Impact of surgical lung biopsy on lung function and survival in patients with idiopathic pulmonary fibrosis in a multi-centre registry cohort.

BACKGROUND AND OBJECTIVE: Establishing an accurate and timely diagnosis of idiopathic pulmonary fibrosis (IPF) is essential for appropriate management and prognostication. In some cases, surgical lung biopsy (SLB) is performed but carries non-negligible risk. The objective of this retrospective study was to determine if SLB is associated with accelerated lung function decline in patients with IPF using the Canadian Registry for Pulmonary Fibrosis. METHODS: Linear mixed models and Cox proportional hazards regression models were used to compare decline in forced vital capacity (FVC)%, diffusion capacity of the lung (DLCO%) and risk of death or lung transplantation between SLB and non-SLB patients. Adjustments were made for baseline age, sex, smoking history, antifibrotic use, and lung function. A similar analysis compared lung function changes 12 months pre- and post-SLB. RESULTS: A total of 81 SLB patients and 468 non-SLB patients were included. In the SLB group, the post-biopsy annual FVC% decline was 2.0% (±0.8) in unadjusted, and 2.1% (±0.8) in adjusted models. There was no difference in FVC% decline, DLCO% decline, or time to death or lung transplantation between the two groups, in adjusted or unadjusted models (all p-values >0.07). In the pre-post SLB group, no differences were identified in FVC% decline in unadjusted or adjusted models (p = 0.07 for both). CONCLUSION: No association between SLB and lung function decline or risk of death or lung transplantation was identified in this multi-centre study of patients with IPF.

Alveolar Hemorrhage in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results of an International Randomized Controlled Trial (PEXIVAS).

Rationale: Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Objectives: Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. Methods: PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). Measurements and Main Results: At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21-1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22-26 vs. 22-27) and fewer with reduced GC (median, 23; IQR, 20-25) versus standard GC (median, 26; IQR, 25-28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Conclusions: Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Original clinical trial registered with www.clinicaltrials.gov (NCT00987389).

Treatment of rheumatoid arthritis-associated interstitial lung disease in a multi-center registry cohort.

Background: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is challenging to manage, with a paucity of robust data to guide treatment. Our aim was to characterize the pharmacologic treatment of RA-ILD utilizing a retrospective design in a national multi-center prospective cohort, and to identify associations between treatment and change in lung function and survival. Methods: Patients with RA-ILD and a radiological pattern of non-specific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) were included. Unadjusted and adjusted linear mixed models and Cox proportional hazards models were used to compare lung function change and risk of death or lung transplant by radiologic patterns and treatment. Results: Of 161 patients with RA-ILD, UIP pattern was more common than NSIP (55.9% vs. 44.1%). Only 44/161 (27%) patients were treated over median follow-up of 4 years with medication choice appearing unrelated to patient-specific variables. Decline in forced vital capacity (FVC) was not associated with treatment. Patients with NSIP had lower risk of death or transplant, compared to UIP (P=0.0042). In patients with NSIP, there was no difference in time to death or transplant comparing treated to untreated in adjusted models [hazard ratio (HR) =0.73; 95% confidence interval (CI): 0.15-3.62; P=0.70]. Similarly, in patients with UIP, there was no difference in time to death or lung transplant between treated and untreated in adjusted models (HR =1.06; 95% CI: 0.49-2.28; P=0.89). Conclusions: Treatment of RA-ILD is heterogeneous, with most patients in this cohort not receiving treatment. Patients with UIP had worse outcomes compared to NSIP, similar to other cohorts. Randomized clinical trials are needed to inform pharmacologic therapy in this patient population.

Non-hormonal treatments for managing vulvovaginal atrophy/genitourinary syndrome of menopause.

The demand for non-hormonal therapies for vulvovaginal atrophy (VVA) is increasing due to an increasing number of patients surviving long term post cancer diagnosis, as well as increased public knowledge of the symptoms of menopause and availability of non-hormonal therapies. Treatment options are wide-ranging and encompass different formulations and methods of application. This review summarizes the key characteristics of the main forms of these therapies, as well as considering the current evidence for each of them and where future clinical studies should be directed. Care for VVA may be in primary care, or under gynecology or oncology. Further research requirements include the need for long-term data as well larger randomized controlled trials into alternatives where vaginal estrogen cannot be used as first-line treatment. Widespread education of health-care providers and patients on VVA and the impact on quality of life is urgently needed, as well as increased use of non-hormonal methods in routine clinical practice.

Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: Interstitial lung disease is a known complication of rheumatoid arthritis, with a lifetime risk of developing the disease in any individual of 7·7%. We aimed to assess the safety, tolerability, and efficacy of pirfenidone for the treatment of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: TRAIL1 was a randomised, double-blind, placebo-controlled, phase 2 trial done in 34 academic centres specialising in interstitial lung disease in four countries (the UK, the USA, Australia, and Canada). Adults aged 18-85 years were eligible for inclusion if they met the 2010 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for rheumatoid arthritis and had interstitial lung disease on a high-resolution CT scan imaging and, when available, lung biopsy. Exclusion criteria include smoking, clinical history of other known causes of interstitial lung disease, and coexistant clinically significant COPD or asthma. Patients were randomly assigned (1:1) to receive 2403 mg oral pirfenidone (pirfenidone group) or placebo (placebo group) daily. The primary endpoint was the incidence of the composite endpoint of a decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or more or death during the 52-week treatment period assessed in the intention-to-treat population. Key secondary endpoints included change in absolute and FVC% over 52 weeks, the proportion of patients with a decline in FVC% of 10% or more, and the frequency of progression as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02808871. FINDINGS: From May 15, 2017, to March 31, 2020, 231 patients were assessed for inclusion, of whom 123 patients were randomly assigned (63 [51%] to the pirfenidone group and 60 [49%] to the placebo group). The trial was stopped early (March 31, 2020) due to slow recruitment and the COVID-19 pandemic. The difference in the proportion of patients who met the composite primary endpoint (decline in FVC% from baseline of 10% or more or death) between the two groups was not significant (seven [11%] of 63 patients in the pirfenidone group vs nine [15%] of 60 patients in the placebo group; OR 0·67 [95% CI 0·22 to 2·03]; p=0·48). Compared with the placebo group, patients in the pirfenidone group had a slower rate of decline in lung function, measured by estimated annual change in absolute FVC (-66 vs -146; p=0·0082) and FVC% (-1·02 vs -3·21; p=0·0028). The groups were similar with regards to the decline in FVC% by 10% or more (five [8%] participants in the pirfenidone group vs seven [12%] in the placebo group; OR 0·52 [95% CI 0·14-1·90]; p=0·32) and the frequency of progression as defined by OMERACT (16 [25%] in the pirfenidone group vs 19 [32%] in the placebo group; OR 0·68 [0·30-1·54]; p=0·35). There was no significant difference in the rate of treatment-emergent serious adverse events between the two groups, and there were no treatment-related deaths. INTERPRETATION: Due to early termination of the study and underpowering, the results should be interpreted with caution. Despite not meeting the composite primary endpoint, pirfenidone slowed the rate of decline of FVC over time in patients with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials. FUNDING: Genentech.

Cyanotoxin Analysis and Amino Acid Profiles of Cyanobacterial Food Items from Chad.

In some parts of the world, cyanobacteria are used as a food in the human diet, due to their ready availability. Lake Chad, has long been a traditional site for the collection of Arthrospira fusiformis which is dried and processed at the lake into thin wafers called Dihé for later consumption or is transported to market for sale. However, Dihé purchased from markets in Chad has not been analyzed for known cyanobacterial toxins or assessed for total amino acid content. Since BMAA in traditional foodstuffs of the indigenous Chamorro people of Guam causes neurodegenerative illness, it is important that Dihé from Chad be analyzed for this neurotoxin. BMAA and its isomer AEG were not detected in our analyses, but a further isomer DAB was detected as both a free and bound amino acid, with an increase in the free concentration after acid hydrolysis of this fraction. Microcystins were present in 6 samples at up to 20 µg/g according to UPLC-PDA, although their presence could not be confirmed using PCR for known microcystin synthetic genes. Amino acid analysis of the cyanobacterial material from Chad showed the presence of large amounts of canonical amino acids, suggesting that this may supplement indigenous people on low protein diets, although regular monitoring of the foodstuffs for the presence of cyanotoxins should be performed.

Toxin Analysis of Freshwater Cyanobacterial and Marine Harmful Algal Blooms on the West Coast of Florida and Implications for Estuarine Environments.

