic Score for Low-Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

: Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P<0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (P<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, P<0.0001; 250-349 mg/dL: 1.02 versus 0.95, P=0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p &lt; 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Correction to: Two years later: Is the SARS-CoV-2 pandemic still having an impact on emergency surgery? An international cross-sectional survey among WSES members

Background: The SARS-CoV-2 pandemic is still ongoing and a major challenge for health care services worldwide. In the first WSES COVID-19 emergency surgery survey, a strong negative impact on emergency surgery (ES) had been described already early in the pandemic situation. However, the knowledge is limited about current effects of the pandemic on patient flow through emergency rooms, daily routine and decision making in ES as well as their changes over time during the last two pandemic years. This second WSES COVID-19 emergency surgery survey investigates the impact of the SARS-CoV-2 pandemic on ES during the course of the pandemic. Methods: A web survey had been distributed to medical specialists in ES during a four-week period from January 2022, investigating the impact of the pandemic on patients and septic diseases both requiring ES, structural problems due to the pandemic and time-to-intervention in ES routine. Results: 367 collaborators from 59 countries responded to the survey. The majority indicated that the pandemic still significantly impacts on treatment and outcome of surgical emergency patients (83.1% and 78.5%, respectively). As reasons, the collaborators reported decreased case load in ES (44.7%), but patients presenting with more prolonged and severe diseases, especially concerning perforated appendicitis (62.1%) and diverticulitis (57.5%). Otherwise, approximately 50% of the participants still observe a delay in time-to-intervention in ES compared with the situation before the pandemic. Relevant causes leading to enlarged time-to-intervention in ES during the pandemic are persistent problems with in-hospital logistics, lacks in medical staff as well as operating room and intensive care capacities during the pandemic. This leads not only to the need for triage or transferring of ES patients to other hospitals, reported by 64.0% and 48.8% of the collaborators, respectively, but also to paradigm shifts in treatment modalities to non-operative approaches reported by 67.3% of the participants, especially in uncomplicated appendicitis, cholecystitis and multiple-recurrent diverticulitis. Conclusions: The SARS-CoV-2 pandemic still significantly impacts on care and outcome of patients in ES. Well-known problems with in-hospital logistics are not sufficiently resolved by now; however, medical staff shortages and reduced capacities have been dramatically aggravated over last two pandemic years

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Evaluation of the efficacy of plant sterols supplement sterolip\uae ESI in patients with type IIA hypercholesterolemia in relation to Genetic variants modulating intestinal absorption of cholesterol

Background and aim: Phytosterols (PS) are recommended by European Guidelines for the treatment of hypercholesterolemia. This study aims to evaluate the lipid-lowering activity of a PS supplement (STEROLIP\uae ESI) in subjects with hypercholesterolemia and the influence of genetic variants involved in cholesterol absorption in the modulation of the individual response to PS. Methods: 60 subjects suffering from hypercholesterolemia were randomized to PS supplement STEROLIP\uae 1.6g/day or to placebo for 6 weeks, and subsequently they were all switched to the supplementation with PS for another 6 weeks. At baseline and every 3 weeks, anthropometric measures and lipid profile were collected. All patients were also genotyped for three genetic polymorphisms involved in intestinal cholesterol absorption (APOE, NPC1L1 and ABCG8). Results: After 3 weeks, TC and LDL-C were significantly lower in PS group. In the 28 patients treated for 12 weeks with PS, we obtained the highest effect after 9 weeks (-8.3% for TC and -12% for LDL-C). We observed a greater reduction of TC and LDL-Cin subjects carrying the E4 allele of APOE gene, in homozygous subjects for the rare allele of NPC1L1 rs2072183 polymorphism and in heterozygous carriers of rare allele rs11887534 in ABCG8 gene than in other genotypes. Conclusion: This study confirms the lipid-lowering effect of PS that is maintained even in the midterm. We highlighted that genetic variants influencing the intestinal cholesterol absorption can contribute to the inter-individual variability of the response of PS supplementatio

Effects of a Mediterranean Diet, Dairy, and Meat Products on Different Phenotypes of Dyslipidemia: A Preliminary Retrospective Analysis

Background: Dyslipidemia is one of the major causes of atherosclerotic cardiovascular disease (ASCVD) and a Mediterranean Diet (MD) is recommended for its prevention. The objectives of this study were to evaluate adherence to an MD at baseline and follow-up, in a cohort of dyslipidemic patients, and to evaluate how different food intakes can influence lipid profile, especially how different sources of saturated fatty acids impact lipid phenotype. Methods: A retrospective analysis was conducted on 106 dyslipidemic patients. Clinical characteristics, lipid profile, and food habits data were collected at baseline and after three months of follow-up with counseling. Adherence to an MD was evaluated with a validated food-frequency questionnaire (MEDI-LITE score). Results: The cross-sectional analysis showed that higher consumption of dairy products correlated independently with higher levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) and with lower triglycerides (TG) levels. Instead, lower HDL-C and TG levels and higher TC levels were independently associated with higher consumption of meat products. Adherence to an MD significantly improved after the follow-up period, from a mean value of 10 ± 3 (median 10, IQR 8–12) to 13 ± 2 (median 14, IQR 12–15), p &lt; 0.0001. Conclusions: Dyslipidemic patients benefit from counseling for improving their adherence to an MD. The high intake of dairy products was associated with less atherogenic hyperlipidemia, which was characterized by higher levels of TC and HDL-C as compared withs the intake of an excessive amount of meat products, which was associated with higher levels of TC and TG and lower levels of HDL-C

Thermo-Vacuum Modification of Poplar Veneers and its Quality Control

Poplar wood is commonly used for many purposes due to its easy machinability, low density, uniform light colour, and relatively low cost. Here, vacuum thermal treatment is proposed for upgrading veneers in the manufacturing of plywood panels with resulting reduced hygroscopicity, improved durability, and dimensional stability. Thirty-eight batch processes with different treatment conditions (temperature ranging from 150 to 240 °C, time from 0.5 to 22.5 h and pressure from 100 to 1000 mbar) were performed to characterize the influence of process parameters on the product properties. Samples were characterized considering their appearance (colour) and their physical (mass loss and equilibrium moisture content), mechanical (bending strength), and chemical (investigated with near infrared spectroscopy (NIR)) properties. The darkening of poplar veneers and the reduction of mechanical strength were observed with increased treatment time and intensity. Mass loss closely correlated with colour change, resulting from chemical changes in wood components. Principal component analysis (PCA) and partial least squares (PLS) were used for evaluation of near infrared spectral data. Both were correlated with several technical properties, and thus NIR allowed the simultaneous prediction of several of these properties. Both colour change and NIR could be used to optimize the thermal treatment of poplar veneers at the industrial scale and for real-time statistical process control