Impact of diabetes mellitus on the respiratory function of amyotrophic lateral sclerosis patients.

BACKGROUND AND PURPOSE: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). The impact of diabetes mellitus (DM) on respiratory function of ALS patients is uncertain. METHODS: A retrospective cohort study was carried out. From the 1710 patients with motor neuron disease followed in our unit, ALS and progressive muscular atrophy patients were included. We recorded demographic characteristics, functional ALS rating scale (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and its subscores at first visit, respiratory function tests, arterial blood gases, phrenic nerve amplitude (PhrenAmpl), and mean nocturnal oxygen saturation (SpO2 mean). We excluded patients with other relevant diseases. Two subgroups were analysed: DIAB (patients with DM) and noDIAB (patients without DM). Independent t-test, χ2 , or Fisher exact test was applied. Binomial logistic regression analyses assessed DM effects. Kaplan-Meier analysis assessed survival. p < 0.05 was considered significant. RESULTS: We included 1639 patients (922 men, mean onset age = 62.5 ± 12.6 years, mean disease duration = 18.1 ± 22.0 months). Mean survival was 43.3 ± 40.7 months. More men had DM (p = 0.021). Disease duration was similar between groups (p = 0.063). Time to noninvasive ventilation (NIV) was shorter in DIAB (p = 0.004); total survival was similar. No differences were seen for ALSFRS-R or its decay rate. At entry, DIAB patients were older (p < 0.001), with lower forced vital capacity (p = 0.001), arterial oxygen pressure (p = 0.01), PhrenAmpl (p < 0.001), and SpO2 mean (p = 0.014). CONCLUSIONS: ALS patients with DM had increased risk of respiratory impairment and should be closely monitored. Early NIV allowed for similar survival rate between groups.

Respiratory phenotypes in amyotrophic lateral sclerosis as determined by respiratory questions on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised and their relation to respiratory tests.

BACKGROUND AND PURPOSE: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). Respiratory symptoms are scored in questions Q10 (dyspnoea) and Q11 (orthopnoea) of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). The association of respiratory test alterations with respiratory symptoms is unclear. METHODS: Patients with ALS and progressive muscular atrophy were included. We retrospectively recorded demographic data, ALSFRS-R, forced vital capacity (FVC), maximal inspiratory (MIP) and expiratory (MEP) pressures, mouth occlusion pressure at 100 ms, nocturnal oximetry (SpO2 mean), arterial blood gases, and phrenic nerve amplitude (PhrenAmpl). Three groups were categorized: G1, normal Q10 and Q11; G2, abnormal Q10; and G3, abnormal Q10 and Q11 or only abnormal Q11. A binary logistic regression model explored independent predictors. RESULTS: We included 276 patients (153 men, onset age = 62.6 ± 11.0 years, disease duration = 13.0 ± 9.6 months, spinal onset in 182) with mean survival of 40.1 ± 26.0 months. Gender, onset region, and disease duration were similar in G1 (n = 149), G2 (n = 78), and G3 (n = 49). Time to noninvasive ventilation (NIV) was shorter in G3 (p < 0.001), but survival was similar. ALSFRS-R subscores were significantly different (G1 > G2 > G3, p < 0.001), except for lower limb subscore (p = 0.077). G2 and G3 patients were older than G1 (p < 0.001), and had lower FVC, MIP, MEP, PhrenAmpl, and SpO2 mean. Independent predictors for G2 were MIP and SpO2 mean; for G3, the only independent predictor was PhrenAmpl. CONCLUSIONS: These three distinct ALS phenotypic respiratory categories represent progressive stages of ventilatory dysfunction, supporting ALSFRS-R clinical relevance. Orthopnoea is a severe symptom that should prompt NIV, phrenic nerve response being an independent predictor. Early NIV promotes similar survival for G2 and G3.

