Monthly ENSO Forecast Skill and Lagged Ensemble Size.

The mean square error (MSE) of a lagged ensemble of monthly forecasts of the Niño 3.4 index from the Climate Forecast System (CFSv2) is examined with respect to ensemble size and configuration. Although the real-time forecast is initialized 4 times per day, it is possible to infer the MSE for arbitrary initialization frequency and for burst ensembles by fitting error covariances to a parametric model and then extrapolating to arbitrary ensemble size and initialization frequency. Applying this method to real-time forecasts, we find that the MSE consistently reaches a minimum for a lagged ensemble size between one and eight days, when four initializations per day are included. This ensemble size is consistent with the 8-10 day lagged ensemble configuration used operationally. Interestingly, the skill of both ensemble configurations is close to the estimated skill of the infinite ensemble. The skill of the weighted, lagged, and burst ensembles are found to be comparable. Certain unphysical features of the estimated error growth were tracked down to problems with the climatology and data discontinuities.

Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial.

We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo control setting. Forty-eight children (mean age 7 years 4 months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2 mg kg-1 per day, maximum 50 mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-α autoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen's d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen's d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.

A new method for determining the optimal lagged ensemble.

We propose a general methodology for determining the lagged ensemble that minimizes the mean square forecast error. The MSE of a lagged ensemble is shown to depend only on a quantity called the cross-lead error covariance matrix, which can be estimated from a short hindcast data set and parameterized in terms of analytic functions of time. The resulting parameterization allows the skill of forecasts to be evaluated for an arbitrary ensemble size and initialization frequency. Remarkably, the parameterization also can estimate the MSE of a burst ensemble simply by taking the limit of an infinitely small interval between initialization times. This methodology is applied to forecasts of the Madden Julian Oscillation (MJO) from version 2 of the Climate Forecast System version 2 (CFSv2). For leads greater than a week, little improvement is found in the MJO forecast skill when ensembles larger than 5 days are used or initializations greater than 4 times per day. We find that if the initialization frequency is too infrequent, important structures of the lagged error covariance matrix are lost. Lastly, we demonstrate that the forecast error at leads ≥10 days can be reduced by optimally weighting the lagged ensemble members. The weights are shown to depend only on the cross-lead error covariance matrix. While the methodology developed here is applied to CFSv2, the technique can be easily adapted to other forecast systems.

Thyroid dysfunction in children with autism spectrum disorder is associated with folate receptor α autoimmune disorder.

Folate receptor α (FRα) autoantibodies (FRAAs) are prevalent in autism spectrum disorder (ASD). FRAAs disrupt folate transport across the blood-brain barrier by binding to the FRα. Thyroid dysfunction is frequently found in children with ASD. We measured blocking and binding FRAAs and thyroid-stimulating hormone (TSH), free thyroxine (T4) (FT4), total triiodothyronine (T3) (TT3), reverse T3 (rT3), thyroid-releasing hormone (TRH) and other metabolites in 87 children with ASD, 84 of whom also underwent behaviour and cognition testing and in 42 of whom FRAAs, TSH and FT4 were measured at two time points. To better understand the significance of the FRα in relation to thyroid development, we examined FRα expression on prenatal and postnatal thyroid. TSH, TT3 and rT3 were above the normal range in 7%, 33% and 51% of the participants and TRH was below the normal range in 13% of the participants. FT4 was rarely outside the normal range. TSH concentration was positively and the FT4/TSH, TT3/TSH and rT3/TSH ratios were inversely related to blocking FRAA titres. On repeated measurements, changes in TSH and FT4/TSH ratio were found to correspond to changes in blocking FRAA titres. TSH and the FT4/TSH, TT3/TSH and rT3/TSH ratios were related to irritability on the Aberrant Behavior Checklist and several scales of the Social Responsiveness Scale (SRS), whereas TT3 was associated with SRS subscales and TRH was related to Vineland Adaptive Behavior Scale subscales. The thyroid showed significant FRα expression during the early prenatal period, although expression decreased significantly in later gestation and postnatal thyroid tissue. The results of the present study suggest that thyroid dysfunction in ASD may be related to blocking FRAA. The high expression of FRα in the early foetal thyroid suggests that foetal and neonatal exposure to maternal FRAAs could affect the development of the thyroid and may contribute to the pathology in ASD.

The Weighted-Average Lagged Ensemble.