Recent marine and freshwater algal and cyanobacterial blooms in Florida have increased public concern and awareness of the risks posed by exposure to these organisms. In 2018, Lake Okeechobee and the Caloosahatchee river, on the west coast of Florida, experienced an extended bloom of Microcystis spp. and a bloom of Karenia brevis in the coastal waters of the Gulf of Mexico that coincided in the Fort Myers area. Samples from the Caloosahatchee at Fort Myers into Pine Island Sound and up to Boca Grande were collected by boat. High concentrations of microcystin-LR were detected in the cyanobacterial bloom along with brevetoxins in the marine samples. Furthermore, ß-N-methylamino-L-alanine (BMAA) and isomers N-(2-aminoethyl)glycine (AEG) and 2,4-diaminobuytric acid (DAB) were detected in marine diatoms and dinoflagellates, and cyanobacteria of freshwater origin. High freshwater flows pushed the cyanobacterial bloom to barrier island beaches and Microcystis and microcystins could be detected into the marine environment at a salinity of 41 mS/cm. For comparison, in 2019 collections of Dapis (a new generic segregate from Lyngbya) mats from Sarasota showed high concentrations of BMAA, suggesting the possibility of long-term exposure of residents to BMAA. The findings highlight the potential for multiple, potentially toxic blooms to co-exist and the possible implications for human and animal health.

Sputum quantitative cytometry in patients with interstitial lung disease and chronic cough.

BACKGROUND: Chronic cough frequently occurs in patients with diffuse interstitial lung diseases (ILDs), and can have negative effects on quality-of-life. While there are multiple possible contributors to cough in this setting, the contribution and consequences of airway inflammation have not been previously measured. We aimed to estimate the prevalence of airway cellular inflammation in patients with chronic cough and ILD, and examine the interaction between airway inflammation and changes in lung function. METHODS: We examined all patients with physician-diagnosed ILD and chronic cough who had sputum quantitative cytometry ordered between 2004 and 2018. The prevalence of airway inflammation was estimated by applying previously established criteria for bronchitis. FEV1 and FVC were compared between individuals based on the presence of airway inflammation. The changes in FEV1 and FVC were compared between individuals who had their treatment tailored to their sputum result, and those who did not. RESULTS: Airway inflammation was present in 50% of patients (n = 173), and was associated with lower FEV1 (1.87 vs 2.05 L, p = 0.043) and FVC (2.39 vs 2.71, p = 0.024). Sputum-guided management of airway eosinophilia was associated with improvements in FEV1 (+120 vs -205mL, p < 0.0001) and stability of FVC (+13 vs -284mL, p = 0.003). CONCLUSIONS: Airway inflammation is common in patients with chronic cough and ILD, and its presence may negatively affect lung function. Further research is required to understand if there is a role for quantitative sputum cytometry in this population, particularly if sputum-guided management of airway inflammation could lead to improvements in cough and other ILD outcomes.

Zero-order and prolonged release of atenolol from microporous FAU and BEA zeolites, and mesoporous MCM-41: Experimental and theoretical investigations.

The potential of microporous zeolites FAU and BEA, and mesoporous MCM-41, for prolonged release of atenolol in drug delivery systems was investigated both experimentally, using drug release studies, and theoretically using classical molecular dynamics simulations. Remarkably, zero-order release of atenolol was achieved from FAU (SiO2:Al2O3 = 80:1) into phosphate buffer for 24 h followed by prolonged release for at least another 48 h. Experimental data also demonstrate the ability for all of the drug-zeolite combinations investigated to achieve prolonged release of atenolol, with the release rates determined by the combination of framework topology, aluminium content and drug release study media. Molecular dynamics simulations give an insight into the reasons for the different release rates observed for FAU and BEA. The results of this work emphasise the need for sophisticated models in order to explain subtle differences in release, such as those observed at different SiO2:Al2O3 ratios.

Cause of intrauterine and neonatal death in twin pregnancies (CoDiT): development of a novel classification system.

