Which are the factors influencing NIV adaptation and tolerance in ALS patients?

Amyotrophic lateral sclerosis (ALS) is a multisystemic disease compromising both the neuromuscular system and the cognitive status. Non-invasive ventilation (NIV) has been shown to improve survival and quality of life in ALS patients with respiratory failure, but scanty literature investigated which are the predictors of NIV tolerance. The aim of this study was to evaluate the impact of functional, cognitive, neurobehavioral, and respiratory status on NIV compliance and tolerance in patients with ALS. We retrospectively evaluated clinical data of ALS patients who consecutively underwent a NIV trial during hospitalization. Cognitive and neurobehavioral assessments have been performed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), the Hospital Anxiety and Depression Scale (HADS), the Frontal Assessment Battery (FAB), the Raven's 47 Colored Progressive Matrices (PM47), and the Neurobehavioral Rating Scale Revised (NRSR). Seventy-two patients (mean age ± SD; 63.9 ± 10.6 years) were included. Patients adapted were 63/72 (87.5%). The average time of adaptation was 7.82 ± 5.27 days. The time required to reach a satisfying NIV adaptation was significantly related to the presence of sialorrhea (p = 0.02), respiratory status (Borg Dyspnoea Scale, p = 0.006, and ALS-FRS-R respiratory subscore, p = 0.03) and behavioral and cognitive impairment (NRSR-F1, p = 0.04, NRSR- F5, p = 0.04). Presence of sialorrhea and neurobehavioral impairment, and absence of respiratory symptoms are negative predictors of NIV adaptation. This study highlights the need of a multidisciplinary patient-tailored approach including cognitive-behavioral assessment and a psychological support program to optimize patient's training and compliance to NIV.

Effect of exercise on telomere length and telomere proteins expression in mdx mice.

In Duchenne muscular dystrophy (DMD), telomere shortening has been postulated to contribute to the failure of regenerative activity promoting the premature senescence of satellite cells. The aim of the present study was to investigate the telomere length and the expression of telomeric repeat-binding factor-1 (TRF1), poly (ADP-ribose) polymerase-1 (PARP1) and mouse telomerase reverse transcriptase (MTERT) in gastrocnemius, tibialis anterior and diaphragm muscles of the murine model of DMD, the mdx mouse and whether a chronic protocol of forced exercise impacts on them. Our results confirmed a telomere shortening in mdx muscles, more evident in the diaphragm, in which exercise induced a greater shortening than in wild-type mice. Moreover, we showed for the first time in mdx an increased TRF1 and PARP1 expression and an augmented activity of MTERT, further enhanced by exercise. These results reinforce the hypothesis that a deregulation of mechanisms involved in telomere length occurs and may pave the way for the test of compounds targeting proteins modulating telomere maintenance as a novel strategy to treat dystrophinopathies.

Changing antimicrobial resistance profiles among Neisseria gonorrhoeae isolates in Italy, 2003 to 2012.

The emergence of Neisseria gonorrhoeae isolates displaying resistance to antimicrobial agents is a major public health concern and a serious issue related to the occurrence of further untreatable gonorrhea infections. A retrospective analysis on 1,430 N. gonorrhoeae isolates, collected from 2003 through 2012, for antimicrobial susceptibility by Etest and molecular characterization by Neisseria gonorrhoeae multiantigen sequence typing (NG-MAST) was carried out in Italy. Azithromycin-resistant gonococci decreased from 14% in 2007 to 2.2% in 2012. Similarly, isolates with high MICs to cefixime (>0.125 mg/liter) decreased from 11% in 2008 to 3.3% in 2012. The ciprofloxacin resistance rate remains quite stable, following an increasing trend up to 64% in 2012. The percentage of penicillinase-producing N. gonorrhoeae (PPNG) significantly declined from 77% in 2003 to 7% in 2012. A total of 81 multidrug-resistant (MDR) gonococci were identified, showing 11 different antimicrobial resistance patterns. These were isolated from men who have sex with men (MSM) and from heterosexual patients. Two sequence types (STs), ST661 and ST1407, were the most common. Genogroup 1407, which included cefixime-, ciprofloxacin-, and azithromycin-resistant isolates, was found. In conclusion, a change in the antimicrobial resistance profiles among gonococci was identified in Italy together with a percentage of MDR isolates.

