Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease.

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson's coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I-V ß = -1.06, P < 0.001; lobules VI-VII ß = -0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion.

On-Demand Cueing for Freezing of Gait in Parkinson's Disease: A Randomized Controlled Trial.

BACKGROUND: Cueing can alleviate freezing of gait (FOG) in people with Parkinson's disease (PD), but using the same cues continuously in daily life may compromise effectiveness. Therefore, we developed the DeFOG-system to deliver personalized auditory cues on detection of a FOG episode. OBJECTIVES: We aimed to evaluate the effects of DeFOG during a FOG-provoking protocol: (1) after 4 weeks of DeFOG-use in daily life against an active control group; (2) after immediate DeFOG-use (within-group) in different medication states. METHOD: In this randomized controlled trial, 63 people with PD and daily FOG were allocated to the DeFOG or active control group. Both groups received feedback on their daily living step counts using the device, but the DeFOG group also received on-demand cueing. Video-rated FOG severity was compared pre- and post-intervention through a FOG-provoking protocol administered at home off and on-medication, but without using DeFOG. Within-group effects were tested by comparing FOG during the protocol with and without DeFOG. RESULTS: DeFOG-use during the 4 weeks was similar between groups, but we found no between-group differences in FOG-severity. However, the within-group analysis showed that FOG was alleviated by DeFOG (effect size d = 0.57), regardless of medication state. Combining DeFOG and medication yielded an effect size of d = 0.67. CONCLUSIONS: DeFOG reduced FOG considerably in a population of severe freezers both off and on medication. Nonetheless, 4 weeks of DeFOG-use in daily life did not ameliorate FOG during the protocol unless DeFOG was worn. These findings suggest that on-demand cueing is only effective when used, similar to other walking aids. © 2024 International Parkinson and Movement Disorder Society.

3-O-Methyltolcapone and Its Lipophilic Analogues Are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity.

Transthyretin (TTR) is an amyloidogenic homotetramer involved in the transport of thyroxine in blood and cerebrospinal fluid. To date, more than 130 TTR point mutations are known to destabilise the TTR tetramer, leading to its extracellular pathological aggregation accumulating in several organs, such as heart, peripheral and autonomic nerves, and leptomeninges. Tolcapone is an FDA-approved drug for Parkinson's disease that has been repurposed as a TTR stabiliser. We characterised 3-O-methyltolcapone and two newly synthesized lipophilic analogues, which are expected to be protected from the metabolic glucuronidation that is responsible for the lability of tolcapone in the organism. Immunoblotting assays indicated the high degree of TTR stabilisation, coupled with binding selectivity towards TTR in diluted plasma of 3-O-methyltolcapone and its lipophilic analogues. Furthermore, in vitro toxicity data showed their several-fold improved neuronal and hepatic safety compared to tolcapone. Calorimetric and structural data showed that both T4 binding sites of TTR are occupied by 3-O-methyltolcapone and its lipophilic analogs, consistent with an effective TTR tetramer stabilisation. Moreover, in vitro permeability studies showed that the three compounds can effectively cross the blood-brain barrier, which is a prerequisite for the inhibition of TTR amyloidogenesis in the cerebrospinal fluid. Our data demonstrate the relevance of 3-O-methyltolcapone and its lipophilic analogs as potent inhibitors of TTR amyloidogenesis.

Functional characterization and transcriptional repression by Lacticaseibacillus paracasei DinJ-YafQ.