A lagged ensemble is an ensemble of forecasts from the same model initialized at different times but verifying at the same time. The skill of a lagged ensemble mean can be improved by assigning weights to different forecasts in such a way as to maximize skill. If the forecasts are bias corrected, then an unbiased weighted lagged ensemble requires the weights to sum to one. Such a scheme is called a weighted-average lagged ensemble. In the limit of uncorrelated errors, the optimal weights are positive and decay monotonically with lead time, so that the least skillful forecasts have the least weight. In more realistic applications, the optimal weights do not always behave this way. This paper presents a series of analytic examples designed to illuminate conditions under which the weights of an optimal weighted-average lagged ensemble become negative or depend nonmonotonically on lead time. It is shown that negative weights are most likely to occur when the errors grow rapidly and are highly correlated across lead time. The weights are most likely to behave nonmonotonically when the mean square error is approximately constant over the range forecasts included in the lagged ensemble. An extreme example of the latter behavior is presented in which the optimal weights vanish everywhere except at the shortest and longest lead times.

Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines.

Propionic acid (PPA) is a ubiquitous short-chain fatty acid, which is a major fermentation product of the enteric microbiome. PPA is a normal intermediate of metabolism and is found in foods, either naturally or as a preservative. PPA and its derivatives have been implicated in both health and disease. Whereas PPA is an energy substrate and has many proposed beneficial effects, it is also associated with human disorders involving mitochondrial dysfunction, including propionic acidemia and autism spectrum disorders (ASDs). We aimed to investigate the dichotomy between the health and disease effects of PPA by measuring mitochondrial function in ASD and age- and gender-matched control lymphoblastoid cell lines (LCLs) following incubation with PPA at several concentrations and durations both with and without an in vitro increase in reactive oxygen species (ROS). Mitochondrial function was optimally increased at particular exposure durations and concentrations of PPA with ASD LCLs, demonstrating a greater enhancement. In contrast, increasing ROS negated the positive PPA effect with the ASD LCLs, showing a greater detriment. These data demonstrate that enteric microbiome metabolites such as PPA can have both beneficial and toxic effects on mitochondrial function, depending on concentration, exposure duration and microenvironment redox state with these effects amplified in LCLs derived from individuals with ASD. As PPA, as well as enteric bacteria, which produce PPA, have been implicated in a wide variety of diseases, including ASD, diabetes, obesity and inflammatory diseases, insight into this metabolic modulator from the host microbiome may have wide applications for both health and disease.

Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines.

There is an increasing recognition that mitochondrial dysfunction is associated with autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction and how mitochondrial abnormalities might interact with other physiological disturbances such as oxidative stress. Reserve capacity is a measure of the ability of the mitochondria to respond to physiological stress. In this study, we demonstrate, for the first time, that lymphoblastoid cell lines (LCLs) derived from children with autistic disorder (AD) have an abnormal mitochondrial reserve capacity before and after exposure to reactive oxygen species (ROS). Ten (44%) of 22 AD LCLs exhibited abnormally high reserve capacity at baseline and a sharp depletion of reserve capacity when challenged with ROS. This depletion of reserve capacity was found to be directly related to an atypical simultaneous increase in both proton-leak respiration and adenosine triphosphate-linked respiration in response to increased ROS in this AD LCL subgroup. In this AD LCL subgroup, 48-hour pretreatment with N-acetylcysteine, a glutathione precursor, prevented these abnormalities and improved glutathione metabolism, suggesting a role for altered glutathione metabolism associated with this type of mitochondrial dysfunction. The results of this study suggest that a significant subgroup of AD children may have alterations in mitochondrial function, which could render them more vulnerable to a pro-oxidant microenvironment as well as intrinsic and extrinsic sources of ROS such as immune activation and pro-oxidant environmental toxins. These findings are consistent with the notion that AD is caused by a combination of genetic and environmental factors.

Impact of nadir lower oesophageal sphincter pressure on bolus clearance assessed by combined manometry and multi-channel intra-luminal impedance measurement.

