Publications by authors named "Letizia Mazzini"

103 Publications

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 Aug 30. Epub 2021 Aug 30.

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes And Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions And Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
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http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
August 2021

Coffee and Tea Consumption Impact on Amyotrophic Lateral Sclerosis Progression: A Multicenter Cross-Sectional Study.

Front Neurol 2021 28;12:637939. Epub 2021 Jul 28.

Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

Amyotrophic lateral sclerosis (ALS) is a devastating and still untreatable motor neuron disease. The causes of ALS are unknown, but nutritional factors may impact the rate of disease progression. We aimed to ascertain the influence of coffee and tea consumption on ALS progression rate. In this multicenter cross-sectional study, we recruited 241 patients, 96 females, and 145 males; the mean age at onset was 59.9 ± 11.8 years. According to El Escorial criteria, 74 were definite ALS, 77 probable, 55 possible, and 35 suspected; 187 patients had spinal onset and 54 bulbar. Patients were categorized into three groups, according to their ΔFS (derived from ALS Functional Rating Scale-Revised score and disease duration from onset): slow (81), intermediate (80), and fast progressors (80). Current coffee consumers were 179 (74.3%), 34 (14.1%) were non-consumers, and 22 (9.1%) were former consumers, whereas six (2.5%) consumed decaffeinated coffee only. The log-ΔFS was weakly correlated with the duration of coffee consumption ( = 0.034), but not with the number of cup-years, or the intensity of coffee consumption (cups/day). Current tea consumers were 101 (41.9%), 6 (2.5%) were former consumers, and 134 (55.6%) were non-consumers. Among current and former consumers, 27 (25.2%) consumed only green tea, 51 (47.7%) only black tea, and 29 (27.1%) both. The log-ΔFS was weakly correlated only with the consumption duration of black tea ( = 0.028) but not with the number of cup-years. Our study does not support the hypothesis that coffee or tea consumption is associated with the ALS progression rate.
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http://dx.doi.org/10.3389/fneur.2021.637939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356721PMC
July 2021

Tailoring patients' enrollment in ALS clinical trials: the effect of disease duration and vital capacity cutoffs.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Aug 6:1-8. Epub 2021 Aug 6.

Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy.

To evaluate how Amyotrophic Lateral Sclerosis (ALS) patients' mortality rates change, based on different levels of forced vital capacity (FVC) and disease duration, providing a scheme of mortality rates of a real population of ALS patients to improve the design of future RCTs. : One random spirometry for each ALS patient was selected during four time intervals from disease onset: (1) ≤12 months; (2) ≤18 months; (3) ≤24 months; (4) ≤36 months. Date of spirometry corresponded to date of trial entry, while time interval onset-spirometry to disease duration at enrollment. Mortality rates from inclusion were computed at different time intervals. Based on progression rates, patients were stratified in slow, intermediate and fast progressors. Survival from recruitment was calculated depending on FVC, disease duration and progression rate. : We included 659 patients in group 1, 888 in group 2, 1019 in group 3 and 1102 in group 4. Mortality rates were higher in each group at reducing the FVC cutoff used for recruitment ( < 0.001). Median survival decreased when lowering FVC and disease duration cutoffs ( < 0.001); a higher median disease progression rate of included patients led to lower median survival from recruitment. The proportion of recruited fast progressors raised when shortening disease duration and lowering FVC cutoff. : This is a simple model for setting eligibility criteria, based on mortality rates of patients depending on FVC and disease duration, to select the best population for RCTs, tailored to trials' primary endpoints and duration.
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http://dx.doi.org/10.1080/21678421.2021.1936063DOI Listing
August 2021

Interplay between immunity and amyotrophic lateral sclerosis: Clinical impact.

Neurosci Biobehav Rev 2021 08 19;127:958-978. Epub 2021 Jun 19.

Department of Neurology and ALS Centre, University of Piemonte Orientale, Maggiore Della Carità Hospital, Corso Mazzini 18, Novara, 28100, Italy. Electronic address:

Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease. Despite decades of research and many new insights into disease biology over the 150 years since the disease was first described, causative pathogenic mechanisms in ALS remain poorly understood, especially in sporadic cases. Our understanding of the role of the immune system in ALS pathophysiology, however, is rapidly expanding. The aim of this manuscript is to summarize the recent advances regarding the immune system involvement in ALS, with particular attention to clinical translation. We focus on the potential pathophysiologic mechanism of the immune system in ALS, discussing local and systemic factors (blood, cerebrospinal fluid, and microbiota) that influence ALS onset and progression in animal models and people. We also explore the potential of Positron Emission Tomography to detect neuroinflammation in vivo, and discuss ongoing clinical trials of therapies targeting the immune system. With validation in human patients, new evidence in this emerging field will serve to identify novel therapeutic targets and provide realistic hope for personalized treatment strategies.
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http://dx.doi.org/10.1016/j.neubiorev.2021.06.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428677PMC
August 2021

What is amyotrophic lateral sclerosis prevalence?

