Relationship Between Cognitive-Behavioral Impairment and Clinical and Functional Parameters in ALS and Reliability of the Edinburgh Cognitive and Behavioural ALS Screen to Assess ALS: Preliminary Findings.

BACKGROUND: Although it is widely recognized that a high percentage of individuals with amyotrophic lateral sclerosis (ALS) have cognitive and behavioral impairment, the associated clinical and functional parameters remain unknown. ALS is typically assessed via screening tests, such as the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). OBJECTIVE: To investigate the relationship between cognitive-behavioral impairment and other clinical and functional parameters and to compare the assessment results from a set of standardized neuropsychological tests with those from the ECAS. METHODS: Forty individuals with ALS participated in the study. We assessed attention, memory and learning ability, and executive function using a set of standardized neuropsychological tests and the ECAS. Sociodemographic variables, time since onset of symptoms, time since diagnosis, and functional respiratory values were recorded. RESULTS: No relationship was found between time since onset of symptoms and time since definitive diagnosis and either attention (P=0.206, 0.314, respectively), memory and learning ability (P=0.618, 0.692), or executive function (P=0.844, 0.583). The set of standardized neuropsychological tests identified an impairment in executive function in 29% of the participants, whereas the ECAS identified it in 89%. CONCLUSIONS: We found no relationship between cognitive-behavioral impairment and time since onset of symptoms nor time since ALS diagnosis. Because the ECAS does not correctly reflect the executive function of individuals with ALS, function-specific neuropsychological tests are preferred. Test selection must take into account individuals' physical characteristics and their consequent ability to respond gesturally or orally.

Performance of a Highly Sensitive Mycobacterium tuberculosis Complex Real-Time PCR Assay for Diagnosis of Pulmonary Tuberculosis in a Low-Prevalence Setting: a Prospective Intervention Study.

The potential impact of routine real-time PCR testing of respiratory specimens from patients with presumptive tuberculosis in terms of diagnostic accuracy and time to tuberculosis treatment inception in low-prevalence settings remains largely unexplored. We conducted a prospective intervention cohort study. Respiratory specimens from 1,020 patients were examined by acid-fast bacillus smear microscopy, tested by a real-time Mycobacterium tuberculosis complex PCR assay (Abbott RealTime MTB PCR), and cultured in mycobacterial media. Seventeen patients tested positive by PCR (5 were acid-fast bacillus smear positive and 12 acid-fast bacillus smear negative), and Mycobacterium tuberculosis was recovered from cultures for 12 of them. Patients testing positive by PCR and negative by culture (n = 5) were treated and deemed to have responded to antituberculosis therapy. There were no PCR-negative/culture-positive cases, and none of the patients testing positive for nontuberculous mycobacteria (n = 20) yielded a positive PCR result. The data indicated that routine testing of respiratory specimens from patients with presumptive tuberculosis by the RealTime MTB PCR assay improves the tuberculosis diagnostic yield and may reduce the time to antituberculosis treatment initiation. On the basis of our data, we propose a novel mycobacterial laboratory algorithm for tuberculosis diagnosis.

Critical role of fractalkine (CX3CL1) in cigarette smoke-induced mononuclear cell adhesion to the arterial endothelium.

BACKGROUND: Cigarette smoking is an important risk factor for the development of cardiovascular disease, yet the pathways through which this may operate are poorly understood. Therefore, the mechanism underlying cigarette smoke (CS)-induced arterial endothelial dysfunction and the potential link with fractalkine/CX(3)CL1 upregulation were investigated. METHODS AND RESULTS: Stimulation of human arterial umbilical endothelial cells (HUAECs) with pathophysiological concentrations of CS extract (1% CSE) increased CX(3)CL1 expression. Neutralisation of CX(3)CL1 activity under dynamic flow conditions significantly inhibited CSE-induced mononuclear cell adhesion to HUAECs (67%). The use of small interfering RNA (siRNA) revealed that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 5 (Nox5) but not Nox2 or Nox4 is the main NADPH isoform involved in CSE-induced CX(3)CL1 upregulation and mononuclear cell arrest. Knock down of HUAEC tumour necrosis factor α expression with siRNA or pharmacological inhibition of p38 mitogen-activated protein kinase and nuclear factor κB also abolished these responses. Interestingly, circulating monocytes and lymphocytes from patients with chronic obstructive pulmonary disease (COPD) (n=29) versus age-matched controls (n=23) showed CX(3)CR1overexpression. Furthermore, CX(3)CL1 neutralisation dramatically diminished their enhanced adhesiveness to CSE-stimulated HUAECs. Finally, when animals were exposed for 3 days to CS, a mild inflammatory response in the lung was observed which was accompanied by enhanced CX(3)CL1 expression in the cremasteric arterioles, an organ distant from the lung. CS exposure resulted in increased leukocyte-arteriolar endothelial cell adhesion which was significantly reduced (51%) in animals lacking CX(3)CL1 receptor (CX(3)CR1). CONCLUSIONS: These results suggest that CS induces functional CX(3)CL1 expression in arterial endothelium and leukocytes from patients with COPD show increased CX(3)CL1-dependent adhesiveness. Therefore, targeting the CX(3)CL1/CX(3)CR1 axis might prevent COPD-associated cardiovascular disorders.