Dynamic Bayesian networks for stratification of disease progression in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Progression rate is quite variable in amyotrophic lateral sclerosis (ALS); thus, tools for profiling disease progression are essential for timely interventions. The objective was to apply dynamic Bayesian networks (DBNs) to establish the influence of clinical and demographic variables on disease progression rate. METHODS: In all, 664 ALS patients from our database were included stratified into slow (SP), average (AP) and fast (FP) progressors, according to the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) rate of decay. The sdtDBN framework was used, a machine learning model which learnt optimal DBNs with both static (gender, age at onset, onset region, body mass index, disease duration at entry, familial history, revised El Escorial criteria and C9orf72) and dynamic (ALSFRS-R scores and sub-scores, forced vital capacity, maximum inspiratory pressure, maximum expiratory pressure and phrenic amplitude) variables. RESULTS: Disease duration and body mass index at diagnosis are the foremost influences amongst static variables. Disease duration is the variable that better discriminates the three groups. Maximum expiratory pressure is the respiratory test with prevalent influence on all groups. ALSFRS score has a higher influence on FP, but lower on AP and SP. The bulbar sub-score has considerable influence on FP but limited on SP. Limb function has a more decisive influence on AP and SP. The respiratory sub-score has little influence in all groups. ALSFRS-R questions 1 (speech) and 9 (climbing stairs) are the most influential in FP and SP, respectively. CONCLUSIONS: The sdtDBN analysis identified five variables, easily obtained during clinical evaluation, which are the most influential for each progression group. This insightful information may help to improve prognosis and care.

Thyroid dysfunction in Portuguese amyotrophic lateral sclerosis patients.

INTRODUCTION: Thyroid hormones influence neuromuscular function, and it has been thought that this might contribute to degeneration of motor neurons. METHODS: We used case-control methods to investigate the prevalence of thyroid dysfunction (hyperthyroidism and hypothyroidism) in ALS patients followed in our centre, between 2015 and 2020. Data from patients with neuromuscular disorders not derived from thyroid dysfunction, followed within the same time frame, were used as controls. Thyroid dysfunction was defined by previous thyroid replacement medication managed by an endocrinologist. We used odds ratios (OR) with a 95% confidence interval (CI) to compare 579 ALS patients and 415 age-gender-matched disease controls. Additionally, we provide a summarized review of the literature. RESULTS: Hypothyroidism (prevalence of 5.0 versus 8.6%; OR = 0.56, 95% CI 0.34-0.92, p = 0.023), hyperthyroidism (prevalence of 0.3 versus 1.2%; OR = 0.28, 95% CI 0.06-1.47, p = 0.134) and overall thyroid dysfunction (prevalence of 5.4 versus 9.9%; OR = 0.52, 95% CI 0.32-0.84, p = 0.015) were less prevalent in ALS patients than in controls, but similar to the national epidemiological data for thyroid disease. Our data are in line with the findings of most previous studies. CONCLUSIONS: We conclude that thyroid dysfunction is not associated with ALS.

Multiscale Sensing of Bone-Implant Loosening for Multifunctional Smart Bone Implants: Using Capacitive Technologies for Precision Controllability.

The world population growth and average life expectancy rise have increased the number of people suffering from non-communicable diseases, namely osteoarthritis, a disorder that causes a significant increase in the years lived with disability. Many people who suffer from osteoarthritis undergo replacement surgery. Despite the relatively high success rate, around 10% of patients require revision surgeries, mostly because existing implant technologies lack sensing devices capable of monitoring the bone-implant interface. Among the several monitoring methodologies already proposed as substitutes for traditional imaging methods, cosurface capacitive sensing systems hold the potential to monitor the bone-implant fixation states, a mandatory capability for long-term implant survival. A multifaceted study is offered here, which covers research on the following points: (1) the ability of a cosurface capacitor network to effectively monitor bone loosening in extended peri-implant regions and according to different stimulation frequencies; (2) the ability of these capacitive architectures to provide effective sensing in interfaces with hydroxyapatite-based layers; (3) the ability to control the operation of cosurface capacitive networks using extracorporeal informatic systems. In vitro tests were performed using a web-based network sensor composed of striped and interdigitated capacitive sensors. Hydroxyapatite-based layers have a minor effect on determining the fixation states; the effective operation of a sensor network-based solution communicating through a web server hosted on Raspberry Pi was shown. Previous studies highlight the inability of current bone-implant fixation monitoring methods to significantly reduce the number of revision surgeries, as well as promising results of capacitive sensing systems to monitor micro-scale and macro-scale bone-interface states. In this study, we found that extracorporeal informatic systems enable continuous patient monitoring using cosurface capacitive networks with or without hydroxyapatite-based layers. Findings presented here represent significant advancements toward the design of future multifunctional smart implants.

