Sensory Involvement in Amyotrophic Lateral Sclerosis.

Although amyotrophic lateral sclerosis (ALS) is pre-eminently a motor disease, the existence of non-motor manifestations, including sensory involvement, has been described in the last few years. Although from a clinical perspective, sensory symptoms are overshadowed by their motor manifestations, this does not mean that their pathological significance is not relevant. In this review, we have made an extensive description of the involvement of sensory and autonomic systems described to date in ALS, from clinical, neurophysiological, neuroimaging, neuropathological, functional, and molecular perspectives.

Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.

Importance: The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. Objective: To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. Design, Setting, and Participants: Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. Interventions: A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. Main Outcomes and Measures: The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). Results: Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%). Conclusions and Relevance: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT03548987.

Energetics and structures of the tilted phases of fatty acid Langmuir monolayers.

Langmuir monolayers are monomolecular deep films composed of amphiphilic molecules which are typically confined to a water/air interface in a bi-dimensional structure. Due to the important applications in many research areas, they have been studied for many years. Their phase diagrams present several condensed phases, showing untilted or tilted structures at low values of surface pressure. In this paper, we present a novel density functional study on tilted phases of different fatty acid Langmuir monolayers. By means of this study, a further understanding of the physical chemistry properties and the nature of the formation of tilted monolayers can be achieved. Our calculations reveal that, regardless of the number of carbon atoms which form the apolar chain, the transversal (or conventional in the case of untilted phases) unit cell shows similar dimensions, ca. 4.9 × 6.8 Å, which is in fair agreement with the range of the observed data. The energy variation of the unit cell as a function of the inclination of the molecules, reveals an abrupt increase in values larger than 45° and 36° for NN- and NNN-tilt, respectively, in fair agreement with the experimental observation of L2h (NN) and L2' (NNN) phases of fatty acids. All of the fatty acids explored (from 10 to 19 carbon atoms) yield similar results. Finally, the energetics and structural changes of the monolayer along the variation of the area per molecule, obtained by enlarging in a-, b- or both axes of the untilted unit cell, have been explored. This study reveals that the untilted phases are energetically more stable at low values of area per molecule (high surface concentration), as it is expected. When the area per molecule values are increased, tilted phases (along NN or NNN-direction) with b/a ratio typical of herringbone (HB) or pseudo-herringbone (PHB) structures are found in the lowest energy configurations, which depend on how the distortion of the untilted unit cell is performed. For example, HB structures are the most stable when the molecules tilt along the enlarged axis of the untilted unit cell (a or b), meanwhile unit cell structures characteristic of PHB configurations occur in the opposite cases and at larger values of the area per molecule (low surface concentrations). All these predictions are in good agreement with the GIXD observations of the different phases of the phase diagram of fatty acid Langmuir monolayers.

A Mediterranean Diet with an Enhanced Consumption of Extra Virgin Olive Oil and Pistachios Improves Pregnancy Outcomes in Women Without Gestational Diabetes Mellitus: A Sub-Analysis of the St. Carlos Gestational Diabetes Mellitus Prevention Study.

AIMS: The aim of the study was to evaluate the effect of a Mediterranean diet (MedDiet), enhanced with extra virgin olive oil (EVOO) and nuts, on a composite of adverse maternofoetal outcomes of women with normoglycemia during pregnancy. METHODS: This was a sub-analysis of the St Carlos gestational diabetes mellitus Prevention Study. Only normoglycemic women were analysed (697). They were randomized (at 8-12th gestational weeks) to: standard-care control group (337), where fat consumption was limited to 30% of total caloric intake; or intervention group (360), where a MedDiet, enhanced with EVOO and pistachios (40-42% fats of total caloric intake) was recommended. The primary outcome was a composite of maternofoetal outcomes (CMFOs): at least having 1 event of emergency C-section, perineal trauma, pregnancy-induced hypertension and preeclampsia, prematurity, large-for-gestational-age and small-for gestational-age. RESULTS: Crude relative risk showed that the intervention was associated with a significant reduction in the risk of CMFOs (0.48 [0.37-0.63]; p = 0.0001), with a number-needed-to-treat = 5. Risk of urinary tract infections, emergency C-sections, perineal trauma, large-for-gestational-age and small-for gestational age new-borns were also significantly reduced. CONCLUSION: A MedDiet, enhanced with EVOO and nuts, was associated with a risk reduction of CMFOs in over 50% in normoglycemic pregnant women. Therefore, it might be a potentially adequate diet for pregnant women. TRIAL REGISTRATION: Identifier ISRCTN84389045. The study was registered on September 27, 2013. Last edited on September 26, 2018.