Paving the Way for Climate Neutral and Resilient Historic Districts.

Climate change is a major global threat to our society's urban areas, with the majority of Europe's population living in cities and their cultural heritage. Historic districts of significant cultural value and the communities connected to these places have an important role to play in fostering location-based identity and economy, social cohesion, innovation, urban regeneration, and climate change adaptation. Thus, it is important to make historic districts climate resilient, by jointly considering climate change adaptation, disaster risk management, heritage management, and sustainable urban development. However, this is often a major challenge for local and regional administrators and relevant stakeholders. This paper constitutes the first major result of the EU R&I Task Force for Climate Neutral and Resilient Historic Urban Districts. It provides an overview of the challenges faced by practitioners and researchers when jointly addressing the needs of resilient historic districts and provides an initial set of recommendations produced by the task force to address these challenges. These challenges cover different issues around five topics (i) data availability, use and its management, (ii) the common responsibility fragmentation in policy and governance, (iii) the challenge on integrating local knowledge and traditions in resilience building, (iv) the difficulties around the co-ownership and co-production in governance and (v) the importance of mainstreaming heritage management in adaptation and resilience policies.

Home tracheotomy mechanical ventilation in patients with amyotrophic lateral sclerosis: causes, complications and 1-year survival.

BACKGROUND: Home tracheotomy mechanical ventilation (HTMV) can prolong survival in patients with amyotrophic lateral sclerosis (ALS) when non-invasive ventilation (NIV) fails, but knowledge about HTMV is scarce. The aim of this study was to determine the causes of tracheotomy and the main issues of 1-year HTMV in a cohort of patients with ALS. METHODS: A prospective study of all patients needing HTMV was performed in a referral respiratory care unit (RCU) from April 2001 to January 2010. Patients' informed decisions about HTMV were fully respected. Caregivers were trained and could telephone the RCU. Hospital staff made home visits. RESULTS: All patients (n=116) agreed to participate and a tracheotomy was needed for 76, mainly due to bulbar dysfunction. Of the 38 who had a tracheotomy, in 21 it was performed in an acute setting and in 17 as a non-emergency procedure. In 19 patients the tracheotomy was related to the inadequacy of mechanically assisted coughing (MAC) to maintain normal oxygen saturation. During HTMV, 19 patients required hospitalisation, 12 with respiratory problems. The 1-year survival rate was 78.9%, with a mean survival of 10.39 months (95% CI 9.36 to 11.43). Sudden death was the main cause of death (n=9) and only one patient died from respiratory causes. No predictive factors for survival were found. CONCLUSIONS: Besides NIV inadequacy, the ineffectiveness of mechanically assisted coughing appears to be a relevant cause of tracheotomy for patients with ALS with severe bulbar dysfunction. Patients choosing HTMV provided by a referral RCU could have a good 1-year survival rate, respiratory problems being the main cause of hospitalisation but not of death.

Mechanical Insufflation-Exsufflation With Oscillations in Amyotrophic Lateral Sclerosis With Home Ventilation via Tracheostomy.