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jun 21:1-6. Epub 2021 Jun 21.

Department of Neuroscience "Rita Levi Montalcini", ALS Center, University of Turin, Turin, Italy.

To assess amyotrophic lateral sclerosis (ALS) prevalence and to analyze how this estimate vary according to the historical depth of data collection. Data from the PARALS register have been used. Crude prevalence ratio was estimated on 31 December 2015 for the period 2015-2013 and then repeated extending the time interval by 3 years each time. For each time interval, prevalence ratio was calculated globally and stratified by sex, age at diagnosis, and phenotype. Prevalence was also calculated considering patients who underwent tracheostomy during the same study period. Prevalence ratios increased proportionally to the length of the time period considered, ranging from 6 (95% CI 5.3-6.7) for a 3-year period to 12.1 (95% CI 11.1-13.1) per 100,000 population for a 21-year period. Prevalence ratio increase was inversely proportional to age at diagnosis, being null in the >85 years class and maximal in the 25-35 age class (+1700%). Among phenotypes, predominant UMN showed the highest increase (from 0.5, 95% CI 0.3-0.8, to 2.1, 95% CI 1.7 - 2.6, +320%). : Because of the variability of ALS survival, prevalence ratio strongly depends on the length of the follow-up period. A 12-year period should be sufficient to get a reliable estimate of ALS prevalence including long-survival patients.
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http://dx.doi.org/10.1080/21678421.2021.1936557DOI Listing
June 2021

The Impact of Lifetime Alcohol and Cigarette Smoking Loads on Amyotrophic Lateral Sclerosis Progression: A Cross-Sectional Study.

Life (Basel) 2021 Apr 17;11(4). Epub 2021 Apr 17.

Neurology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

Background-Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease; smoking and alcohol drinking may impact its progression rate. Objective-To ascertain the influence of smoking and alcohol consumption on ALS progression rates. Methods-Cross-sectional multicenter study, including 241 consecutive patients (145 males); mean age at onset was 59.9 ± 11.8 years. Cigarette smoking and alcohol consumption data were collected at recruitment through a validated questionnaire. Patients were categorized into three groups according to ΔFS (derived from the ALS Functional Rating Scale-Revised and disease duration from onset): slow ( = 81), intermediate (80), and fast progressors (80). Results-Current smokers accounted for 44 (18.3%) of the participants, former smokers accounted for 10 (4.1%), and non-smokers accounted for 187 (77.6%). The age of ALS onset was lower in current smokers than non-smokers, and the ΔFS was slightly, although not significantly, higher for smokers of >14 cigarettes/day. Current alcohol drinkers accounted for 147 (61.0%) of the participants, former drinkers accounted for 5 (2.1%), and non-drinkers accounted for 89 (36.9%). The log(ΔFS) was weakly correlated only with the duration of alcohol consumption ( = 0.028), but not with the mean number of drinks/day or the drink-years. Conclusions: This cross-sectional multicenter study suggested a possible minor role for smoking in worsening disease progression. A possible interaction with alcohol drinking was suggested.
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http://dx.doi.org/10.3390/life11040352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072690PMC
April 2021

Looking backward to move forward: a meta-analysis of stem cell therapy in amyotrophic lateral sclerosis.

NPJ Regen Med 2021 Apr 1;6(1):20. Epub 2021 Apr 1.

Andalusian Network for the Design and Translation of Advanced Therapies, Andalusian Health Ministry, Sevilla, Spain.

Transplantation of several types of stem cells (SC) for the treatment of amyotrophic lateral sclerosis (ALS) has been evaluated in numerous Phase I/II clinical trials with inconclusive results. Here, we conducted a meta-analysis to systematically assess the outcome of SC therapy trials which report the evolution of each patient before and after cell administration. In this way, we aimed to determine the effect of the SC intervention despite individual heterogeneity in disease progression. We identified 670 references by electronic search and 90 full-text studies were evaluated according to the eligibility criteria. Eleven studies were included comprising 220 cell-treated patients who received mesenchymal (M) SC (n = 152), neural (N) SC (n = 57), or mononuclear cells (MNC: CD34, CD117, and CD133 positive cells) (n = 11). Our analyses indicate that whereas intrathecal injection of mesenchymal stromal cells appears to have a transient positive effect on clinical progression, as measured by the ALS functional rating score, there was a worsening of respiratory function measured by forced vital capacity after all interventions. Based on current evidence, we conclude that optimal cell product and route of administration need to be determined in properly controlled preclinical models before further advancing into ALS patients. In addition, in-depth understanding of disease mechanisms in subsets of patients will help tailoring SC therapy to specific targets and increase the likelihood of improving outcomes.
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http://dx.doi.org/10.1038/s41536-021-00131-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016966PMC
April 2021

Telehealth in Neurodegenerative Diseases: Opportunities and Challenges for Patients and Physicians.