OBJECTIVE: Twin pregnancies have a significantly higher perinatal mortality than singleton pregnancies. Current classification systems for perinatal death lack twin-specific categories, potentially leading to loss of important information regarding cause of death. We introduce and test a classification system designed to assign a cause of death in twin pregnancies (CoDiT). DESIGN: Retrospective cross-sectional study. SETTING: Tertiary maternity unit in England with a perinatal pathology service. POPULATION: Twin pregnancies in the West Midlands affected by fetal or neonatal demise of one or both twins between 1 January 2005 and 31 December 2016 in which postmortem examination was undertaken. METHODS: A multidisciplinary panel designed CoDiT by adapting the most appropriate elements of singleton classification systems. The system was tested by assigning cause of death in 265 fetal and neonatal deaths from 144 twin pregnancies. Cause of death was validated by another obstetrician blinded to the original classification. MAIN OUTCOME MEASURES: Inter-rater, intra-rater, inter-disciplinary agreement and cause of death. RESULTS: Cohen's Kappa demonstrated 'strong' (>0.8) inter-rater, intra-rater and inter-disciplinary agreement (95% CI 0.70-0.91). The commonest cause of death irrespective of chorionicity was the placenta; twin-to-twin transfusion syndrome (TTTS) was the commonest placental cause in monochorionic twins and acute chorioamnionitis in dichorionic twins. CONCLUSIONS: This novel classification system records causes of death in twin pregnancies from postmortem reports with high inter-user agreement. We highlight differences in aetiology of death between monochorionic and dichorionic twins. TWEETABLE ABSTRACT: New classification system for #twin cause of death 'CoDiT' shows high rater agreement.

Vulvovaginal atrophy in women after cancer.

The number of women surviving longer after a cancer diagnosis is increasing. This means that more awareness regarding their health is required. This review will focus on vulvovaginal atrophy (VVA)/genitourinary syndrome of menopause, one of the most distressing adverse iatrogenic effects of the menopause, secondary to cancer therapies. The cancer therapies themselves, such as radiotherapy, chemotherapy, and surgery, have a direct impact on the lower genital tract which interplays with the ensuing hypoestrogenic state of the menopause. Symptoms of VVA are still under-reported and undertreated as neither clinicians nor patients are forthcoming in discussing the problem, despite its profound negative impact on quality of life. In terms of treatment of VVA, this review will look at the use of various options, including estrogen post cancer diagnosis, as well as considering newer emerging therapies such as dehydroepiandrosterone, ospemifene, and laser. The care of a woman post cancer diagnosis should be a multidisciplinary responsibility. However, further research is required into emerging treatment options as well as long-term safety data, to ensure all health-care providers and women are fully informed and confident to effectively address the impact of VVA post cancer diagnosis.

Hirayama disease.

PURPOSE: Hirayama disease is an initially progressive disease caused by cervical neck flexion compressing the anterior horns of the lower cervical spinal cord. It is primarily seen in young males of Indian or Asian descent. With increasing dispersion of these populations this condition is increasingly being encountered internationally. This grand round reviews this rare but increasingly recognized condition. MATERIALS AND METHODS: We present a classic case of a young Indian male with progressive hand and forearm weakness. We discuss the typical clinical presentation, appropriate investigations and management of this condition. RESULTS: Our patient presented with oblique amyotrophy and underwent a diagnostic flexion MRI scan which revealed anterior translation of the posterior dura with compression of the anterior horns of the lower cervical cord. He has been successfully treated in a cervical collar. CONCLUSIONS: This case illustrates the typical presentation, diagnostic investigations and treatment of Hirayama syndrome. It is hoped that this review will alert clinicians of this condition and optimize the management of affected individuals.

Sputum Eosinophilia and Magnetic Resonance Imaging Ventilation Heterogeneity in Severe Asthma.