Cardiovascular Risk Factors After Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy (SADI-S): a New Effective Therapeutic Approach?

Obesity and its associated comorbidities entail a significantly increased cardiovascular mortality. Therefore, approaching obesity control must include among its aims the reduction of the associated comorbidities and the higher cardiovascular mortality risk and not only weight loss. Many observational studies indicate that bariatric surgery (BS) is associated with a better long-term survival than standard care. Furthermore, in general, these epidemiological studies included patients who underwent gastric bypass (GB), not biliopancreatic diversion/duodenal switch (BPD/DS), so the potential additional benefit of this latter technique remains unknown. In this regard, in theory, derivative techniques are usually associated to a higher rate of long-term improvement of metabolic comorbidities, so their potential impact on cardiovascular morbidity and mortality could be even greater than what has been published up to date. In 2007, our group proposed a simplification of the bariatric technique based on the duodenal switch, which we termed "single anastomosis duodeno-ileal bypass with sleeve gastrectomy" or SADI-S. In this review, and 10 years later, we describe some of the main results of those patients who underwent this procedure, specifically regarding their outcome on metabolic comorbidities and cardiovascular risk. Considering the findings presented in this review, in which a significant improvement of all metabolic comorbidities was observed, we may confidently suggest that SADI-S seems comparable to a BPD/DS procedure in the mid-term outcome. After all, the SADI-S procedure was conceived as a simplified version of the BPD/DS technique and not necessarily intended to maximize the improvement of cardiovascular and metabolic comorbidities, which is already sufficiently optimal. In this regard, in our experience, we have encountered a new satisfactory result, which combines more pros than cons. In fact, as we have seen, after a follow-up of 3 years, the outcomes of weight loss and improvement of blood pressure, lipid profile, and insulin resistance seem to be better with SADI-S than with Roux-en-Y gastric bypass (RYGB), and this difference may be probably still relevant in the long-term evaluation. SUMMARY: Mid-term follow-up of patients who underwent SADI-S has proven that this procedure seems, at least, as effective as other malabsorptive techniques such as BPD/DS and significantly reduces the four main cardiovascular risk factors to a higher extent than RYGB. One of the main advantages inherent to this intervention modality is that it truly simplifies any of the prior derivative procedures and that it may be specifically adapted and individualized to each patient, according to his BMI and associated metabolic comorbidities.

Involvement of sensory innervation in the skin of SOD1(G93A) ALS mice.

Sensory alterations have been described in both amyotrophic lateral sclerosis (ALS) patients and mouse models. While involvement of intraepidermal and subepidermal axons has been shown in skin biopsies of ALS patients, it is unclear if the SOD1(G93A) mouse presents similar alterations. We analyzed the epidermal and dermal innervation, based on PGP9.5 immunostaining, of SOD1(G93A) mice at different stages. The results showed a marked reduction of intraepidermal nerve fibers, Meissner's corpuscles, and subepidermal nerve density already at 4 weeks. This loss of innervation progressed over time. Dermal axonal density decreased at a later stage of the disease. There was a gradient of axonal loss, with a more severe decline in the epidermis compared with deeper structures, indicating a distal axonal neuropathy as the mechanism of degeneration. These findings suggest that the analysis of the cutaneous sensory innervation may be an accessible and useful tool to assess the neurodegeneration process in motoneuron diseases.

Carbon and water footprint of pork supply chain in Catalonia: From feed to final products.