Brain Sci 2021 Feb 13;11(2). Epub 2021 Feb 13.

Department of Neurology and ALS Centre, Traslational Medicine, University of Piemonte Orientale, Maggiore della Carità Hospital, 28100 Novara, Italy.

Telehealth, by definition, is distributing health-related services while using electronic technologies. This narrative Review describes the technological health services (telemedicine and telemonitoring) for delivering care in neurodegenerative diseases, Alzheimer's disease, Parkinson's Disease, and amyotrophic lateral Sclerosis, among others. This paper aims to illustrate this approach's primary experience and application, highlighting the strengths and weaknesses, with the goal of understanding which could be the most useful application for each one, in order to facilitate telehealth improvement and use in standard clinical practice. We also described the potential role of the COVID-19 pandemic to speed up this service's use, avoiding a sudden interruption of medical care.
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http://dx.doi.org/10.3390/brainsci11020237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917616PMC
February 2021

Do ecological factors influence the clinical presentation of amyotrophic lateral sclerosis?

J Neurol Neurosurg Psychiatry 2021 Sep 9;92(9):1017-1019. Epub 2021 Feb 9.

ALS Center, 'Rita Levi Montalcini' Department of Neurosciences, University of Turin, Torino, Italy.

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http://dx.doi.org/10.1136/jnnp-2020-325625DOI Listing
September 2021

Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series.

Neurogenetics 2021 03 20;22(1):65-70. Epub 2021 Jan 20.

Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.

Primary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.
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http://dx.doi.org/10.1007/s10048-021-00634-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997821PMC
March 2021

Functional status and oral health in patients with amyotrophic lateral sclerosis: A cross-sectional study.

NeuroRehabilitation 2021 ;48(1):49-57

Dental Clinic, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting upper and lower motor neurons. The current practice of caring for patients affected by ALS involves a multidisciplinary team without any indication about oral health care.

Objective: We sought to investigate the functional status and oral health in patients with ALS to define a specific multidisciplinary management.

Methods: In this cross-sectional study, we included patients affected by ALS, evaluating their functional status, using the Revised ALS Functional Rating Scale (ALSFRS-R) and their oral health status through specific parameters, including Brief Oral Health Status Examination (BOHSE), Winkel Tongue Coating Index (WTCI), and Oral Food Debris Index (OFDI).

Results: All 37 patients (mean age: 61.19±11.56 years) showed a poor oral status, independent from the functional status and strictly correlated to the severity of sialorrhea (p = 0.01). OFDI index was negatively correlated with the ALSFRS-R upper limb (p = 0.03). Patients with bulbar onset had significantly lower ability to perform adequate tongue movements in terms of protrusion (p = 0.006) and lateralization (p < 0.001). Significant negative correlations between survival rate and BOHSE (p = 0.03) was found.

Conclusions: Taken together, our findings showed that a poor oral health status might be correlated to a worse functional status and survival time. Thus, an adequate oral health care and rehabilitation should be considered as crucial in the multidisciplinary management of patients with ALS.
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http://dx.doi.org/10.3233/NRE-201537DOI Listing
April 2021

Detection of White Matter Ultrastructural Changes for Amyotrophic Lateral Sclerosis Characterization: A Diagnostic Study from Dti-Derived Data.

Brain Sci 2020 Dec 16;10(12). Epub 2020 Dec 16.

ALS Center & Department of Neurology, "Maggiore della Carità" Hospital, University of Piemonte Orientale (UPO), Via Solaroli 17, 28100 Novara, Italy.

In amyotrophic lateral sclerosis (ALS), magnetic resonance imaging (MRI) allows investigation at the microstructural level, employing techniques able to reveal white matter changes. In the current study, a diffusion tensor imaging (DTI) analysis, with a collection of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) indexes, was performed in ALS patients to correlate geno- and phenotype features with MRI data, to investigate an in-vivo correlation of different neuropathological patterns. All patients who underwent the MR-DTI analysis were retrospectively recruited. MRI scan was collected within three months from diagnosis. FA and ADC values were collected in corpus callosum (CC), corona radiata (CR), cerebral peduncle (CR), cerebellar peduncle (CbP) and corticospinal tract at posterior limb of internal capsule (CST). DTI analysis performed in the whole ALS cohort revealed significant FA reduction and ADC increase in all selected regions, as widespread changes. Moreover, we observed a higher value of FA in rCR in bulbar patients. A positive correlation between ALS Functional Rating Scale-Revised and FA in rCP was evident. In consideration of the non-invasiveness, the reliability and the easy reproducibility of the method, we believe that brain MRI with DTI analyses may represent a valid tool usable as a diagnostic marker in ALS.
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http://dx.doi.org/10.3390/brainsci10120996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766961PMC
December 2020

Mutational Analysis of Known ALS Genes in an Italian Population-Based Cohort.