DinJ-YafQ is a bacterial type II TA system formed by the toxin RNase YafQ and the antitoxin protein DinJ. The activity of YafQ and DinJ has been rigorously studied in Escherichia coli, but little has been reported about orthologous systems identified in different microorganisms. In this work, we report an in vitro and in vivo functional characterization of YafQ and DinJ identified in two different strains of Lacticaseibacillus paracasei and isolated as recombinant proteins. While DinJ is identical in both strains, the two YafQ orthologs differ only for the D72G substitution in the catalytic site. Both YafQ orthologs digest ribosomal RNA, albeit with different catalytic efficiencies, and their RNase activity is neutralized by DinJ. We further show that DinJ alone or in complex with YafQ can bind cooperatively to a 28-nt inverted repeat overlapping the -35 element of the TA operon promoter. Atomic force microscopy imaging of DinJ-YafQ in complex with DNA harboring the cognate site reveals the formation of different oligomeric states that prevent the binding of RNA polymerase to the promoter. A single amino acid substitution (R13A) within the RHH DNA-binding motif of DinJ is sufficient to abolish DinJ and DinJ-YafQ DNA binding in vitro. In vivo experiments confirm the negative regulation of the TA promoter by DinJ and DinJ-YafQ and unveil an unexpected high expression-related toxicity of the gfp reporter gene. A model for the binding of two YafQ-(DinJ)2-YafQ tetramers to the promoter inverted repeat showing the absence of protein-protein steric clash is also presented. KEY POINTS: • The RNase activity of L. paracasei YafQ toxin is neutralized by DinJ antitoxin. • DinJ and DinJ-YafQ bind to an inverted repeat to repress their own promoter. • The R13A mutation of DinJ abolishes DNA binding of both DinJ and DinJ-YafQ.

Contribution of clinical severity and geriatric risk factors in predicting short-term mortality of older hospitalized pneumonia patients: the Pneumonia in Italian Acute Care for Elderly units (PIACE) study.

BACKGROUND: Clinical severity of pneumonia in older persons increases the risk for short-term mortality. Comprehensive geriatric assessment (CGA) may provide further insight in prognostic stratification. AIMS: To investigate whether CGA may improve prognostic stratification among older patients with pneumonia admitted to hospital. METHODS: Our series consisted of 318 consecutive patients hospitalized for pneumonia in a multicenter observational study. Disease severity was assessed by Sequential Organ Failure Assessment (SOFA) and Pneumonia Severity Index (PSI). CGA included the occurrence of delirium, Basic Activities of Daily Living (BADL) disability, cognitive impairment at Short Portable Mental Status Questionnaire (SPMSQ) and overall comorbidity assessed by Cumulative Illness Rating Scale (CIRS). The outcomes were in-hospital and post-discharge 3 month mortality. Statistical analysis was carried out by Cox regression, area under receiver operating curve (AUC) and net reclassification index (NRI). RESULTS: Overall, 53 patients died during hospitalization and 52 after discharge. Delirium, SOFA score and admission BADL disability were significant predictors of in-hospital mortality. SOFA score, CIRS, previous long-term oxygen therapy and discharge BADL dependency significantly predicted post-discharge mortality. The accuracy of SOFA in predicting in-hospital and post-discharge mortality was fair (AUC = 0.685, 95% CI = 0.610-0.761 and AUC = 0.663, 95% CI = 0.593-0.734, respectively). BADL dependency and delirium improved predictive accuracy for in-hospital mortality (ΔAUC = 0.144, 95% CI = 0.062-0.227, p < 0.001), while pre-admission oxygen therapy, CIRS and BADL dependency improved predictivity for 3 month mortality (ΔAUC = 0.177, 95% CI = 0.102-0.252, p < 0.001). DISCUSSION: Among older pneumonia patients, prognostic stratification obtained by clinical severity indexes is significantly improved by CGA risk factors. CONCLUSIONS: CGA provides important information for prognostic stratification and clinical management of older pneumonia patients.

Subclinical biliary strictures as a cause of long-term allograft dysfunction in children who underwent liver transplantation.