A systematic tool to assess the Carbon Footprint (CF) and Water Footprint (WF) of pork production companies was developed and applied to representative Catalan companies. To do so, a cradle-to-gate environmental assessment was carried out by means of the LCA methodology, taking into account all the stages involved in the pork chain, from feed production to the processing of final products, ready for distribution. In this approach, the environmental results are reported based on eight different functional units (FUs) according to the main pork products obtained. With the aim of ensuring the reliability of the results and facilitating the comparison with other available reports, the Product Category Rules (PCR) for Catalan pork sector were also defined as a basis for calculations. The characterization results show fodder production as the main contributor to the global environmental burdens, with contributions higher than 76% regardless the environmental indicator or the life cycle stage considered, which is in agreement with other published data. In contrast, the results in terms of CF and WF lay above the range of values reported elsewhere. However, major discrepancies are mainly due to the differences in the co-products allocation criteria. In this sense, economic/physical allocation and/or system expansion have been mostly considered in literature. In contrast, no allocation was considered appropriate in this study, according to the characteristics of the industries and products under assessment; thus, the major impacts fall on the main product, which derives on comparatively higher environmental burdens. Finally, due to the relevance of fodder production in the overall impact assessment results, strategies to reduce greenhouse gases (GHG) emissions as well as water use associated to this stage were proposed in the pork supply chain.

A Simplified Screening Model to Predict the Risk of Gestational Diabetes Mellitus in Caucasian and Latin American Pregnant Women.

The pathophysiology of gestational diabetes mellitus (GDM) comprises clinical and genetic factors. In fact, GDM is associated with several single nucleotide polymorphisms (SNPs). This study aimed to build a prediction model of GDM combining clinical and genetic risk factors. A total of 1588 pregnant women from the San Carlos Cohort participated in the present study, including 1069 (67.3%) Caucasian (CAU) and 519 (32.7%) Latin American (LAT) individuals, and 255 (16.1%) had GDM. The incidence of GDM was similar in both groups (16.1% CAU and 16.0% LAT). Genotyping was performed via IPLEX Mass ARRAY PCR, selecting 110 SNPs based on literature references. SNPs showing the strongest likelihood of developing GDM were rs10830963, rs7651090, and rs1371614 in CAU and rs1387153 and rs9368222 in LAT. Clinical variables, including age, pre-pregnancy body mass index, and fasting plasma glucose (FPG) at 12 gestational weeks, predicted the risk of GDM (AUC 0.648, 95% CI 0.601-0.695 in CAU; AUC 0.688, 95% CI 0.628-9.748 in LAT), and adding SNPs modestly improved prediction (AUC 0.722, 95%CI 0.680-0.764 in CAU; AUC 0.769, 95% CI 0.711-0.826 in LAT). In conclusion, adding genetic variants enhanced the prediction model of GDM risk in CAU and LAT pregnant women.

Which criteria should be used to define type 2 diabetes remission after bariatric surgery?

BACKGROUND: Comparison of diabetes remission rates after bariatric surgery using two different models of criteria. METHODS: Retrospective analysis of data from 110 patients with type 2 diabetes and morbid obesity who underwent bariatric surgery, preoperatively and at 18-month follow-up. Comparison of two models of remission: 1) 2009 consensus statement criteria; 2) simple criteria using ADA's HbA1c diabetes diagnostic cut-off values. RESULTS: Patients' mean ± SD preoperative characteristics were: age 53.3 ± 9.5 years, BMI 43.6 ± 5.5 kg/m(2), HbA1c 7.9 ± 1.8%, duration of diabetes 7.6 ± 7.5 years. 44.5% of patients with previous insulin therapy. With 2009 consensus statement criteria: complete, partial and no remission in 50%, 12.7% and 37.3%, respectively; with HbA1c criteria: 50%, 15% and 34.5% in the analogous categories (p=0.673). CONCLUSIONS: We suggest a simpler approach to evaluate diabetes remission after bariatric surgery, following the rationale of the definition of diabetes itself.

An Early Mediterranean-Based Nutritional Intervention during Pregnancy Reduces Metabolic Syndrome and Glucose Dysregulation Rates at 3 Years Postpartum.