Neurology 2021 01 18;96(4):e600-e609. Epub 2020 Nov 18.

From "Rita Levi Montalcini" Department of Neuroscience (M.G., A. Calvo, C.M., A. Canosa, U.M., R.V., A. Chiò), University of Turin, Italy; Biocomputational Group (J.D., R.J.G.) and Neuromuscular Diseases Research Section (M.G., R.C., B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD; Laboratory of Genetics, Department of Clinical Pathology (M. Brunetti, M. Barberis, L.S.), Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin; Department of Health Sciences Interdisciplinary Research Center of Autoimmune Diseases (L.C., S.D.), "Amedeo Avogadro" University of Eastern Piedmont; ALS Center (L.M.), Department of Neurology, Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy; Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics (S.W.S.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; Department of Neurology (S.W.S., B.J.T.), Johns Hopkins University Medical Center; Department of Anatomy, Physiology & Genetics (C.D.), and The American Genome Center, Collaborative Health Initiative Research Program (C.D.), Uniformed Services University of the Health Sciences, Bethesda, MD; and Institute of Cognitive Sciences and Technologies (A. Chiò), National Council of Research, Rome, Italy.

Objective: To assess the burden of rare genetic variants and to estimate the contribution of known amyotrophic lateral sclerosis (ALS) genes in an Italian population-based cohort, we performed whole genome sequencing in 959 patients with ALS and 677 matched healthy controls.

Methods: We performed genome sequencing in a population-based cohort (Piemonte and Valle d'Aosta Registry for ALS [PARALS]). A panel of 40 ALS genes was analyzed to identify potential disease-causing genetic variants and to evaluate the gene-wide burden of rare variants among our population.

Results: A total of 959 patients with ALS were compared with 677 healthy controls from the same geographical area. Gene-wide association tests demonstrated a strong association with , whose rare variants are the second most common cause of disease after expansion. A lower signal was observed for , proving that its effect on our cohort is driven by a few known causal variants. We detected rare variants in other known ALS genes that did not surpass statistical significance in gene-wise tests, thus highlighting that their contribution to disease risk in our cohort is limited.

Conclusions: We identified potential disease-causing variants in 11.9% of our patients. We identified the genes most frequently involved in our cohort and confirmed the contribution of rare variants in disease risk. Our results provide further insight into the pathologic mechanism of the disease and demonstrate the importance of genome-wide sequencing as a diagnostic tool.
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http://dx.doi.org/10.1212/WNL.0000000000011209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905787PMC
January 2021

Telehealth approach for amyotrophic lateral sclerosis patients: the experience during COVID-19 pandemic.

Acta Neurol Scand 2021 May 24;143(5):489-496. Epub 2020 Nov 24.

Department of Neurology and ALS Centre, University of Piemonte Orientale, Maggiore della Carità Hospital, Novara, Italy.

Background And Objective: Specialized multidisciplinary ALS care has been shown to extend survival and improve patient's and caregiver's quality of life. During the COVID-19 pandemic, the management of patients suddenly changed and telemedicine has been proven to be as effective as outpatient care. We elaborate the experience with Telemedicine of a Tertiary ALS Center from an Italian geographical area with high infectious risk during the COVID-19 pandemic.

Methods: 19 patients were evaluated in telemedicine by a multidisciplinary team including a neurologist (clinical evaluation, intercurrent events, and drug prescriptions); a dietician (diet and weight monitoring); a psychologist (psychological assessment and support); and a physiotherapist (physiotherapy treatment and device prescription). Telemedicine was performed using the online platform "IoMT Connected Care Platform (Ticuro Reply)."

Results: All patients reported a positive perception of talking face to face with healthcare professionals and were satisfied with how the team understood their problems. During video televisits, there was a change in the patient's medication regimen in 11/19; 2/19 required pneumological evaluation and started NIV; and 9/16 patients required prescription of devices. The mean monthly decline of ALSFRS-R before televisit was 0.88 (SD 1.17) and during televisit of 0.49 (SD 0.75). Bodyweight and daily caloric content remain stable. Reduction in HADS scores and stability in ALSAQ-40 were observed.