We aimed to evaluate the role of liver biopsy to predict subclinical biliary strictures (BS) and assess the impact of BS on long-term allograft dysfunction following liver transplantation in children (LT). We reviewed all liver biopsies performed from 2012-2018. Percutaneous transhepatic cholangiography (PTC) was performed in patients presenting cholangiolar proliferation on cytokeratin-7 stained sections. We performed 271 biopsies in 161 children (86% with a left lateral segment); 44/161 (27%) presented with diffuse or multifocal cholangiolar proliferation. Among them, a tight BS was confirmed in 38/44 (86%, 24% of total) and it was managed by balloon dilatation. Cholangiolar proliferation showed a positive predictive value (PPV) for BS of 86.4%. Levels of alkaline phosphatase >325 IU/L predicted BS (P = .007). Dilatation of intrahepatic bile ducts on ultrasound was found only in 44% of patients with BS. Following a median follow-up of 9.2 years, only 15/38 (39%) patients resolved the BS. In conclusion subclinical BS is very common and probably underdiagnosed in these patients. Histological evidence of cholangiolar proliferation detectable by cytokeratin-7 immunostain should be preferred to liver function tests and ultrasound to suspect BS. BS in this setting should be regarded as a main cause of long-term allograft dysfunction.

Prevalence and risk factors for Pulmonary Hypertension associated with chronic Myeloproliferative Neoplasms.

OBJECTIVES: Pulmonary hypertension (PH) is commonly reported in Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). PH may be diagnosed directly by right heart catheterization (RHC) or estimated by transthoracic echocardiography (TTE). Survival is shortened by PH but despite the potential significance of PH to management and prognosis of MPN, estimates of its prevalence in MPNs vary and risk factors for the condition are poorly established. We performed a systematic review and meta-analysis of available studies to fill this void. METHODS: We searched EMBASE, MEDLINE, and Clinicaltrials.gov for the terms "pulmonary hypertension," "myeloproliferative disorders," "polycythemia vera," "essential thrombocythemia," and "myelofibrosis." We restricted analysis to the 1999-2019 window to improve uniformity of MPN diagnostic criteria. We retrieved 221 records and, after abstract and full-text screening, identified 17 papers meeting criteria for inclusion in our meta-analysis. A modified Newcastle-Ottawa scale was used to assess quality. RESULTS: Results for 935 patients were available, 309 of these having PH (33%). Using logistic mixed-effect regression, we found that diagnosis mode (RHC vs TTE) and MPN duration influenced PH prevalence. Studies employing predominantly TTE yielded prevalence estimates ~5-fold higher than those using RHC (35% vs 7.2%). We identified MF and duration of MPN as significant risk factors for development of PH. CONCLUSIONS: Prevalence of PH in MPNs is poorly understood with estimates ranging from 3.8% to 58%. Patients with MF and longer duration of disease seem at particularly high risk and should be carefully monitored for PH.

Scoring Endoscopy in Pediatric Inflammatory Bowel Disease: A Way to Improve Quality.

OBJECTIVES AND STUDY: There is a large interobserver variability in evaluating mucosal lesions of inflammatory bowel disease (IBD), especially in pediatric patients. This multicenter prospective observational study aims to evaluate interobserver agreement (IOA) among pediatric endoscopists in assigning validated IBD endoscopic scores in children. METHODS: Fifteen videos of follow-up ileocolonoscopies in children with IBD were recorded and selected as cases. Eleven pediatric endoscopists from different centers blindly evaluated all videos and calculated scores: either Ulcerative Colitis Endoscopic Index of Severity (UCEIS) or Simple Endoscopic Score for Crohn Disease (SES-CD). Scores from all reviewers were compared in order to calculate IOA for general videos and specific sections. Scores from an expert adult reader were used to calculate possible reviewer's characteristics affecting scores' reliability. RESULTS: Intraclass correlation was 0.298 (95% confidence interval [CI]: 0.13-0.55) for ulcerative colitis (UC) and 0.266 (0.11-0.52) for Crohn disease (CD). When a disease activity categorization was adopted (remission, mild, moderate, severe activity) Fleiss kappa coefficient was 0.408 (0.29-0.53) for UC and 0.552 (0.43-0.73) for CD. When stratified by item, vascular pattern of UC was the most reliable item IC: 0.624 (0.321-0.854). In multivariable analysis, none of the reviewer's characteristics affected the readers' errors. CONCLUSIONS: This multicenter study shows low agreement among pediatric endoscopists in evaluating endoscopic scores in children with IBD. By using disease activity categorization, agreement slightly increased, mostly for CD. All readers showed a low-grade concordance with the expert adult gastroenterologist's evaluations. Future-specific training programs should be considered to increase IOA in using IBD endoscopic activity scores.