A Mediterranean diet (MedDiet)-based intervention reduces the rate of immediate postpartum maternal metabolic disorders. Whether these effects persist long-term remains to be determined. A total of 2526 normoglycemic women were randomized before the 12th gestational week (GW). IG women followed a MedDiet with extra virgin olive oil (EVOO) (>40 mL/day) and a handful of nuts daily, whereas CG women had to restrict all kinds of dietary fat. At 3 months postpartum, a motivational lifestyle interview was held. The endpoint of the study evaluated the rate of abnormal glucose regulation (AGR) and metabolic syndrome (MetS) at 3 years postpartum in women of the San Carlos cohort. A total of 369/625 (59%) CG women and 1031/1603 (64.3%) IG women were finally analyzed. At 3 months and 3 years postdelivery, the IG women showed higher adherence to the MedDiet, which was associated with lower values of body mass index (BMI) and lipid and glycemic profiles. Body weight change and waist circumference were lower in the IG women. After applying multiple regression analysis, the ORs (95%CI) resulted in AGR (3.18 (2.48-4.08); p < 0.001)/MetS (3.79 (1.81-7.95); p = 0.001) for women with GDM and higher OR for development of MetS in CG women (3.73 (1.77-7.87); p = 0.001). A MedDiet-based intervention early in pregnancy demonstrated persistent beneficial effects on AGR and MetS rates at 3 years postpartum.

Modifiable Risk Factors and Trends in Changes in Glucose Regulation during the First Three Years Postdelivery: The St Carlos Gestational Diabetes Mellitus Prevention Cohort.

OBJECTIVE: Evaluation of the influence of potential risk factors (RFs) on glycemic changes at 3 years postpartum. METHODS: The glycemic status of 1400 women, in absence of a new pregnancy, was evaluated at 3 months (3 m) and 3 years (3 y) postpartum, after participation in the St. Carlos Gestational Study (2228 normoglycemic pregnant women followed from before gestational week 12 to delivery, from 2015-2017). Abnormal glucose regulation (AGR) was defined as fasting serum glucose ≥ 100 mg/dL and/or HbA1c ≥ 5.7% and/or 2 h 75 g OGTT glucose ≥ 140 mg/dL. In total, 12 modifiable and 3 unmodifiable RFs were analyzed. RESULTS: 3 m postpartum, 110/1400 (7.9%) women had AGR; 3 y postpartum, 137 (9.8%) women exhibited AGR (110 with 3 m normal glucose tolerance [NGT]); 1263 (90.2%) had NGT (83 with 3 m AGR). More women with gestational diabetes mellitus (GDM) progressed to AGR at 3 y (OR: 1.60 [1.33-1.92]) than women without GDM. Yet, most women with 3 m and/or 3 y AGR had no GDM history. Having ≥2 unmodifiable RFs was associated with increased risk for progression to AGR (OR: 1.90 [1.28-2.83]) at 3 y postpartum. Having >5/12 modifiable RFs was associated with increased progression from NGT to AGR (OR: 1.40 [1.00-2.09]) and AGR persistence (OR: 2.57 [1.05-6.31]). Pregestational BMI ≥ 25 kg/m2 (OR: 0.59 [0.41-0.85]), postdelivery weight gain (OR: 0.53 [0.29-0.94]), and waist circumference > 89.5 cm (OR: 0.54 [0.36-0.79]) reduced the likelihood of NGT persisting at 3 y. CONCLUSIONS: 3-month and/or 3-year postpartum AGR can be detected if sought in women with no prior GDM. Modifiable and unmodifiable RF predictors of AGR at 3 y postpartum were identified. Universal screening for glycemic alterations should be considered in all women following delivery, regardless of prior GDM. These findings could be useful to design personalized strategies in women with risk factors for 3 y AGR.

Personality profiles between obese and control subjects assessed with five standardized personality scales.

BACKGROUND/AIM: Psychopathology may exert influence on developing and maintaining obesity. Studies of personality traits or psychopathology of personality in obesity are scarce and contradictory. The aim of this study was to compare personality profiles between obese and normal-weight subjects and to determine the most useful tool to detect differences, considering that psychological assessment and psychotherapeutical support should be included within the overall management of these patients.* METHOD: We examined 55 obese subjects (mean BMI=43kg/ m2) and 66 controls (mean BMI =21.7kg/m2). We used the personality assessment tools: MCMI-II, TCI-R, EPQ-A, BIS-111 and SSS. Factorial multivariate analysis of variance was applied; with factors BMI, Gender and Age as a covariate. RESULTS: Significant differences between groups were more marked in the clinical syndrome scales of MCMI-II, particularly in Major-Depression, Thought-Disorder, Anxiety, Somatoform and Alcohol-Dependence. Among obese, women scored higher than men in all scales but not significantly. We have found significant differences in normal personality dimensions between both groups in TCI-R. Obese showed higher scores in Harm Avoidance, and lower in Novelty Seeking, Persistence and Self-transcendence. The remaining tests have not been useful for differentiating personality traits between both groups. CONCLUSION: Obese subjects showed different personality profiles than control subjects. The most useful scales for determining these differences might be those designed to assess pathological personality such as MCMI-II. Less important would be those intended to measure normal personality traits, such as TCI-R and EPQ-A.