Discussion: Our study positively reproduced the multidisciplinary approach currently used with ALS patients, trying to stabilize the functional and metabolic status and improving the psychological one. Future directions include a personalized telemedicine program according to the patient's needs.
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http://dx.doi.org/10.1111/ane.13373DOI Listing
May 2021

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses.

Brain Commun 2020 13;2(2):fcaa124. Epub 2020 Aug 13.

Laboratory for Molecular Immunology, Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia.

Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions-excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in , , and , could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, non-selective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.
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http://dx.doi.org/10.1093/braincomms/fcaa124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585698PMC
August 2020

Critical illness neuro-myopathy (CINM) and focal amyotrophy in intensive care unit (ICU) patients with SARS-CoV-2: a case series.

Neurol Sci 2021 Mar 13;42(3):1119-1121. Epub 2020 Oct 13.

Intensive Care Department, ASL NO, Borgomanero Hospital, Novara, Italy.

We found four patients with some characteristic phenotype in our ICU, characterized by focal hypotrophies of the shoulder girdle and the bilateral peroneal district and underlying critical illness neuro-myopathy. In our opinion, these hypotrophies are secondary to the prone position. Is our intention to start early treatment protocol with electrostimulation to evaluate the effectiveness in the prevention of critical illness and focal hypotrophies in ICU SARS-CoV-2 patients, to increase chances of returning to a preinfection functional status.
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http://dx.doi.org/10.1007/s10072-020-04820-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553728PMC
March 2021

Metal(loid)s role in the pathogenesis of amyotrophic lateral sclerosis: Environmental, epidemiological, and genetic data.

Environ Res 2021 01 4;192:110292. Epub 2020 Oct 4.

Department of Earth and Environmental Sciences, University of Milano - Bicocca, Piazza della Scienza, 1, 20133, Milan, Italy. Electronic address:

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. The etiology is still unknown and the pathogenesis remains unclear. ALS is familial in the 10% of cases with a Mendelian pattern of inheritance. In the remaining sporadic cases, a multifactorial origin is supposed in which several predisposing genes interact with environmental factors. The etiological role of environmental factors, such as pesticides, exposure to electromagnetic fields, and metals has been frequently investigated, with controversial findings. Studies in the past two decades have highlighted possible roles of metals, and ionic homeostasis dysregulation has been proposed as the main trigger to motor-neuron degeneration. This study aims at evaluating the possible role of environmental factors in etiopathogenesis of ALS, with a particular attention on metal contamination, focusing on the industrial Briga area in the province of Novara (Piedmont region, North Italy), characterized by: i) a higher incidence of sporadic ALS (sALS) in comparison with the entire province, and ii) the reported environmental pollution. Environmental data from surface, ground and discharge waters, and from soils were collected and specifically analyzed for metal content. Considering the significance of genetic mechanisms in ALS, a characterization for the main ALS genes has been performed to evaluate the genetic contribution for the sALS patients living in the area of study. The main findings of this study are the demonstration that in the Briga area the most common metal contaminants are Cu, Zn, Cr, Ni (widely used in tip-plating processes), that are above law limits in surface waters, discharge waters, and soil. In addition, other metals and metalloids, such as Cd, Pb, Mn, and As show a severe contamination in the same area. Results of genetic analyses show that sALS patients in the Briga area do not carry recurrent mutations or an excess of mutations in the four main ALS causative genes (SOD1, TARDBP, FUS, C9ORF72) and for ATXN2 CAG repeat locus. This study supports the hypothesis that the higher incidence of sALS in Briga area may be related to environmental metal(loid)s contamination, along with other environmental factors. Further studies, implementing analysis of genetic polymorphisms, as well as investigation with long term follow-up, may yield to key aspects into the etiology of ALS. The interplay between different approaches (environmental, chemical, epidemiological, genetic) of our work provides new insights and methodology to the comprehension of the disease etiology.
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http://dx.doi.org/10.1016/j.envres.2020.110292DOI Listing
January 2021

Reply to Comment on "Environmental and Occupational Risk Factors of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study".

Int J Environ Res Public Health 2020 09 7;17(18). Epub 2020 Sep 7.

CREAGEN-Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

We much appreciate the positive comments and interest concerning our study on the environmental and occupational risk factors of amyotrophic lateral sclerosis (ALS) [...].
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http://dx.doi.org/10.3390/ijerph17186492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559024PMC
September 2020

Generation of an induced pluripotent stem cell line, CSSi011-A (6534), from an Amyotrophic lateral sclerosis patient with heterozygous L145F mutation in SOD1 gene.

Stem Cell Res 2020 Jul 25;47:101924. Epub 2020 Jul 25.