Familial clustering of primary lateral sclerosis and amyotrophic lateral sclerosis: Supplementary evidence for a continuum.

BACKGROUND AND PURPOSE: Primary lateral sclerosis (PLS) is a motor neuron disorder characterized by a pure upper motor neuron degeneration in the bulbar and spinal regions. The key difference with amyotrophic lateral sclerosis (ALS) is the lower motor neuron system integrity. Despite important literature on this disease, the pathophysiology of PLS remains unknown, and the link with ALS still balances between a continuum and a separate entity from ALS. METHODS: We report nine families in which both PLS and ALS cases occurred, in general among first-degree relatives. RESULTS: The patients with PLS and ALS had a typical disease presentation. Genetic studies revealed mutations in SQSMT1, TBK1, and TREM2 genes in two PLS patients and one ALS patient. CONCLUSIONS: These results strongly support a phenotypic continuum between PLS and ALS.

Lobectomy Compared to Total Thyroidectomy for Low-Risk Papillary Thyroid Cancer: A Systematic Review.

BACKGROUND: The 2015 American Thyroid Association (ATA) guidelines called for consideration of thyroid lobectomy (TL) as an acceptable surgical treatment for small and less aggressive papillary thyroid cancers (PTC) with no clinical evidence of metastasis or extrathyroidal extension. Optimal extent of surgery, however, remains controversial. METHODS: A systematic literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. PUBMED, EMBASE, Scopus, and Cochrane Library databases were searched to identify studies comparing TL to total thyroidectomy (TT) for low-risk PTC. Studies were grouped according to the major outcomes in the literature: survival and the need for completion thyroidectomy (CT). RESULTS: Overall survival for low-risk PTC patients who underwent TL was comparable to TT. Locoregional recurrence (LRR) rate following TL was less than 6% and salvaged with CT. The proportion of patients meeting the 2015 ATA guidelines selection criteria for TL who subsequently would need CT varied by study but averaged 34%. After excluding microscopic extrathyroidal extension and positive resection margin as indications for CT to facilitate radioactive iodine ablation, the estimated rate across the included studies was 11%. CONCLUSIONS: We performed a systematic review of outcomes following TL or CT for low-risk PTC according to 2015 ATA guidelines. Initial operative approach did not have a negative impact on overall survival. There is a paucity of high-quality data on this topic across the literature. Long-term follow-up studies on oncologic and patient-centered outcomes are essential.

Hot-spot KIF5A mutations cause familial ALS.

Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 × 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p.Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 × 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.

Lifestyle behaviours in patients with established cardiovascular diseases: a European observational study.