Characterization of somatosensory neuron involvement in the SOD1G93A mouse model.

SOD1G93A mice show loss of cutaneous small fibers, as in ALS patients. Our objective is to characterize the involvement of different somatosensory neuron populations and its temporal progression in the SOD1G93A mice. We aim to further define peripheral sensory involvement, analyzing at the same time points the neuronal bodies located in the dorsal root ganglia (DRG) and the distal part of their axons in the skin, in order to shed light in the mechanisms of sensory involvement in ALS. We performed immunohistochemical analysis of peptidergic (CGRP), non-peptidergic (IB4) fibers in epidermis, as well as sympathetic sudomotor fibers (VIP) in the footpads of SOD1G93A mice and wild type littermates at 4, 8, 12 and 16 weeks of age. We also immunolabeled and quantified neuronal bodies of IB4, CGRP and parvalbumin (PV) positive sensory neurons in lumbar DRG. We detected a reduction of intraepidermal nerve fiber density in the SOD1G93A mice of both peptidergic and non-peptidergic axons, compared with the WT, being the non-peptidergic the fewest. Sweat gland innervation was similarly affected in the SOD1G93A mouse at 12 weeks. Nonetheless, the number of DRG neurons from different sensory populations remained unchanged during all stages. Cutaneous sensory axons are affected in the SOD1G93A mouse, with non-peptidergic being slightly more vulnerable than peptidergic axons. Loss or lack of growth of the distal portion of sensory axons with preservation of the corresponding neuronal bodies suggest a distal axonopathy.

TDP-43 Cytoplasmic Translocation in the Skin Fibroblasts of ALS Patients.

Diagnosis of ALS is based on clinical symptoms when motoneuron degeneration is significant. Therefore, new approaches for early diagnosis are needed. We aimed to assess if alterations in appearance and cellular localization of cutaneous TDP-43 may represent a biomarker for ALS. Skin biopsies from 64 subjects were analyzed: 44 ALS patients, 10 healthy controls (HC) and 10 neurological controls (NC) (Parkinson's disease and multiple sclerosis). TDP-43 immunoreactivity in epidermis and dermis was analyzed, as well as the percentage of cells with TDP-43 cytoplasmic localization. We detected a higher amount of TDP-43 in epidermis (p < 0.001) and in both layers of dermis (p < 0.001), as well as a higher percentage of TDP-43 cytoplasmic positive cells (p < 0.001) in the ALS group compared to HC and NC groups. Dermal cells containing TDP-43 were fibroblasts as identified by co-labeling against vimentin. ROC analyses (AUC 0.867, p < 0.001; CI 95% 0.800-0.935) showed that detection of 24.1% cells with cytoplasmic TDP-43 positivity in the dermis had 85% sensitivity and 80% specificity for detecting ALS. We have identified significantly increased TDP-43 levels in epidermis and in the cytoplasm of dermal cells of ALS patients. Our findings provide support for the use of TDP-43 in skin biopsies as a potential biomarker.

Effect of Obesity and Roux-En-Y Gastric Surgery on Omeprazole Pharmacokinetics.