RATIONALE: Inflammation and smooth muscle dysfunction are integral components of severe asthma that contribute to luminal obstruction causing airflow limitation, ventilation heterogeneity, and symptoms. This is important for guiding treatment decisions directed at the inflammatory (e.g., anti-T-helper cell type 2 monoclonal antibodies) and noninflammatory, smooth muscle-mediated (e.g., bronchial thermoplasty) components of severe asthma. OBJECTIVES: To investigate the contribution of eosinophilic bronchitis and smooth muscle dysfunction to magnetic resonance imaging (MRI) ventilation heterogeneity in patients with severe asthma. METHODS: We measured the inhaled hyperpolarized gas MRI response to salbutamol as a marker of smooth muscle dysfunction, and sputum eosinophils as a marker of airway inflammation, and their contributions to ventilation heterogeneity (quantified as the ventilation defect percent [VDP]) in 27 patients with severe asthma. Spirometry and forced oscillation airway resistance measurements were also acquired pre- and postsalbutamol. Patients were dichotomized on the basis of sputum eosinophilia, and pre- and postsalbutamol VDP and physiological measurements were evaluated. MEASUREMENTS AND MAIN RESULTS: MRI VDP improved with salbutamol inhalation in patients in whom sputum eosinophilia was uncontrolled (≥3%, n = 16) (P = 0.002) and in those in whom it was controlled (<3%, n = 11) (P = 0.02), independent of improvements in FEV1, indicating smooth muscle response. In those patients in whom sputum eosinophilia was uncontrolled, greater VDP persisted postsalbutamol (P = 0.004). Postsalbutamol VDP correlated with sputum eosinophils (r = 0.63; P = 0.005). CONCLUSIONS: In patients with severe asthma, MRI regionally identifies the inflammatory and noninflammatory components of airway disease. Ventilation heterogeneity persists postsalbutamol in patients with uncontrolled eosinophilic bronchitis, which may be the functional consequence of airway inflammation.

L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential.

In human neuroblastoma cell cultures, non-human primates and human beings, L-serine is neuroprotective, acting through a variety of biochemical and molecular mechanisms. Although L-serine is generally classified as a non-essential amino acid, it is probably more appropriate to term it as a "conditional non-essential amino acid" since, under certain circumstances, vertebrates cannot synthesize it in sufficient quantities to meet necessary cellular demands. L-serine is biosynthesized in the mammalian central nervous system from 3-phosphoglycerate and serves as a precursor for the synthesis of the amino acids glycine and cysteine. Physiologically, it has a variety of roles, perhaps most importantly as a phosphorylation site in proteins. Mutations in the metabolic enzymes that synthesize L-serine have been implicated in various human diseases. Dosing of animals with L-serine and human clinical trials investigating the therapeutic effects of L-serine support the FDA's determination that L-serine is generally regarded as safe (GRAS); it also appears to be neuroprotective. We here consider the role of L-serine in neurological disorders and its potential as a therapeutic agent.

Mechanisms of L-Serine Neuroprotection in vitro Include ER Proteostasis Regulation.

ß-N-methylamino-L-alanine (L-BMAA) is a neurotoxic non-protein amino acid produced by cyanobacteria. Recently, chronic dietary exposure to L-BMAA was shown to trigger neuropathology in nonhuman primates consistent with Guamanian ALS/PDC, a paralytic disease that afflicts Chamorro villagers who consume traditional food items contaminated with L-BMAA. However, the addition of the naturally occurring amino acid L-serine to the diet of the nonhuman primates resulted in a significant reduction in ALS/PDC neuropathology. L-serine is a dietary amino acid that plays a crucial role in central nervous system development, neuronal signaling, and synaptic plasticity and has been shown to impart neuroprotection from L-BMAA-induced neurotoxicity both in vitro and in vivo. We have previously shown that L-serine prevents the formation of autofluorescent aggregates and death by apoptosis in human cell lines and primary cells. These effects are likely imparted by L-serine blocking incorporation of L-BMAA into proteins hence preventing proteotoxic stress. However, there are likely other mechanisms for L-serine-mediated neuroprotection. Here, we explore the molecular mechanisms of L-serine neuroprotection using a human unfolded protein response real-time PCR array with genes from the ER stress and UPR pathways, and western blotting. We report that L-serine caused the differential expression of many of the same genes as L-BMAA, even though concentrations of L-serine in the culture medium were ten times lower than that of L-BMAA. We propose that L-serine may be functioning as a small proteostasis regulator, in effect altering the cells to quickly respond to a possible oxidative insult, thus favoring a return to homeostasis.

L-Serine-Mediated Neuroprotection Includes the Upregulation of the ER Stress Chaperone Protein Disulfide Isomerase (PDI).