Fondazione IRCCS Casa Sollievo della Sofferenza, Cellular Reprogramming Unit - Viale dei Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy. Electronic address:

Among the known causative genes of familial ALS, SOD1mutation is one of the most common. It encodes for the ubiquitous detoxifying copper/zinc binding SOD1 enzyme, whose mutations selectively cause motor neuron death, although the mechanisms are not as yet clear. What is known is that mutant-mediated toxicity is not caused by loss of its detoxifying activity but by a gain-of-function. In order to better understand the pathogenic mechanisms of SOD1 mutation, a human induced pluripotent stem cell (hiPSC) line was generated from the somatic cells of a female patient carrying a missense variation in SOD1 (L145F).
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http://dx.doi.org/10.1016/j.scr.2020.101924DOI Listing
July 2020

The Italian multicenter experience with edaravone in amyotrophic lateral sclerosis.

J Neurol 2020 Nov 17;267(11):3258-3267. Epub 2020 Jun 17.

"Rita Levi Montalcini" Department of Neuroscience, ALS Centre, University of Turin, Via Cherasco 15, 10126, Turin, Italy.

Objectives: The aim of the study is to analyze the ALS disease progression and respiratory function of Italian patients treated with edaravone (EVN), as well as the adherence to, and the effects of, the therapy.

Methods: We performed an observational study of patients treated with EVN from May 2017 to May 2019, in 39 Italian ALS Centers. Taking into account ALS patients with at least 12 months of EVN treatment, we compared the decline of ALSFRS-R and FVC with a group of matched historical controls from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, using both descriptive and survival analysis approaches.

Results: A total of 331 ALS Italian patients treated with EVN and 290 matched historical controls were recruited in this study. No significant differences on disease progression or respiratory function were found comparing the two cohorts in both descriptive and survival analyses. The EVN treatment was overall well tolerated.

Conclusions: The study showed that EVN treatment was well tolerated. No significant differences were reported in ALS patients treated and not treated with EVN, in terms of both disease progression and respiratory function. These findings prove that further studies are required to better clarify whether EVN could be considered an effective treatment for ALS disease.
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http://dx.doi.org/10.1007/s00415-020-09993-zDOI Listing
November 2020

A prospective longitudinal study on the microbiota composition in amyotrophic lateral sclerosis.

BMC Med 2020 06 17;18(1):153. Epub 2020 Jun 17.

Department of Neurology and ALS Centre, University of Piemonte Orientale, Maggiore della Carità Hospital, Corso Mazzini 18, 28100, Novara, Italy.

Background: A connection between amyotrophic lateral sclerosis (ALS) and altered gut microbiota composition has previously been reported in animal models. This work is the first prospective longitudinal study addressing the microbiota composition in ALS patients and the impact of a probiotic supplementation on the gut microbiota and disease progression.

Methods: Fifty patients and 50 matched controls were enrolled. The microbial profile of stool samples from patients and controls was analyzed via PCR-Denaturing Gradient Gel Electrophoresis, and the main microbial groups quantified via qPCR. The whole microbiota was then analyzed via next generation sequencing after amplification of the V3-V4 region of 16S rDNA. Patients were then randomized to receive probiotic treatment or placebo and followed up for 6 months with ALSFRS-R, BMI, and FVC%.

Results: The results demonstrate that the gut microbiota of ALS patients is characterized by some differences with respect to controls, regardless of the disability degree. Moreover, the gut microbiota composition changes during the course of the disease as demonstrated by the significant decrease in the number of observed operational taxonomic unit during the follow-up. Interestingly, an unbalance between potentially protective microbial groups, such as Bacteroidetes, and other with potential neurotoxic or pro-inflammatory activity, such as Cyanobacteria, has been shown. The 6-month probiotic treatment influenced the gut microbial composition; however, it did not bring the biodiversity of intestinal microbiota of patients closer to that of control subjects and no influence on the progression of the disease measured by ALSFRS-R was demonstrated.

Conclusions: Our study poses the bases for larger clinical studies to characterize the microbiota changes as a novel ALS biomarker and to test new microbial strategy to ameliorate the health status of the gut.

Trial Registration: CE 107/14, approved by the Ethics Committee of the "Maggiore della Carità" University Hospital, Italy.
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http://dx.doi.org/10.1186/s12916-020-01607-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298784PMC
June 2020

Decline of cognitive and behavioral functions in amyotrophic lateral sclerosis: a longitudinal study.

Amyotroph Lateral Scler Frontotemporal Degener 2020 08 2;21(5-6):373-379. Epub 2020 Jun 2.

ALS Center, Department of Neurology, Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy.