BACKGROUND: Mechanical insufflation-exsufflation (MI-E) applied via tracheostomy tubes in patients with amyotrophic lateral sclerosis (ALS) who are on home mechanical ventilation via tracheostomy is an effective procedure for respiratory secretion management. Nonetheless, tenacious secretions may remain and increase the risk of respiratory infections. The aim of this study was to determine whether adding oscillations to MI-E could reduce the rate of respiratory infections and the need for bronchoscopy to remove secretions in patients with ALS on home mechanical ventilation via tracheostomy. METHODS: This was a 2-y, prospective, crossover study. Subjects were treated with conventional MI-E and MI-E with oscillations for 2 alternate 6-month periods. Data were collected on episodes of respiratory infections, hospital admission, and number of bronchoscopy procedures. RESULTS: In the 19 ALS subjects enrolled, the median (interquartile range [IQR]) number of acute respiratory infections per subject was 1.0 (0.5-2.0) in the MI-E period and 0.0 (0.0-2.0) in the MI-E plus oscillations period (P = .92). The median (IQR) number of hospital stays was 0.0 (0.0-1.0) in the MI-E period and 0.0 (0.0-1.0) in the MI-E plus oscillations period (P = .80). The median (IQR) number of bronchoscopies per subject was 0.0 (0.0-1.0) in MI-E period and 0.0 (0.0-0.5) in the MI-E plus oscillations period (P = .26). MI-E plus oscillations treatment had no impact on the risk of respiratory infections (odds ratio 3.71, 95% CI 0.81-16.84, P = .09) or the need for bronchoscopy (odds ratio 2.70, 95% CI 0.44-16.68, P = .29). CONCLUSIONS: Adding oscillations to MI-E therapy in subjects with ALS on home mechanical ventilation via tracheostomy did not decrease the risk of respiratory infections, hospital admission, or need for bronchoscopy.

Effect of one-year dextromethorphan/quinidine treatment on management of respiratory impairment in amyotrophic lateral sclerosis.

Treatment with Dextromethorphan/Quinidine (DM/Q) has demonstrated benefit on pseudobulbar affect and bulbar function in amyotrophic lateral sclerosis (ALS). The aim of this study was to assess whether DM/Q could provide long-term improvement in bulbar function and thereby prolong noninvasive respiratory management in ALS. MATERIALS AND METHODS: This prospective, case-cohort study, recruited ALS patients with bulbar dysfunction. Subjects included were compared with cross-matched historical controls. Cases received DM/Q (20/10 mg twice daily) during one-year follow-up; bulbar dysfunction was evaluated with the Norris scale bulbar subscore (NBS) and bulbar subscale of AlSFRS-R (ALSFRSb). RESULTS: In total, 21 cases and 20 controls were enrolled, of whom noninvasive respiratory muscle assistance failed in 6 (28.5%) patients in the DM/Q group, compared with 4 patients (20.0%) in the control group (p = 0.645). Time from study onset to failure of respiratory muscle aids was 5.50 + 1.31 months in the DM/Q group and 5.20 + 1.15 months in the control group (p = 0.663). The adjusted OR for the effect of treatment on failure of noninvasive respiratory muscle aids was 2.12 (95%CI 0.23-33.79, p = 0.592). In the DM/Q group an impairment in scores was found in NBS (F = 19.26, p = 0.000) and ALSFRS-Rb (F = 12.71, p = 0.001) across different months of the study. CONCLUSION: Treatment with DM/Q in ALS is unable to prolong noninvasive respiratory management, and moreover, has no effect on long-term deterioration of bulbar function. Notwithstanding the results on bulbar function, DM/Q was found to improve pseudobulbar affect during one-year follow-up.

Usefulness of Oscillations Added to Mechanical In-Exsufflation in Amyotrophic Lateral Sclerosis.