BACKGROUND: Patients who have experienced a cardiovascular clinical event such as a myocardial infarction or stroke qualify for intensive risk factor evaluation and management. The aim of this study is to explore lifestyle changes as well as the achievement of targets for risk factors in patients with established cardiovascular disease. METHODS: Cross-sectional study conducted in primary care practices. The study was carried out in six European countries (Croatia, France, Portugal, Slovenia, Spain and Turkey). Patients with established cardiovascular disease (coronary heart disease and stroke) attended in primary care were selected and assessed from January to June 2016. Patients were recruited and assessed at the practice by research assistants between 6 months and 3 years after the event. Statistical comparisons were done with the unpaired two-sided Student's t-test for continuous variables and Chi-square test for categorical variables. RESULTS: Nine hundred and seventy-three patients (32.4% females) were assessed. About 14% of them were smokers, 32% were physically inactive, and 30% had nutritionally poor eating behaviours. LDL cholesterol target value below 70 mg/dl was achieved in about 23% of patients, and in general, women were less cardio-protected by drugs than men. CONCLUSIONS: Many patients with established cardiovascular disease who attended in general practice still fail to achieve the lifestyle, risk factor, and therapeutic targets set by European guidelines. These results are relevant to general practitioners because these patients have a high risk of subsequent cardiovascular events, including MI, stroke, and death.

Preparation and Characterization of Graphene Oxide Aerogels: Exploring the Limits of Supercritical CO2 Fabrication Methods.

The supercritical carbon dioxide (scCO2 ) synthesis of non-reduced graphene oxide (GO) aerogels from dispersions of GO in ethanol is here reported as a low-cost, efficient, and environmentally friendly process. The preparation is carried out under the mild conditions of 333 K and 20 MPa. The high aspect ratio of the used GO sheets (ca. 30 µm lateral dimensions) allowed the preparation of aerogel monoliths by simultaneous scCO2 gelation and drying. Solid-state characterization results indicate that a thermally-stable mesoporous non-reduced GO aerogel was obtained by using the supercritical procedure, keeping most of the surface oxygenated groups on the GO sheets, thus, facilitating further functionalization. Moreover, the monoliths have a very low density, high specific surface area, and excellent mechanical integrity; characteristics which rival those of most light-weight reduced graphene aerogels reported in the literature.

Beyond fractional anisotropy in amyotrophic lateral sclerosis: the value of mean, axial, and radial diffusivity and its correlation with electrophysiological conductivity changes.

PURPOSE: This paper aims to analyze the contribution of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in the detection of microstructural abnormalities in amyotrophic lateral sclerosis (ALS) and to evaluate the degree of agreement between structural and functional changes through concomitant diffusion tensor imaging (DTI), transcranial magnetic stimulation (TMS), and clinical assessment. METHODS: Fourteen patients with ALS and 11 healthy, age- and gender-matched controls were included. All participants underwent magnetic resonance imaging including DTI. TMS was additionally performed in ALS patients. Differences in the distribution of DTI-derived measures were assessed using tract-based spatial statistical (TBSS) and volume of interest (VOI) analyses. Correlations between clinical, imaging, and neurophysiological findings were also assessed through TBSS. RESULTS: ALS patients showed a significant increase in AD and MD involving the corticospinal tract (CST) and the pre-frontal white matter in the right posterior limb of the internal capsule (p < 0.05) when compared to the control group using TBSS, confirmed by VOI analyses. VOI analyses also showed increased AD in the corpus callosum (p < 0.05) in ALS patients. Fractional anisotropy (FA) in the right CST correlated significantly with upper motor neuron (UMN) score (r = - 0.79, p < 0.05), and right abductor digiti minimi central motor conduction time was highly correlated with RD in the left posterior internal capsule (r = - 0.81, p < 0.05). No other significant correlation was found. CONCLUSION: MD, AD, and RD, besides FA, are able to further detect and characterize neurodegeneration in ALS. Furthermore, TMS and DTI appear to have a role as complementary diagnostic biomarkers of UMN dysfunction.

Health Status Perspectives in Amyotrophic Lateral Sclerosis.