: A cognitive impairment, ranging from frontotemporal dementia (FTD) to milder forms of dysexecutive or behavioral dysfunction, is detected in 30-50% of patients affected by amyotrophic lateral sclerosis (ALS) at diagnosis. Such condition considerably influences the prognosis, and possibly impacts on the decision-making process with regards to end-of-life choices. The aim of our study is to examine the changes of cognitive and behavioral impairment in a large population of ALS from the time of diagnosis to a 6-month follow-up (IQR 5.5-9.0 months), and to examine to what extent the progression of cognitive impairment affects survival time and rate of disease progression.: We recruited 146 ALS patients classified according to revised criteria of ALS and FTD spectrum disorder. In a multidisciplinary setting, during two subsequent visits we examined clinical features with ALSFRS-r score, FVC% and BMI, and cognitive status with an extensive neuropsychological evaluation.: At second examination, one-third of patients showed a worsening of cognitive impairment, namely 88% of ALSbi, 27% of ALSci, 40% of ALScbi, and, interestingly, also 24% of cognitive normal ALS developed a significant cognitive dysfunction. We find that those who changed their cognitive status presented a lower ALSFRS-r score at t1 and a shorter survival time compared to those who did not change, regardless of the type of cognitive impairment.: We show how cognitive disorders in ALS patients can not only be present at diagnosis, but also manifest during disease and influence the progression of motor deficit and the prognosis.
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http://dx.doi.org/10.1080/21678421.2020.1771732DOI Listing
August 2020

Telemedicine and technological devices for amyotrophic lateral sclerosis in the era of COVID-19.

Neurol Sci 2020 06 21;41(6):1365-1367. Epub 2020 May 21.

Department of Neurology and ALS Centre, University of Piemonte Orientale, Maggiore della Carità Hospital, Corso Mazzini 18, 28100, Novara, Italy.

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http://dx.doi.org/10.1007/s10072-020-04457-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240164PMC
June 2020

Environmental and Occupational Risk Factors of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study.

Int J Environ Res Public Health 2020 04 22;17(8). Epub 2020 Apr 22.

CREAGEN-Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with still unknown etiology. We aimed at investigating the association between environmental and occupational factors with ALS risk. We performed a population-based case-control study in four Italian provinces (Catania, Modena, Novara, and Reggio Emilia) by administration of tailored questionnaires to ALS cases ( = 95) and randomly selected population referents ( = 135). We estimated ALS risk by calculating the odds ratio (OR) with its 95% confidence interval (CI) using an unconditional logistic regression model. We found a positive association with disease risk for history of occupation in the agricultural sector (OR = 2.09, 95% CI 0.79-7.54), especially for longer than 10 years (OR = 2.72, 95% 1.02-7.20). Overall occupational exposure to solvents also suggested a positive association, especially for thinners (OR = 2.27, 95% CI 1.14-4.54) and paint removers (OR = 2.01, 95% CI 0.90-4.48). Both occupational and environmental exposure to electromagnetic fields show a slightly increased risk with OR = 1.69 (95% CI 0.70-4.09) and 2.41 (95% CI 1.13-5.12), respectively. Occupational but not environmental exposure to pesticides (OR = 1.22, 95% CI 0.63-2.37), particularly fungicides, and exposure to metals (OR = 4.20, 95% CI 1.88-9.38), particularly lead, mercury, and selenium, showed an imprecise but positive association. Finally, there was an indication of increased risk for living in proximity to water bodies. Despite the caution that needs to be used due to some study limitations, such as the low number of exposed subjects and the possibility of recall bias, these results suggest the potential role of some environmental and occupational factors in ALS etiology.
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http://dx.doi.org/10.3390/ijerph17082882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216189PMC
April 2020

G-CSF (filgrastim) treatment for amyotrophic lateral sclerosis: protocol for a phase II randomised, double-blind, placebo-controlled, parallel group, multicentre clinical study (STEMALS-II trial).

BMJ Open 2020 03 24;10(3):e034049. Epub 2020 Mar 24.

'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Torino, Piemonte, Italy.

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo.

Methods And Analysis: STEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34 cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment.

Ethics And Dissemination: The study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria 'Città della Salute e della Scienza', Torino, Italy. Results will be presented during scientific symposia or published in scientific journals.

Trial Registration Number: Eudract 2014-002228-28.
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http://dx.doi.org/10.1136/bmjopen-2019-034049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202695PMC
March 2020

Reply to: Amyotrophic lateral sclerosis with depression, cognitive impairment, and mortality.

Acta Neurol Scand 2020 07;142(1):86-87

Department of Neurology and ALS Centre, Maggiore della Carità Hospital, University of Piemonte Orientale, Novara, Italy.

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http://dx.doi.org/10.1111/ane.13238DOI Listing
July 2020

Disease-modifying therapies in amyotrophic lateral sclerosis.

Neuropharmacology 2020 05 3;167:107986. Epub 2020 Feb 3.