INTRODUCTION: The prevalence of obesity is increasing globally. The principal aim was to evaluate whether gastric bypass surgery modifies the bioavailability and pharmacokinetic (PK) parameters of omeprazole. METHODS: Controlled, open-label, bioavailability clinical trial in patients undergoing Roux-en-Y gastric bypass (RYGB). Healthy patients with obesity (body mass index >35) were included and assessed for omeprazole PKs before and after RYGB (1 and 6 months). PK sampling was done at baseline and several times up to 12 h after drug dosing. Pre- and post-surgery parameters were compared using paired ANOVA or Wilcoxon tests, and control versus cases using ANOVA or Mann-Whitney tests. Given the post-surgery change in body weight, parameters were corrected by dose/body weight. RESULTS: Fourteen case and 24 control subjects were recruited; 92% were women (N = 35/38). In patients who underwent RYGB, maximum plasma concentration (Cmax) was significantly reduced at 1 and 6 months after surgery compared with presurgery values (p = 0.001). Regarding the AUC, the values are lower at 1 and 6 months after surgery than at baseline (p < 0.001). The drug clearance was also increased in the first month after surgery. No differences were found between patients 6 months after surgery and controls. Cmax and AUC corrected by dose/body weight were significantly different between the baseline surgery subjects and controls. Discusion/Conclusions: Omeprazole bioavailability is reduced in patients with obesity at 1 and 6 months after RYGB. However, omeprazole PK parameters 6 months after RYGB are similar to control subjects, and thus no dose correction is required after RYGB for a given indication.

Genetic variants for prediction of gestational diabetes mellitus and modulation of susceptibility by a nutritional intervention based on a Mediterranean diet.

Hypothesis: Gestational diabetes mellitus (GDM) entails a complex underlying pathogenesis, with a specific genetic background and the effect of environmental factors. This study examines the link between a set of single nucleotide polymorphisms (SNPs) associated with diabetes and the development of GDM in pregnant women with different ethnicities, and evaluates its potential modulation with a clinical intervention based on a Mediterranean diet. Methods: 2418 women from our hospital-based cohort of pregnant women screened for GDM from January 2015 to November 2017 (the San Carlos Cohort, randomized controlled trial for the prevention of GDM ISRCTN84389045 and real-world study ISRCTN13389832) were assessed for evaluation. Diagnosis of GDM was made according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Genotyping was performed by IPLEX MassARRAY PCR using the Agena platform (Agena Bioscience, SanDiego, CA). 110 SNPs were selected for analysis based on selected literature references. Statistical analyses regarding patients' characteristics were performed in SPSS (Chicago, IL, USA) version 24.0. Genetic association tests were performed using PLINK v.1.9 and 2.0 software. Bioinformatics analysis, with mapping of SNPs was performed using STRING, version 11.5. Results: Quality controls retrieved a total 98 SNPs and 1573 samples, 272 (17.3%) with GDM and 1301 (82.7%) without GDM. 1104 (70.2%) were Caucasian (CAU) and 469 (29.8%) Hispanic (HIS). 415 (26.4%) were from the control group (CG), 418 (26.6%) from the nutritional intervention group (IG) and 740 (47.0%) from the real-world group (RW). 40 SNPs (40.8%) presented some kind of significant association with GDM in at least one of the genetic tests considered. The nutritional intervention presented a significant association with GDM, regardless of the variant considered. In CAU, variants rs4402960, rs7651090, IGF2BP2; rs1387153, rs10830963, MTNR1B; rs17676067, GLP2R; rs1371614, DPYSL5; rs5215, KCNJ1; and rs2293941, PDX1 were significantly associated with an increased risk of GDM, whilst rs780094, GCKR; rs7607980, COBLL1; rs3746750, SLC17A9; rs6048205, FOXA2; rs7041847, rs7034200, rs10814916, GLIS3; rs3783347, WARS; and rs1805087, MTR, were significantly associated with a decreased risk of GDM, In HIS, variants significantly associated with increased risk of GDM were rs9368222, CDKAL1; rs2302593, GIPR; rs10885122, ADRA2A; rs1387153, MTNR1B; rs737288, BACE2; rs1371614, DPYSL5; and rs2293941, PDX1, whilst rs340874, PROX1; rs2943634, IRS1; rs7041847, GLIS3; rs780094, GCKR; rs563694, G6PC2; and rs11605924, CRY2 were significantly associated with decreased risk for GDM. Conclusions: We identify a core set of SNPs in their association with diabetes and GDM in a large cohort of patients from two main ethnicities from a single center. Identification of these genetic variants, even in the setting of a nutritional intervention, deems useful to design preventive and therapeutic strategies.

Clinical trials in pediatric ALS: a TRICALS feasibility study.

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

Flow field-based data analysis in interfacial shear rheometry.