The Lack of Ad Hoc Neuropsychological Assessment in Adults with Neurofibromatosis: A Systematic Review.

Background: Neurofibromatosis Type 1 (NF1) is a genetic autosomal dominant disorder that affects both the central and peripheral nervous systems. Children and adolescents with NF1 commonly experience neuropsychological, motor, and behavioral deficits. The cognitive profile hallmark of this disorder includes visuospatial and executive function impairments. These cognitive disorders may persist into adulthood. This study aims to analyze previous research studies that have described cognitive dysfunctions in adults with NF1. The purpose of this analysis is to review the neuropsychological and psychological assessment methods used. Methods: A total of 327 articles were identified based on the search terms in their titles and abstracts. The evaluation was conducted by scrutinizing each article's title, abstract, and text. Results: Only 16 articles were found to be eligible for inclusion based on the pre-defined criteria. The selected studies primarily focus on the development of diagnostic protocols for individuals with NF1. Conclusions: The management of NF1 disease requires a multidisciplinary approach to address symptoms, preserve neurological functions, and ensure the best possible quality of life. However, cognitive impairment can negatively affect psychological well-being. This study suggested that cognitive functions in NF1 patients were not tested using specific measures, but rather were evaluated through intelligence scales. Additionally, the findings revealed that there is no standardized neuropsychological assessment for adults with NF1. To address this gap, it would be helpful to create a specific neuropsychological battery to study cognitive function in NF1 patients during clinical studies. This battery could also serve as a tool to design models for cognitive rehabilitation by using reliable and sensitive measures of cognitive outcomes.

Importance of telemedicine in mild cognitive impairment and Alzheimer disease patients population during admission to emergency departments with COVID-19.

In March 2020, the World Health Organization declared a global pandemic due to the new coronavirus SARS-CoV-2, and several governments have planned a national quarantine to control the spread of the virus. Acute psychological effects during hospitalization in frail elderly individuals with special needs, such as patients with dementia, have been little studied. The greatest distress manifested by these kinds of patients was isolation from their families during hospitalization. Thus, structured video call interventions were carried out to family caregivers of patients diagnosed with dementia during their hospitalization in the COVID-19 ward. The purpose of this quasi-experimental study was to assess changes in cognitive and behavioral symptoms in both patients and caregivers. All study participants underwent psychological assessments. Specifically, the psychological well-being states of patients and their caregivers were measured at admission (T0) and discharge (T1) using psychometric tests and clinical scales. Each participant received an electronic device to access video calls in addition meetings were scheduled with the psychologist and medical team to keep caregivers updated on the health status of their relatives. A psychological support and cognitive rehabilitation service was also provided. Significant differences were found in all clinical variables of the caregiver group. Results showed a significant relationship in the quality of life score between the patient and caregiver groups. The results of this study has highlighted the importance of maintaining significantly effective relationships during the hospitalization period of patients admitted to COVID wards.

Paving the Way for Predicting the Progression of Cognitive Decline: The Potential Role of Machine Learning Algorithms in the Clinical Management of Neurodegenerative Disorders.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder. The prodromal phase of AD is mild cognitive impairment (MCI). The capacity to predict the transitional phase from MCI to AD represents a challenge for the scientific community. The adoption of artificial intelligence (AI) is useful for diagnostic, predictive analysis starting from the clinical epidemiology of neurodegenerative disorders. We propose a Machine Learning Model (MLM) where the algorithms were trained on a set of neuropsychological, neurophysiological, and clinical data to predict the diagnosis of cognitive decline in both MCI and AD patients. METHODS: We built a dataset with clinical and neuropsychological data of 4848 patients, of which 2156 had a diagnosis of AD, and 2684 of MCI, for the Machine Learning Model, and 60 patients were enrolled for the test dataset. We trained an ML algorithm using RoboMate software based on the training dataset, and then calculated its accuracy using the test dataset. RESULTS: The Receiver Operating Characteristic (ROC) analysis revealed that diagnostic accuracy was 86%, with an appropriate cutoff value of 1.5; sensitivity was 72%; and specificity reached a value of 91% for clinical data prediction with MMSE. CONCLUSION: This method may support clinicians to provide a second opinion concerning high prognostic power in the progression of cognitive impairment. The MLM used in this study is based on big data that were confirmed in enrolled patients and given a credibility about the presence of determinant risk factors also supported by a cognitive test score.