ALS Center, Istituti Clinici Scientifici Maugeri, IRCCS Milano, Milan, Italy.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of adult life, causing weakness and wasting of voluntary muscles, associated in about 50% of cases with a cognitive impairment. Pathologically, the disease is characterized by a degeneration of upper and lower motor neurons. A hallmark of the pathological process is the aggregation of the protein TDP43 in the cytoplasm of affected neurons detected in almost 97% of cases. About 15% of cases has a family history. Currently, only two drugs have been demonstrated to be effective in ALS, riluzole and edaravone, which show only modest effects on disease progression. The quest for disease-modifying therapies in ALS has several obstacles, the most important being the sub-optimal quality of the design of clinical trials, and the clinical and pathological heterogeneity of the disease. In this paper the pathological mechanisms relevant to ALS and current and future pharmacological and non-pharmacological trials, including gene and stem cells therapies, will be presented. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.
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http://dx.doi.org/10.1016/j.neuropharm.2020.107986DOI Listing
May 2020

Prognostic role of slow vital capacity in amyotrophic lateral sclerosis.

J Neurol 2020 Jun 12;267(6):1615-1621. Epub 2020 Feb 12.

Department of Neuroscience, ALS Center, "Rita Levi Montalcini", University of Turin, Via Cherasco 15, 1026, Turin, Italy.

Objectives: To compare the prognostic role of FVC and SVC at diagnosis in amyotrophic lateral sclerosis (ALS) patients.

Methods: We included all patients from the Piemonte and Valle D'Aosta ALS register (PARALS) who had been diagnosed with ALS between 1995 and 2015 and underwent spirometry at diagnosis. Survival was considered as time to death/tracheostomy; to assess the prognostic value in typical trial timeframes, survival at 12 and 18 months was calculated too. Cox proportional hazard regression models adjusted by sex, age at diagnosis, diagnostic delay, onset site, and ALSFRS-R total score at the moment of diagnosis were used to assess the prognostic role of FVC and SVC.

Results: A total of 795 ALS patients underwent spirometry at diagnosis during the study period. Four hundred and sixteen (52.3%) performed both FVC and SVC, whereas the others performed FVC only. FVC and SVC values were highly correlated (r = 0.92, p < 0.001) in the overall population and slightly less correlated in patients with bulbar onset (r = 0.86, p < 0.001). Both FVC and SVC proved to have a prognostic role with comparable hazard ratios (HRs) (HR 1.83, 95% CI 1.48-2.27 and 1.88, 95% CI 1.51-2.33, respectively). When considering typical trial timeframes, HRs remained similar and were inversely proportional to FVC and SVC values.

Discussion: FVC and SVC at diagnosis can be used interchangeably as independent predictors of survival in both clinical and research settings.
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http://dx.doi.org/10.1007/s00415-020-09751-1DOI Listing
June 2020

Clinical and Lifestyle Factors and Risk of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study.

Int J Environ Res Public Health 2020 01 30;17(3). Epub 2020 Jan 30.

CREAGEN-Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease of the motor neurons. The etiology of ALS remains largely unknown, particularly with reference to the potential environmental determinants. : We performed a population-based case-control study in four provinces from both Northern and Southern Italy in order to assess non-genetic ALS risk factors by collecting through tailored questionnaires information about clinical and lifestyle factors. We estimated ALS risk by calculating odds ratio (OR) with its 95% confidence interval (CI) using unconditional logistic regression models adjusted for sex, age and educational attainment. : We recruited 230 participants (95 cases and 135 controls). We found a possible positive association of ALS risk with trauma, particularly head trauma (OR = 2.61, 95% CI 1.19-5.72), electric shock (OR = 2.09, 95% CI 0.62-7.06), and some sports, although at a competitive level only. In addition, our results suggest an increased risk for subjects reporting use of private wells for drinking water (OR = 1.38, 95% CI 0.73-2.27) and for use of herbicides during gardening (OR = 1.95, 95% CI 0.88-2.27). Conversely, there was a suggestion of an inverse association with overall fish consumption (OR = 0.27, 95% CI 0.12-0.60), but with no dose-response relation. Consumption of some dietary supplements, namely those containing amino acids and, in the Southern Italy population, vitamins and minerals such as selenium, seemed associated with a statistically imprecise increased risk. : Our results suggest a potential etiologic role a number of clinical and lifestyle factors with ALS risk. However, caution is needed due to some study limitations. These include the small sample size and the low number of exposed subjects, which affect statistical precision of risk estimates, the potential for exposure misclassification, and the uncertainties about mechanisms underpinning the possible association between these factors and disease risk.
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http://dx.doi.org/10.3390/ijerph17030857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037077PMC
January 2020
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