Augmented Reality Application for Handheld Devices: How to Make It hAPPen at the Pavia University History Museum.

The Pavia University History Museum, which houses historic items mainly connected to the physics and medicine fields, has focused in the past years on new ways to involve its public and to attract new audiences. Among different approaches, digital technologies have proven important to both external and internal communication. Lately, an Augmented Reality application has been made available to visitors, offering in one tool multimedia material of a historical-scientific nature: stories, 3D animations, images and user-generated video storytelling (developed mainly by University students, one of our least present demographics before the App, and younger students, who typically participate in the annual co-creative project). The App was designed to be as non-intrusive and discreet as possible, to preserve the historic ambiance of the museum, to unite social and educational aspects, to register user behaviour and to make the museum experience more vibrant and active and therefore captivating.

Trend of Antitissue Transglutaminase Antibody Normalization in Children With Celiac Disease Started on Gluten-free Diet: A Comparative Study Between Chemiluminescence and ELISA Serum Assays.

BACKGROUND: The aim of this study is to compare the performance of antitissue transglutaminase (atTG) chemiluminescence immunoassay (CLIA) with the standard enzyme-linked immunosorbent assay (ELISA) methods in monitoring celiac children after the start of gluten-free diet (GFD). METHODS: Celiac children diagnosed between 2005 and 2016 at our centre were classified into 2 groups based on serum assay (ELISA vs CLIA) used for atTG monitoring, and were compared on percentage of decrease and time to normalization of atTG on GFD. RESULTS: Among 260 included children, the rate of normalization of atTG levels at 30 months' follow-up was 86% and 70% in ELISA and CLIA group, respectively (P < 0.01). Median time to normalization was 11.7 and 14.7 months in ELISA and CLIA group respectively (P = 0.003). Marsh score at diagnosis was not associated with time to atTG normalization (P = 0.770), whereas older age at diagnosis and higher baseline atTG predicted longer time to atTG normalization (P = 0.01, P < 0.01). CONCLUSIONS: The percentage and the time of the atTG normalization in celiac children on GFD should be interpreted according to the utilized assay: at 30 months' follow-up children tested by CLIA are less likely to normalize atTG levels compared to those tested by ELISA. Younger age at diagnosis and lower baseline atTG are predictors of earlier atTG normalization, regardless of the adopted assay.

The effects of cerebrospinal fluid tap-test on idiopathic normal pressure hydrocephalus: an inertial sensors based assessment.

BACKGROUND: Gait disturbances are typical of persons with idiopathic normal pressure hydrocephalus (iNPH) without signs distinctive from other neurodegenerative and vascular conditions. Cerebrospinal fluid tap-test (CSF-TT) is expected to improve the motor performance of iNPH patients and is a prognostic indicator in their surgical management. This observational prospective study aims to determine which spatio-temporal gait parameter(s), measured during instrumented motor tests, and clinical scale(s) may provide a relevant contribution in the evaluation of motor performance pre vs. post CSF-TT on iNPH patients with and without important vascular encephalopathy. METHODS: Seventy-six patients (20 with an associated vascular encephalopathy) were assessed before, and 24 and 72 h after the CSF-TT by a timed up and go test (TUG) and an 18 m walking test (18 mW) instrumented using inertial sensors. Tinetti Gait, Tinetti Balance, Gait Status Scale, and Grading Scale were fulfilled before and 72 h after the CSF-TT. Stride length, cadence and total time were selected as the outcome measures. Statistical models with mixed effects were implemented to determine the relevant contribution to response variables of each quantitative gait parameter and clinical scales. RESULTS AND CONCLUSION: From baseline to 72 h post CSF-TT patients improved significantly by increasing cadence in 18 mW and TUG (on average of 1.7 and 2.4 strides/min respectively) and stride length in 18 mW (on average of 3.1 cm). A significant reduction of gait apraxia was reflected by modifications in double support duration and in coordination index. Tinetti Gait, Tinetti Balance and Gait Status Scale were able to explain part of the variability of response variables not covered by instrumental data, especially in TUG. Grading Scale revealed the highest affinity with TUG total time and cadence when considering clinical scales alone. Patients with iNPH and an associated vascular encephalopathy showed worst performances compared to pure iNPH but without statistical significance. Gait improvement following CSF-TT was comparable in the two groups. Overall these results suggest that, in order to augment CSF-TT accuracy, is key to assess the gait pattern by analyzing the main spatio-temporal parameters and set post evaluation at 72 h. TRIAL REGISTRATION: Approved by ethics committee: CE 14131 23/02/2015.