The unfolded protein response (UPR) is a highly evolutionarily conserved response to endoplasmic reticulum (ER) stress, which functions to return cells to homeostasis or send them into apoptosis, depending on the degree of cellular damage. ß-N-methylamino-L-alanine (L-BMAA) has been shown to induce ER stress in a variety of models and has been linked to several types of neurodegenerative disease including Guamanian amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC). L-Serine, an amino acid critical for cellular metabolism and neurological signaling, has been shown to be protective against L-BMAA-induced neurotoxicity in both animal and cell culture models. While the mechanisms of L-BMAA neurotoxicity have been well characterized, less is known about L-serine neuroprotection. We recently reported that L-serine and L-BMAA generate similar differential expression profiles in a human ER stress/UPR array, despite L-serine being neuroprotective and L-BMAA being linked to neurodegenerative disease. Here, we further investigate the mechanism(s) of L-serine-induced UPR dysregulation by examining key genes and proteins in the ER stress/UPR pathways. We report that L-serine selectively increased protein disulfide isomerase (PDI) protein translation, an ER chaperone involved in refolding misfolded proteins, suggesting it may be modulating the UPR to favor recovery from ER stress. This constitutes a new mechanism for L-serine-mediated neuroprotection and has implications for its use as a therapy for neurodegenerative illnesses.

Studies of Environmental Risk Factors in Amyotrophic Lateral Sclerosis (ALS) and a Phase I Clinical Trial of L-Serine.

ß-N-Methylamino-L-alanine (BMAA) has been linked to Guam ALS/PDC and shown to produce neurodegeneration in vitro and in vivo (Drosophila, mice, rats, primates). BMAA misincorporation into neuroproteins produces protein misfolding and is inhibited by L-serine. Case-control studies in Northern New England indicate that living near to water-bodies with cyanobacterial blooms increases the risk of developing amyotrophic lateral sclerosis (ALS). The distribution of addresses of ALS cases in New Hampshire, Vermont, and Florida was compared to that of controls. Areas of statistically significantly increased numbers of ALS cases were examined for sources of environmental toxins. A phase I trial of oral L-serine was performed in 20 ALS patients (0.5 to 15 g twice daily). Safety and tolerability were assessed by comparing the rate of deterioration with 430 matched placebo controls. The distribution of residential addresses of ALS cases in New England and Florida revealed many areas where the age- and gender-adjusted frequency of ALS was greater than expected (P < 0.01). GIS studies of these "hot spots" in relation to sources of environmental pollutants, like cyanobacterial blooms, Superfund and Brownfield sites, and landfills, are ongoing. In the phase I trial of L-serine, two patients withdrew from because of gastrointestinal side effects. Three patients died during the study, which was about the expected number. The ALSFRS-R in the L-serine-treated patients showed a dose-related decrease in the rate of progression (34% reduction in slope, P = 0.044). The non-random distribution of addresses of ALS patients suggests that residential exposure to environmental pollutants may play an important role in the etiology of ALS. L-Serine in doses up to 15 g twice daily appears to be safe in patients with ALS. Exploratory studies of efficacy suggested that L-serine might slow disease progression. A phase II trial is planned.

Accuracy, Precision, and Trending Ability of Electrical Cardiometry Cardiac Index versus Continuous Pulmonary Artery Thermodilution Method: A Prospective, Observational Study.

INTRODUCTION: Evaluation of accuracy, precision, and trending ability of cardiac index (CI) measurements using the Aesculon™ bioimpedance electrical cardiometry (Aesc) compared to the continuous pulmonary artery thermodilution catheter (PAC) technique before, during, and after cardiac surgery. METHODS: A prospective observational study with fifty patients with ASA 3-4. At six time points (T), measurements of CI simultaneously by continuous cardiac output pulmonary thermodilution and thoracic bioimpedance and standard hemodynamics were performed. Analysis was performed using Bland-Altman, four-quadrant plot, and polar plot methodology. RESULTS: CI obtained with pulmonary artery thermodilution and thoracic bioimpedance ranged from 1.00 to 6.75 L min-1 and 0.93 to 7.25 L min-1, respectively. Bland-Altman analysis showed a bias between CIBIO and CIPAC of 0.52 liters min-1 m-2, with LOA of [-2.2; 1.1] liters min-1 m-2. Percentage error between the two techniques was above 30% at every time point. Polar plot methodology and 4-quadrant analysis showed poor trending ability. Skin incision had no effect on the results. CONCLUSION: CI obtained by continuous PAC and CI obtained by Aesculon bioimpedance are not interchangeable in cardiac surgical patients. No effects of skin incision were found. International clinical trial registration number is ISRCTN26732484.