Developments in interfacial shear rheometers have considerably improved the quality of experimental data. However, data analysis in interfacial shear rheometry is still an active field of research and development due to the intrinsic complexity introduced by the unavoidable contact of the interface with, at least, one supporting bulk subphase. Nonlinear velocity profiles, both at the interface and the bulk phases, pervade the system dynamical behavior in the most usual experimental geometries, particularly in the case of soft interfaces. Such flow configurations demand data analysis schemes based on the explicit calculation of the flow field in both the interface and the bulk phases. Such procedures are progressively becoming popular in this context. In this review, we discuss the most recent advances in interfacial shear rheology data analysis techniques. We extensively review some recently proposed flow field-based data analysis schemes for the three most common interfacial shear rheometer geometries (magnetic needle, double wall-ring, and bicone), showing under what circumstances the calculation of the flow field is mandatory for a proper analysis of the experimental data. All cases are discussed starting at the appropriate hydrodynamical models and using the equation of motion of the probe to set up an iterative procedure to compute the value of the complex Boussinesq number and, from it, the complex interfacial viscosity or, equivalently, the complex interfacial modulus. Moreover, two examples of further extensions of such techniques are proposed, concerning the micro-button interfacial shear rheometer and the potential application of interfacial rheometry instruments, together with adapted flow field-based data analysis techniques, for bulk rheometry, particularly in the case of soft samples.

DNA damaging bystander signalling from stem cells, cancer cells and fibroblasts after Cr(VI) exposure and its dependence on telomerase.

The bystander effect is a feature of low dose radiation exposure and is characterized by a signaling process from irradiated cells to non irradiated cells, which causes DNA and chromosome damage in these 'nearest neighbour' cells. Here we show that a low and short dose of Cr(VI) can induce stem cells, cancer cells and fibroblasts to chronically secrete bystander signals, which cause DNA damage in neighboring cells. The Cr(VI) induced bystander signaling depended on the telomerase status of either cell. Telomerase negative fibroblasts were able to receive DNA damaging signals from telomerase positive or negative fibroblasts or telomerase positive cancer cells. However telomerase positive fibroblasts were resistant to signals from Cr(VI) exposed telomerase positive fibroblasts or cancer cells. Human embryonic stem cells, with positive Oct4 staining as a marker of pluripotency, showed no significant increase of DNA damage from adjacent Cr and mitomycin C exposed fibroblasts whilst those cells that were negatively stained did. This selectivity of DNA damaging bystander signaling could be an important consideration in developing therapies against cancer and in the safety and effectiveness of tissue engineering and transplantation using stem cells.

Effect of a Mediterranean Diet-Based Nutritional Intervention on the Risk of Developing Gestational Diabetes Mellitus and Other Maternal-Fetal Adverse Events in Hispanic Women Residents in Spain.

Gestational diabetes mellitus (GDM) is the most frequent morbidity found in pregnancy, and it increases the risk for several maternal-fetal complications. Hispanic women are considered at high risk. The St. Carlos GDM prevention study is a randomized controlled trial (RCT) conducted from 2016-2017. Normoglycemic women were randomized at 12-14 Gestation week (WG) to an intervention group (IG) receiving recommendations based on the MedDiet (supplemented with ExtraVirgin Olive Oil/pistachios), or to a control group (CG), recommended to limit fat intake. After RCT conclusion, IG recommendations were applied to a real-world group (RW) in routine clinical practice. The primary endpoint of the current study is an assessment of the GDM rate in Hispanic participants of the aforementioned studies: 132 RCT, 128 CT, 284 RW participants. The GDM rate was lower in IG: 19/128(14.8%), p = 0.021, and RW: 38/284(13.4%), p = 0.029) than in CG: 34/132(25.8%). Adjusted RR (95%CI) for GDM: 0.72 (0.50-0.97), p = 0.037 in IG and 0.77 (0.61-0.97), p = 0.008 in RW. Rates of urinary tract infections, emergency caesarean-sections and perineal trauma were also lower in IG and RW. Other adverse outcomes were lower in IG vs. CG. In conclusion, a MedDiet-based intervention reduces the rate of GDM and several adverse maternal-fetal outcomes in Hispanic women residing in Spain.