Structure-activity relationships of flurbiprofen analogues as stabilizers of the amyloidogenic protein transthyretin.

The inherent amyloidogenic potentialof wild type transthyretin (TTR) is enhanced by a large number of point mutations, which destabilize the TTR tetramer, thereby promoting its disassembly and pathological aggregation responsible for TTR-related amyloidosis. TTR stabilizers are able to interact with the thyroxine-binding sites of TTR, stabilizing its tetrameric native state and inhibiting amyloidogenesis. Herein, we report on in vitro, ex vivo, and X-ray analyses to assess the TTR structural stabilization by analogues of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID). Overall, considering together binding selectivity and protective effects on TTR native structure by flurbiprofen analogues in the presence of plasma proteins, as determined by Western Blot,the aforementioned properties of analyzed compounds appear to be better (CHF5075 and CHF4802) or similar (CHF4795) or worse (CHF5074, also known as CSP-1103) as compared to those of diflunisal, used as a reference TTR stabilizer. Molecular details of the determinants affecting the interactionsof CHF5075, CHF4802, and CHF4795 with wild type TTRand of CHF5074 withtheamyloidogenic A25TTTR variant havebeen elucidated by X-ray analysis. Distinct interactions with TTR appear to characterize flurbiprofen analogues and the NSAID diflunisal and its analogues as TTR stabilizers. Relationships between stabilizing effect on TTR by flurbiprofen analogues determined experimentally and molecular details of their interactions with TTR have been established, providing the rationale for their protective effects on the native protein structure.

Clinical outcomes under hydroxyurea treatment in polycythemia vera: a systematic review and meta-analysis.

Hydroxyurea is the standard treatment in high-risk patients with polycythemia vera. However, estimates of its effect in terms of clinical outcomes (thrombosis, bleeding, hematologic transformations and mortality) are lacking. We performed a meta-analysis to determine the absolute risk of events in recent cases of patients under hydroxyurea treatment. We searched for relevant articles or abstracts in the following databases: Medline, EMBASE, clinicaltrials.gov, WHO International Clinical Trials Registry, LILACS. Sixteen studies published from 2008 to 2018 reporting number of events using World Health Organization diagnosis for polycythemia vera were selected. Through a random effect logistic model, incidences, study heterogeneity and confounder effects were estimated for each outcome at different follow ups. Overall, 3,236 patients were analyzed. While incidences of thrombosis and acute myeloid leukemia were stable over time, mortality and myelofibrosis varied depending on follow-up duration. Thrombosis rates were 1.9%, 3.6% and 6.8% persons/year at median ages 60, 70 and 80 years, respectively. Higher incidence of arterial events was predicted by previous cardiovascular complication. Leukemic transformation incidence was 0.4% persons/year. Incidence of transformation to myelofibrosis and mortality were significantly dependent on age and follow-up duration. For myelofibrosis, rates were 5.0 at five years and 33.7% at ten years; overall mortality was 12.6% and 56.2% at five and ten years, respectively. In conclusion, we provide reliable risk estimates for the main outcomes in polycythemia vera patients under hydroxyurea treatment. These findings can help design comparative clinical trials with new cytoreductive drugs and prove the feasibility of using critical end points for efficacy, such as major thrombosis.

The association of indwelling urinary catheter with delirium in hospitalized patients and nursing home residents: an explorative analysis from the "Delirium Day 2015".