Seven Years of Culture Collection of Neisseria gonorrhoeae: Antimicrobial Resistance and Molecular Epidemiology.

The emergence of Neisseria gonorrhoeae isolates displaying resistance to antimicrobials, in particular to ceftriaxone monotherapy or ceftriaxone plus azithromycin, represents a global public health concern. This study aimed to analyze the trend of antimicrobial resistance in a 7-year isolate collection retrospective analysis in Italy. Molecular typing on a subsample of gonococci was also included. A total of 1,810 culture-positive gonorrhea cases, collected from 2013 to 2019, were investigated by antimicrobial susceptibility, using gradient diffusion method, and by the N. gonorrhoeae multiantigen sequence typing (NG-MAST). The majority of infections occurred among men with urogenital infections and 57.9% of male patients were men who have sex with men. Overall, the cefixime resistance remained stable during the time. An increase of azithromycin resistance was observed until 2018 (26.5%) with a slight decrease in the last year. In 2019, gonococci showing azithromycin minimum inhibitory concentration above the EUCAST epidemiological cutoff value (ECOFF) accounted for 9.9%. Ciprofloxacin resistance and penicillinase-producing N. gonorrhoeae (PPNG) percentages increased reaching 79.1% and 18.7% in 2019, respectively. The most common sequence types identified were 5,441, 1,407, 6,360, and 5,624. The predominant genogroup (G) was the 1,407; moreover, a new genogroup G13070 was also detected. A variation in the antimicrobial resistance rates and high genetic variability were observed in this study. The main phenotypic and genotypic characteristics of N. gonorrhoeae isolates were described to monitor the spread of drug-resistant gonorrhea.

Amino acid sequence homology between thyroid autoantigens and central nervous system proteins: Implications for the steroid-responsive encephalopathy associated with autoimmune thyroiditis.

A few patients with Hashimoto's thyroiditis or Graves' disease develop a multiform syndrome of the central nervous system (CNS) termed Hashimoto's encephalopathy or steroid-responsive encephalopathy associated with autoimmune thyroid disease (HE/SREAT). They have high levels of thyroid autoantibodies (TgAb, TPOAb and/or TSH-R-Ab) in blood and cerebrospinal fluid. Autoantibodies against alpha-enolase, aldehyde reductase-I (AKRIA) and/or dimethylargininase-I (DDAHI), proteins expressed in the CNS among other tissues, were detected in the blood and, when searched, in the cerebrospinal fluid of HE/SREAT patients. Recently, we reported that alpha-enolase, AKRIA and DDAHI share local sequence homology with each of the three autoantigens (TgAb, TPOAb, TSH-R-Ab), often in epitope-containing segments of the thyroid autoantigens. We hypothesized that there might be additional CNS-expressed proteins homologous to thyroid autoantigens, possibly overlapping known epitopes of the thyroid autoantigens. We used bioinformatic methods to address this hypothesis. Six, 27 and 47 of 46,809 CNS-expressed proteins share homology with TSH-R, Tg and TPO, respectively. The homologous regions often contain epitopes, and some match regions of thyroid autoantigens which have homology with alpha-enolase, AKRIA and/or DDAHI. Several of the aforementioned proteins are present in CNS areas that show abnormalities at neuroimaging in HE/SREAT patients. Furthermore, autoantibodies against some of the said six, 27 and 47 proteins were reported to be associated with a number of autoimmune diseases. Not only we validated our hypothesis, but we think that such a variety of potential CNS targets for thyroid Ab against epitopes contained in regions that have local homology with CNS proteins may explain the polymorphic phenotypes of HE/SREAT. Only when elevated amounts of these Ab are synthesized and trespass the blood-brain barrier, HE/SREAT appears. This might explain why HE/SREAT is so relatively rare.

Methotrexate as a Steroid-Sparing Agent in Myasthenia Gravis: A Preliminary Retrospective Study.

