Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Spread patterns and effectiveness for surgery after ultrasound-guided rectus sheath block in adult day-case patients scheduled for umbilical hernia repair

Background and Aims: We conducted a prospective study to examine the local anesthetic (LA) spread and the effectiveness for surgical anesthesia of ultrasound (US)-guided rectus sheath block (RSB) in adult patients undergoing umbilical hernia repair. Material and Methods: Thirty patients received at T-10 level a bilateral US-guided injection of 20 mL levobupivacaine 0.375% + epinephrine 5 μg/mL behind the rectus muscle to detach it from its sheath. Anesthetic spread into the rectus sheath was evaluated ultrasonographically at T-9 and T-11 levels and scored from 0 to 4. The RSB was defined effective for surgical anesthesia if it was able to guarantee an anesthetic level sufficient for surgery without any mepivacaine supplementation. Results: Overall, the block was effective for surgical anesthesia in 53.3% of patients (95% confidence interval, ±17.8). In the remaining patients, anesthesia supplementation was needed at cutaneous incision, whereas manipulation of the muscle and fascial planes was painless. No patients required general anesthesia. LA spreads as advocated (to T-9 and to T-11 bilaterally = spread score 4) in 8/30 patients (26.6%); in these cases, the block was 75% effective for surgery. The anesthetic spread was most negatively influenced by increased body mass index. Postoperative analgesia was excellent in 97% of patients. Conclusion: Use of RSB as an anesthetic management of umbilical herniorrhaphy is recommended only with anesthetic supplementation at the incision site

Barley starch

This thesis examined barley amylopectin structure and looked for correlations between the structure and physical properties of starch. The structure of amylopectin and gelatinisation and retrogradation of starch were studied in 10 different barley cultivars/breeding lines with differing genetic background. Amylopectin is built up of thousands of chains of glucose monomers, organised into clusters. The detailed fine structure of amylopectin was studied by isolating clusters of amylopectin and their building blocks, which are the tightly branched units building up the clusters. Barley cultivars/breeding lines possessing the amo1 mutation had fewer long chains of DP≥38 in amylopectin and more large building blocks. The structure of building blocks was rather conserved between the different barley cultivars/breeding lines studied and was categorized into different size groups. These different building blocks were shown to be randomly distributed in the amylopectin molecule. The C-chains in amylopectin can be of any length and are a category of chains different from the B-chains. The backbone in amylopectin consists of a special type of B-chains which, when cleaved by α-amylase, become chains of a similar type to C-chains. Gelatinisation and retrogradation (recrystallisation of gelatinised starch) of barley starch was studied by differential scanning calorimetry. The amo1 mutation resulted in a broader gelatinisation temperature range and a higher enthalpy of retrogradation. Other structural features were also found to influence the physical properties of starch. Small clusters and denser structure of the building blocks resulted in higher gelatinisation temperature. Fast retrogradation was observed in barley which had amylopectin with shorter chains and many large building blocks consisting of many chains. Amylopectin structure was also studied in developing barley kernels. Three barley cultivars/breeding lines were grown in a phytotron and kernels were harvested at 9, 12 and 24 days after flowering. The results showed that amylopectin synthesized at later stages of development had a more tightly branched structure. Expression of the enzymes involved in starch biosynthesis is also known to change during endosperm development

Early weight loss in amyotrophic lateral sclerosis: outcome relevance and clinical correlates in a population-based cohort