BACKROUND: Use of indwelling urinary catheter (IUC) in older adults has negative consequences, including delirium. AIM: This analysis, from the "Delirium Day 2015", a nationwide multicenter prevalence study, aim to evaluate the association of IUC with delirium in hospitalized and Nursing Homes (NHs) patients. METHODS: Patients underwent a comprehensive geriatric assessment, including the presence of IUC; inclusion criteria were age > 65 years, being Italian speaker and providing informed consent; exclusion criteria were coma, aphasia, end-of-life status. Delirium was assessed using the 4AT test (score ≥ 4: possible delirium; scores 1-3: possible cognitive impairment). RESULTS: Among 1867 hospitalized patients (mean age 82.0 ± 7.5 years, 58% female), 539 (28.9%) had IUC, 429 (22.9%) delirium and 675 (36.1%) cognitive impairment. IUC was significantly associated with cognitive impairment (OR 1.60, 95% CI 1.19-2.16) and delirium (2.45, 95% CI 1.73-3.47), this latter being significant also in the subset of patients without dementia (OR 2.28, 95% CI 1.52-3.43). Inattention and impaired alertness were also independently associated with IUC. Among 1454 NHs residents (mean age 84.4 ± 7.4 years, 70.% female), 63 (4.3%) had IUC, 535 (36.8%) a 4AT score ≥ 4, and 653 (44.9%) a 4AT score 1-3. The multivariate logistic regression analysis did not show a significant association between 4AT test or its specific items with IUC, neither in the subset of patients without dementia. DISCUSSION: We confirmed a significant association between IUC and delirium in hospitalized patients but not in NHs residents. CONCLUSION: Environmental and clinical factors of acute setting might contribute to IUC-associated delirium occurrence.

A Point Prevalence Study of Delirium in Italian Nursing Homes.

BACKGROUND: Delirium is a common geriatric syndrome. Few studies have been conducted in nursing home (NH) residents. The aim of this project was to perform a point prevalence study of delirium in Italian NHs. METHODS: Data collected in 71 NHs are presented. Inclusion criteria were age ≥65 years and native Italian speaker. Exclusion criteria were coma, aphasia, and end-of-life status. Sociodemographic and medical data were recorded. Delirium was assessed using the Assessment Test for Delirium and Cognitive Impairment (4-AT). Patients with a 4-AT score ≥4 were considered to have delirium. Motor subtype was evaluated using the Delirium Motor Subtype Scale (DMSS). RESULTS: A total of 1,454 patients were evaluated (mean age 84.4 ± 7.4 years, 70.2% female), of whom 535 (36.8%) had delirium. In multivariate logistic regression analysis, variables significantly associated with delirium were education (OR 0.94, 95% CI 0.91-0.97), dementia (OR 3.12, 95% CI 2.38-4.09), functional dependence (OR 6.13, 95% CI 3.08-12.19 for ADL score 0; OR 1.99, 95% CI 1.03-3.84 for ADL score 1-5), malnutrition (OR 4.87, 95% CI 2.68-8.84), antipsychotics (OR 2.40, 95% CI 1.81-3.18), and physical restraints (OR 2.48, 95% CI 1.71-3.59). CONCLUSION: Delirium is common in older NH residents. Simple assessment tools might facilitate its recognition in this vulnerable population.

A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy.

BACKGROUND: Hereditary myopathy with lactic acidosis and myopathy with deficiency of succinate dehydrogenase and aconitase are variants of a recessive disorder characterised by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, metabolic acidosis and rhabdomyolysis may occur. So far, this disease has been molecularly defined only in Swedish patients, all homozygous for a deep intronic splicing affecting mutation in ISCU encoding a scaffold protein for the assembly of iron-sulfur (Fe-S) clusters. A single Scandinavian family was identified with a different mutation, a missense change in compound heterozygosity with the common intronic mutation. The aim of the study was to identify the genetic defect in our proband. METHODS: A next-generation sequencing (NGS) approach was carried out on an Italian male who presented in childhood with ptosis, severe muscle weakness and exercise intolerance. His disease was slowly progressive, with partial recovery between episodes. Patient's specimens and yeast models were investigated. RESULTS: Histochemical and biochemical analyses on muscle biopsy showed multiple defects affecting mitochondrial respiratory chain complexes. We identified a single heterozygous mutation p.Gly96Val in ISCU, which was absent in DNA from his parents indicating a possible de novo dominant effect in the patient. Patient fibroblasts showed normal levels of ISCU protein and a few variably affected Fe-S cluster-dependent enzymes. Yeast studies confirmed both pathogenicity and dominance of the identified missense mutation. CONCLUSION: We describe the first heterozygous dominant mutation in ISCU which results in a phenotype reminiscent of the recessive disease previously reported.