BACKGROUND/AIMS: The global perception of the health status (HS) of amyotrophic lateral sclerosis (ALS) patients before the initial diagnosis has not been addressed previously. METHODS: We recorded the following at the first visit, before diagnostic information: (1) visual analog scale (VAS) of the EQ-5D; (2) the revised ALS functional rating scale (ALSFRS- R), bulbar (ALSFRSb), upper limb (ALSFRSul), lower limb (ALSFRSll), and respiratory (RofALSFRS-R) subscores; and (3) forced and slow vital capacities. Correlations were tested by the Pearson correlation test. Variables were compared between groups defined by the VAS median value. p < 0.05 was considered significant. RESULTS: Of the 156 patients included in the study (91 spinal-onset, 49 bulbar-onset, 16 axial/respiratory-onset; 95 men; mean onset age 63.9 ± 13 years; mean disease duration 18.4 ± 26.5 months), HS VAS was significantly lower in spinal-onset patients (p = 0.047), and particularly in spinal-onset women (p = 0.027). Disease duration had no influence. HS VAS was moderately correlated with ALSFRS, ALSFRSul and ALSFRSll (0.4 < r < 0.5, p < 0.01), weakly correlated with RofALSFRS-R in the whole population (r = 0.171, p < 0.05), and not correlated with ALSFRSb or the respiratory tests. ALSFRSb was similar between groups defined by the HS VAS median value, but the other scores were significantly lower for poorer HS values. CONCLUSION: HS before diagnosis is mostly dependent on the perception of upper and lower limb function. A tool tailored to evaluate HS in bulbar-onset patients should be developed.

Quality of life in amyotrophic lateral sclerosis patients and caregivers: Impact of assistive communication from early stages.

INTRODUCTION: In this study we performed a longitudinal investigation to assess the impact of early introduction of assistive communication devices (ACDs) on quality of life (QoL) in amyotrophic lateral sclerosis (ALS) patients and their caregivers. METHODS: Patients were followed for 7-10 months (3 evaluation periods). Bulbar-onset ALS patients (N = 27) and paired caregivers (N = 17) were included. Fifteen randomly selected patients received early support in ACD use. Patients were assessed using the ALS Functional Rating Scale-revised (ALSFRS-R), the McGill QoL (MQoL), the Communication Effectiveness Index (CETI), and performance in writing; and caregivers were assessed with the MQoL and World Health Organization Quality of Life questionnaire (WHOQOL-BREF). RESULTS: Patients with early support had higher MQoL Psychological and MQoL Existential well-being domains; caregivers had higher MQoL Support domain and their MQoL Psychological domain positively associated with patient CETI. Most patients could communicate using a touchscreen keyboard to write, even when handwriting and speech were not possible. CONCLUSION: Early intervention with an ACD seems to have a positive impact on QoL and gives patients the opportunity to improve skills for communication in later disease stages.

Prognostic models based on patient snapshots and time windows: Predicting disease progression to assisted ventilation in Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a devastating disease and the most common neurodegenerative disorder of young adults. ALS patients present a rapidly progressive motor weakness. This usually leads to death in a few years by respiratory failure. The correct prediction of respiratory insufficiency is thus key for patient management. In this context, we propose an innovative approach for prognostic prediction based on patient snapshots and time windows. We first cluster temporally-related tests to obtain snapshots of the patient's condition at a given time (patient snapshots). Then we use the snapshots to predict the probability of an ALS patient to require assisted ventilation after k days from the time of clinical evaluation (time window). This probability is based on the patient's current condition, evaluated using clinical features, including functional impairment assessments and a complete set of respiratory tests. The prognostic models include three temporal windows allowing to perform short, medium and long term prognosis regarding progression to assisted ventilation. Experimental results show an area under the receiver operating characteristics curve (AUC) in the test set of approximately 79% for time windows of 90, 180 and 365 days. Creating patient snapshots using hierarchical clustering with constraints outperforms the state of the art, and the proposed prognostic model becomes the first non population-based approach for prognostic prediction in ALS. The results are promising and should enhance the current clinical practice, largely supported by non-standardized tests and clinicians' experience.

A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories.

BACKGROUND: The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories. METHODS: The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference. RESULTS: Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories. CONCLUSIONS: Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.