Objectives: To assess the role of body mass index (BMI) and of the rate of weight loss as prognostic factors in amyotrophic lateral sclerosis (ALS) and to explore the clinical correlates of weight loss in the early phases of the disease. Methods: The study cohort included all ALS patients in Piemonte/Valle d'Aosta in the 2007-2011 period. Overall survival and the probability of death/tracheostomy at 18 months (logistic regression model) were calculated. Results: Of the 712 patients, 620 (87.1%) were included in the study. Patients ' survival was related to the mean monthly percentage of weight loss at diagnosis (p<0.0001), but not to pre-morbid BMI or BMI at diagnosis. Spinal onset patients with dysphagia at diagnosis had a median survival similar to bulbar onset patients. About 20% of spinal onset patients without dysphagia at diagnosis had severe weight loss and initial respiratory impairment, and had a median survival time similar to bulbar onset patients. Conclusions: The rate of weight loss from onset to diagnosis was found to be a strong and independent prognostic factor in ALS. Weight loss was mainly due to the reduction of nutritional intake related to dysphagia, but a subgroup of spinal onset patients without dysphagia at diagnosis had a severe weight loss and an outcome similar to bulbar patients. According to our findings, we recommend that in clinical trials patients should be stratified according to the presence of dysphagia at the time of enrolment and not by site of onset of symptoms

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Implementation of the ERAS (Enhanced Recovery after Surgery) protocol for colorectal cancer surgery in the Piemonte Region with an Audit and Feedback approach: Study protocol for a stepped wedge cluster randomised trial: A study of the EASY-NET project

Introduction The ERAS protocol (Enhanced Recovery After Surgery) is a multimodal pathway aimed to reduce surgical stress and to allow a rapid postoperative recovery. Application of the ERAS protocol to colorectal cancer surgery has been limited to a minority of hospitals in Italy. To promote the systematic adoption of ERAS in the entire regional hospital network in Piemonte an Audit and Feedback approach (A&F) has been adopted together with a cluster randomised trial to estimate the true impact of the protocol on a large, unselected population. Methods A multicentre stepped wedge cluster randomised trial is designed for comparison between standard perioperative management and the management according to the ERAS protocol. The primary outcome is the length of hospital stay (LOS). Secondary outcomes are: incidence of postoperative complications, time to patients' recovery, control of pain and patients' satisfaction. With an A&F approach the adherence to the ERAS items is monitored through a dedicated area in the study web site. The study includes 28 surgical centres, stratified by activity volume and randomly divided into four groups. Each group is randomly assigned to a different activation period of the ERAS protocol. There are four activation periods, one every 3 months. However, the planned calendar and the total duration of the study have been extended by 6 months due to the COVID-19 pandemic. The expected sample size of about 2200 patients has a high statistical power (98%) to detect a reduction of LOS of 1 day and to estimate clinically meaningful changes in the other endpoints. Ethics and dissemination The study protocol has been approved by the Ethical Committee of the coordinating centre and by all participating centres. Study results will be timely circulated within the hospital network and published in peer-reviewed journals. Trial registration number NCT04037787

Risk of Guillain-Barr\ue9 syndrome after 2010-2011 influenza vaccination

Influenza vaccination has been implicated in Guillain Barr\ue9 Syndrome (GBS) although the evidence for this link is controversial. A case-control study was conducted between October 2010 and May 2011 in seven Italian Regions to explore the relation between influenza vaccination and GBS. The study included 176 GBS incident cases aged 6518 years from 86 neurological centers. Controls were selected among patients admitted for acute conditions to the Emergency Department of the same hospital as cases. Each control was matched to a case by sex, age, Region and admission date. Two different analyses were conducted: a matched case-control analysis and a self-controlled case series analysis (SCCS). Case-control analysis included 140 cases matched to 308 controls. The adjusted matched odds ratio (OR) for GBS occurrence within 6 weeks after influenza vaccination was 3.8 (95 % CI: 1.3, 10.5). A much stronger association with gastrointestinal infections (OR = 23.8; 95 % CI 7.3, 77.6) and influenza-like illness or upper respiratory tract infections (OR = 11.5; 95 % CI 5.6, 23.5) was highlighted. The SCCS analysis included all 176 GBS cases. Influenza vaccination was associated with GBS, with a relative risk of 2.1 (95 % CI 1.1, 3.9). According to these results the attributable risk in adults ranges from two to five GBS cases per 1,000,000 vaccinations