OBJECTIVES: Treatment approach of myasthenia gravis (MG) is still debated; corticosteroids alone or in combination with immunosuppressive agents are the most used drugs. Azathioprine (AZA) has been shown to be effective for MG with a significant steroid-sparing activity, although burdened by side effects. Few studies on methotrexate (MTX) administration showed controversial results. In this cohort, we evaluated the role of MTX as a effective steroid-sparing agent. METHODS: Fifteen MG patients treated with MTX, previously treated with AZA for at least 12 months, with poor benefits and uncomfortable side effects AZA related, have been selected. Each patient was evaluated through MG-Activity of Daily Living and Quantitative MG scores 5 times/yr. RESULTS: Patients treated with MTX had a significant improvement of MG-Activity of Daily Living and Quantitative MG scores. Furthermore, all patients reduced prednisone dosage, and none complained of side effects. CONCLUSIONS: We suggest MTX is effective and well tolerated and could be considered as a steroid-sparing agent in MG treatment.

MuSK-Associated Myasthenia Gravis: Clinical Features and Management.

Muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG) is a rare, frequently more severe, subtype of MG with different pathogenesis, and peculiar clinical features. The prevalence varies among countries and ethnic groups, affecting 5-8% of all MG patients. MuSK-MG usually has an acute onset affecting mainly the facial-bulbar muscles. The symptoms usually progress rapidly, within a few weeks. Early respiratory crises are frequent. The disease may lead to generalized muscle weakness up to muscle atrophy. The main bulbar involvement, the absence of significant thymus alterations, and the association with HLA class II DR14, DR16, and DQ5 alleles have been confirmed. Atypical onset, such as ocular involvement, lack of symptom fluctuations, acetylcholinesterase inhibitors failure, and negative results of electrophysiologic testing, if not specifically performed in the mainly involved muscle groups, makes MuSK-MG diagnosis challenging. In most cases, steroids are effective. Conventional immunosuppressants are not commonly able to replace steroids in maintaining a satisfactory long-term control of symptoms. However, the majority of MuSK-MG patients are refractory to treatment. In these cases, the use of rituximab showed promising results, resulting in sustained symptom control.

Myasthenia gravis after etanercept and ustekinumab treatment for psoriatic arthritis: A case report.

A 35-year-old man was diagnosed with psoriatic arthritis treated with methotrexate and cyclosporine, the latter was then interrupted. Subsequently, etanercept was introduced, administered for 10 years and then replaced with ustekinumab. Six months after treatment with ustekinumab, patient underwent a chest CT scan for pneumonia, showing an anterior mediastinal mass which turned out to be a thymoma. He was referred to our department with fatigue, difficulty in raising arms and transient episodes of diplopia after exertion. Clinical history revealed that these symptoms had begun about 7 years previously but were ascribed to psoriatic arthritis. A diagnosis of anti-acetylcholine receptor antibodies positive myasthenia gravis was made; a higher dosage of methotrexate and prednisone were started with regression of symptoms. Our case increases the number of clinical reports of myasthenia gravis onset in patients with a history of rheumatic disease treated with anti-TNFα drugs. We speculate that ustekinumab could contribute to clinical worsening.

Endocrine myopathies: clinical and histopathological features of the major forms.

Endocrinopathies, such as thyroid and parathyroid diseases, disorders of the adrenal axis, and acromegaly are included among the many causes of myopathy. Muscle disturbances caused by endocrine disorders are mainly due to alterations in the protein and carbohydrate metabolisms. Either a deficiency or excess of hormones produced by the glands can cause muscle dysfunction that can be reversed by starting hormone replacement therapy or acting on hormone dysfunction. The diagnosis is usually easy if a muscle disorder occurs in an overt endocrinopathy; however, in few patients, myopathy could be the first manifestation of the underlying endocrinopathy. In this article we discuss pathophysiology, clinical features and management of muscle involvement related to the major endocrine diseases.

Severe congenital myasthenic syndrome associated with novel biallelic mutation of the CHRND gene.