BACKGROUND: Assisted coughing via mechanical in-exsufflation (MI-E) is a first-line treatment for secretion management in patients with amyotrophic lateral sclerosis (ALS) with unassisted CPF < 4.25 L/s. Some devices enable oscillations to be added to MI-E (MI-E+O). We sought to determine whether adding oscillations to MI-E enables a reduction in the use of invasive secretion management procedures (ie, bronchoscopy or tracheostomy) in subjects with ALS. METHODS: We conducted a 12-month, prospective, randomized follow-up study of subjects with ALS for whom assisted coughing techniques were indicated. One group was treated with oscillations in addition to MI-E (MI-E+O), and the other group was treated with conventional MI-E. RESULTS: 29 subjects were included in the MI-E group and 27 subjects were included in the MI-E+O group. Five subjects (8.9%) required invasive techniques for secretion management (3 in the MI-E group and 2 in the MI-E+O group, P = .70). Treatment with MI-E+O did not alter the risk of invasive procedures (odds ratio 0.69, 95% CI 0.10-4.50, P = .70). The mean number of respiratory infections was 0.58 ± 0.16 in the MI-E group and 0.025 ± 0.08 in the MI-E+O group (P = .10). Survival was 8.96 ± 0.18 months in the MI-E group and 7.70 ± 0.70 months in the MI-E+O group (P = .10). CONCLUSION: Adding oscillations to MI-E did not enable a reduction in the need to perform invasive procedures for secretion management in subjects with ALS.

Unstable control of breathing can lead to ineffective noninvasive ventilation in amyotrophic lateral sclerosis.

Upper airway obstruction with decreased central drive (ODCD) is one of the causes of ineffective noninvasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS). The aim of this study is to determine the mechanism responsible for ODCD in ALS patients using NIV. This is a prospective study that included ALS patients with home NIV. Severity of bulbar dysfunction was assessed with the Norris scale bulbar subscore; data on upper or lower bulbar motor neuron predominant dysfunction on physical examination were collected. Polysomnography was performed on every patient while using NIV and the ODCD index (ODCDI: number of ODCD events/total sleep time) was calculated. To determine the possible central origin of ODCD, controller gain was measured by inducing a hypocapnic hyperventilation apnoea. Sonography of the upper airway during NIV was performed to determine the location of the ODCD. 30 patients were enrolled; three (10%) had ODCDI >5 h-1. The vast majority of ODCD events were produced during non-rapid eye movement sleep stages and were a consequence of an adduction of the vocal folds. Patients with ODCDI >5 h-1 had upper motor neuron predominant dysfunction at the bulbar level, and had greater controller gain (1.97±0.33 versus 0.91±0.36 L·min-1·mmHg-1; p<0.001) and lower carbon dioxide (CO2) reserve (4.00±0.00 versus 10.37±5.13 mmHg; p=0.043). ODCDI was correlated with the severity of bulbar dysfunction (r= -0.37; p=0.044), controller gain (r=0.59; p=0.001) and CO2 reserve (r= -0.35; p=0.037). ODCD events in ALS patients using NIV have a central origin, and are associated with instability in the control of breathing and an upper motor neuron predominant dysfunction at the bulbar level.

Importance of noninvasively measured respiratory muscle overload among the causes of hospital readmission of COPD patients.

AIM: To evaluate the influence of respiratory muscle overload and right cardiac overload among the possible risk factors of hospital readmission in a 1-year follow-up of a cohort of patients with moderate-to-severe COPD. METHODS: A total of 112 COPD patients who were admitted consecutively to the hospital for acute exacerbation. At hospital discharge, we evaluated the conventional clinical and functional determinations in addition to the pressure-time index (PTI), which is obtained using the equation PTI = (Pawo/Pimax) x (Ti/Ttot) x 100, where Pawo represents the mean airway pressure measured at the mouth during spontaneous breathing, Pimax is the maximal inspiratory pressure, Ti is the inspiratory time, and Ttot is the total breathing cycle time. A cardiac echo-Doppler examination was carried out when patients were in stable condition and presented clinical signs of right cardiac overload prior to inclusion in the study. RESULTS: Multivariate analysis showed that the use of long-term oxygen therapy (LTOT) and high PTI (> 0.25) were independently related to the risk of hospital readmission. Patients receiving LTOT had higher Paco(2) (p < 0.05), FEV(1) percent predicted (p < 0.05), FVC percent predicted (p < 0.05), and Pao(2) (p < 0.05), and had higher Paco(2) (p < 0.05). An elevated systolic pulmonary arterial pressure (> 40 mm Hg) was also independently related, but only 28 patients had echo-Doppler data that could be used. CONCLUSIONS: At hospital discharge, noninvasively measured respiratory muscle overload as well as the use of LTOT were associated with an increased risk of hospital readmission for exacerbation in patients with moderate-to-severe COPD.