Clinical Features Associated with Delirium Motor Subtypes in Older Inpatients: Results of a Multicenter Study.

OBJECTIVE: To date motor subtypes of delirium have been evaluated in single-center studies with a limited examination of the relationship between predisposing factors and motor profile of delirium. We sought to report the prevalence and clinical profile of subtypes of delirium in a multicenter study. METHODS: This is a point prevalence study nested in the "Delirium Day 2015", which included 108 acute and 12 rehabilitation wards in Italy. Delirium was detected using the 4-AT and motor subtypes were measured with the Delirium Motor Subtype Scale (DMSS). A multinomial logistic regression was used to determine the factors associated with delirium subtypes. RESULTS: Of 429 patients with delirium, the DMSS was completed in 275 (64%), classifying 21.5% of the patients with hyperactive delirium, 38.5% with hypoactive, 27.3% with mixed and 12.7% with the non-motor subtype. The 4-AT score was higher in the hyperactive subtype, similar in the hypoactive, mixed subtypes, while it was lowest in the non-motor subtype. Dementia was associated with all three delirium motor subtypes (hyperactive, OR 3.3, 95% CI: 1.2-8.7; hypoactive, OR 2.8, 95% CI: 1.2-6.5; mixed OR 2.6, 95% CI: 1.1-6.2). Atypical antipsychotics were associated with hypoactive delirium (OR 0.23, 95% CI: 0.1-0.7), while intravenous lines were associated with mixed delirium (OR 2.9, 95% CI: 1.2-6.9). CONCLUSIONS: The study shows that hypoactive delirium is the most common subtype among hospitalized older patients. Specific clinical features were associated with different delirium subtypes. The use of standardized instruments can help to characterize the phenomenology of different motor subtypes of delirium.

Modeling Information Content Via Dirichlet-Multinomial Regression Analysis.

Shannon entropy is being increasingly used in biomedical research as an index of complexity and information content in sequences of symbols, e.g. languages, amino acid sequences, DNA methylation patterns and animal vocalizations. Yet, distributional properties of information entropy as a random variable have seldom been the object of study, leading to researchers mainly using linear models or simulation-based analytical approach to assess differences in information content, when entropy is measured repeatedly in different experimental conditions. Here a method to perform inference on entropy in such conditions is proposed. Building on results coming from studies in the field of Bayesian entropy estimation, a symmetric Dirichlet-multinomial regression model, able to deal efficiently with the issue of mean entropy estimation, is formulated. Through a simulation study the model is shown to outperform linear modeling in a vast range of scenarios and to have promising statistical properties. As a practical example, the method is applied to a data set coming from a real experiment on animal communication.

"Delirium Day": a nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool.

BACKGROUND: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. METHODS: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. RESULTS: The mean sample age was 82.0 ± 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. CONCLUSIONS: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys.

Recognizing Physisorption and Chemisorption in Carbon Nanotubes Gas Sensors by Double Exponential Fitting of the Response.

Multi-walled carbon nanotubes (CNTs) have been grown in situ on a SiO 2 substrate and used as gas sensors. For this purpose, the voltage response of the CNTs as a function of time has been used to detect H 2 and CO 2 at various concentrations by supplying a constant current to the system. The analysis of both adsorptions and desorptions curves has revealed two different exponential behaviours for each curve. The study of the characteristic times, obtained from the fitting of the data, has allowed us to identify separately chemisorption and physisorption processes on the CNTs.