Congenital myasthenic syndromes (CMS) are a group of inherited disorders caused by mutations in genes encoding proteins essential for neuromuscular transmission. CMS is characterized by fatigable muscle weakness with onset at birth or in early childhood; rarely, symptoms may present later. The most frequently involved proteins are choline acetyltransferase, the endplate species of acetylcholinesterase and the acetylcholine receptor subunits. Defects in the cholinergic receptor nicotinic delta subunit (CHRND) are a rare cause for CMS but they should be considered in patients with a severe, early onset disease, with respiratory distress. We describe two sisters, clinically and genetically diagnosed with CMS, carrying two heteroallelic variants in the CHRND gene: c.730C>T; p.(Arg244Cys) and c.1304T>C; p.(Leu435Pro). The first variant has already been described yet no clinical relevance has been proved; the second one, is a novel variant documented here for the first time. These two cases expand the clinical spectrum of CMS linked to CHRND mutations.

Molecular Characterization of Penicillinase-Producing Neisseria gonorrhoeae Isolated in Two Time Periods, 2003-2004 and 2014-2015, in Italy.

The emergence of antibiotic resistant strains poses a great concern for gonorrhea treatment. The aim of this study was to characterize penicillinase-producing Neisseria gonorrhoeae (PPNG) isolates collected in Italy in two time frames, 2003-2004 and 2014-2015. A total of 80 PPNG were characterized for the blaTEM gene variant and the plasmid type. Furthermore, gonococci were typed using Neisseria gonorrhoeae multiantigen sequence typing. Antibiotic susceptibility assay was performed for penicillin, ciprofloxacin, ceftriaxone, and spectinomycin by Etest and minimum inhibitory concentration (MIC) test strip methods. The ß-lactamase production was detected using nitrocefin test. Among PPNG isolates, four blaTEM alleles were identified as follows: blaTEM-1, blaTEM-228, blaTEMP14S, and blaTEM-135. The African plasmid possessed the blaTEM-1, blaTEM-228, and blaTEMP14S, whereas blaTEM-135 was identified in Toronto/Rio and Asian plasmids. The percentage of isolates with the blaTEM-1-carrying African plasmid increased from 42.5% in 2003-2004 to 55% in 2014-2015; conversely, the isolates with blaTEM-135-carrying Toronto/Rio plasmid decreased from 57.5% to 35%. Among the isolates carrying the Toronto/Rio plasmids possessing blaTEM-135, sequence type (ST)661 and ST5624 were found to be the predominant STs in both periods 2003-2004 and 2014-2015, respectively. More than half of the PPNG isolates were resistant to ciprofloxacin. Increase in the isolates carrying the African plasmid possessing blaTEM-1 and a parallel decrease of the blaTEM-135-carrying Toronto/Rio plasmid was observed. Moreover, PPNG isolate harbored Toronto/Rio plasmid with blaTEM-135 belonged mainly to two major STs (ST661 and ST5624). Given the possible role of a mutated blaTEM gene as an additional mechanism to extended spectrum ß-lactamase resistance, it is crucial to monitor gonococci carrying these resistance genes.

Gut microbiota and development of atopic eczema in 3 European birth cohorts.

BACKGROUND: Stimulation of the immune system by gut microbes might prevent allergy development. OBJECTIVE: The present study examined the hypothesis that sensitization to food allergens and atopic eczema are influenced by the infantile intestinal colonization pattern. METHODS: Infants were recruited perinatally in Göteborg (n = 116), London (n = 108), and Rome (n = 100). Commensal bacteria were identified to the genus or species level in rectal (3 days) and quantitative stool cultures (7, 14, and 28 days and 2, 6, and 12 months of age). At 18 months of age, atopic eczema and total and food-specific IgE levels were assessed. These outcomes were modeled in relation to time to colonization with 11 bacterial groups and to ratios of strict anaerobic to facultative anaerobic bacteria and gram-positive to gram-negative bacteria at certain time points. Study center, mode of delivery, parity, and infant diet were included as covariates. RESULTS: Neither atopic eczema nor food-specific IgE by 18 months of age were associated with time of acquisition of any particular bacterial group. Cesarean section delayed colonization by Escherichia coli and Bacteroides and Bifidobacterium species, giving way to, for example, Clostridium species. Lack of older siblings was associated with earlier colonization by Clostridium species and lower strict anaerobic/facultative anaerobic ratio at 12 months. CONCLUSIONS: This study does not support the hypothesis that sensitization to foods or atopic eczema in European infants in early life is associated with lack of any particular culturable intestinal commensal bacteria. CLINICAL IMPLICATIONS: The nature of the microbial stimulus required for protection from allergy remains to be identified.