This study aimed to assess the relationship between nadir lower oesophageal sphincter pressure (LOSP) and wave amplitude (WA) in oesophageal bolus clearance. Concurrent oesophageal manometry and impedance were performed in 146 subjects [41 healthy, 24 non-obstructive dysphagia (NOD) and 81 gastro-oesophageal reflux (GOR)]. Patients with achalasia and diffuse oesophageal spasm were excluded. Swallow responses were categorized by nadir LOSP. For each category of nadir LOSP, WA at the distal 2 recording sites were grouped into bins of 10 mmHg and the proportion of waves in each bin associated with a normal bolus presence time (BPT) was determined. Nadir LOSP, distal BPT, total bolus transit time and the proportion of impaired oesophageal clearance in patients with NOD were greater than those of healthy subjects and patients with GOR. Overall, responses with impaired oesophageal clearance had significantly lower WA (54 +/- 1 vs 81 +/- 1 mmHg; P < 0.0001) and higher nadir LOSP (2.7 +/- 0.4 vs 1.0 +/- 0.1 mmHg, P < 0.001). For each level of nadir LOSP, there was a direct relationship between distal WA and successful bolus clearance of both liquid and viscous boluses from the distal oesophagus. As nadir LOSP increased, the relationship between WA and bolus clearance shifted to the right and higher amplitudes were required to achieve the same effectiveness of clearance. Hypotensive responses with nadir LOSP > or = 3 mmHg were less likely to clear than those with nadir LOSP < 3 mmHg, for both liquid (7/29 vs 162/276; P < 0.001) or viscous boluses (11/46 vs 176/279; P < 0.0001). Nadir LOSP is an important determinant of bolus clearance from the distal oesophagus, particularly in patients with NOD.

Assessment of oesophageal motor function using combined perfusion manometry and multi-channel intra-luminal impedance measurement in normal subjects.

Multichannel intraluminal impedance (MII) is being used increasingly to assess oesophageal bolus clearance. However, there is no good standardization of the impedance parameters that define 'effective bolus clearance'. The aim of this study was to define these important impedance parameters and to determine their normal values. Concurrent perfusion manometry and MII were performed in 42 healthy volunteers. Ten, 5-mL liquid (saline) boluses and then, 10x5-mL low impedance viscous boluses were tested in each subject in the right-lateral position. Normal values for bolus presence time (BPT) at each site and total bolus transit time (TBTT) were determined from either 'normal' peristaltic responses (amplitude>or=30 mmHg in distal oesophagus) or 'super-normal' peristaltic responses (amplitudes>or=50 mmHg at all sites). The relationship between BPT and TBTT within a response and per-individual performance was determined. A total of 840 swallows of liquids and viscous responses were analysed. BPT and TBTT of viscous swallows were longer than those for liquids. Non-peristaltic responses were significantly more likely not to clear a viscous than a liquid bolus. Within a response, the number of sites with prolonged BPT strongly predicted the incidence of prolonged TBTT. Using impedance criteria, normal oesophageal bolus clearance is defined when an individual completely clears at least 70% of liquid responses and at least 60% of viscous responses. This study provides normal values for impedance measurement of bolus clearance when combined with perfusion manometry. These values will allow standardization of impedance application in oesophageal function testing, in both research and clinical setting.

Features of the Value Function for Voice and Their Consistency across Participants from Four Countries: Great Britain, Mexico, The Netherlands, and the United States.

This study investigated features of the value function for voice using subjects from four countries: Great Britain, Mexico, The Netherlands, and the United States. Across these four groups of subjects the shape of the value function was found to be similar, though differences in the estimated reference points were detected. Consistent with predictions derived from prospect theory (Kahneman & Tversky, 1979) the relationship between the value of voice and the magnitude of voice was found to be direct, monotonic, and nonlinear. The largest increment in value occurred when the magnitude of voice shifted from mute to some voice. Thereafter, increments in value tended to decline in magnitude suggesting diminishing marginal returns on the response measure of procedural fairness. An unexpected finding was that the final segment of the value function was convex indicating increasing marginal returns as the magnitude of voice shifted from its penultimate level to its maximum possible level. The study also investigated whether subjects' reported expectations of voice correspond to the value function reference point as theorized in the literature. Findings suggest that self-reported expectations of voice are higher than the estimated value function reference point.

Relationship between esophageal motility and transit in patients with type I diabetes mellitus.

OBJECTIVES: Delayed esophageal transit and abnormal esophageal motility occur frequently in patients with long-standing diabetes mellitus. However, the relationship between transit and motility has not been assessed directly. The aim of this study was to investigate the patterns of esophageal motor function documented previously to have delayed esophageal emptying and esophageal transit in patients with insulin-dependent diabetes mellitus. METHODS: Concurrent esophageal manometry and radionuclide measurement of transit of liquids and solids were performed in 11 patients with insulin-dependent diabetes, 10 age-matched controls, and 11 young normal subjects. RESULTS: Patients with diabetes had a greater frequency of transit hold-up for solids (96%) than did older controls (65%) or young normals (42%) (p < 0.001), whereas the frequency of transit hold-up for liquid boluses was similar among the three groups (diabetics, 36%; older normals, 17%; young normals, 17%). The major mechanism responsible for bolus hold-up in diabetics was peristaltic failure (liquid, 52%; solid, 67%) and the level of hold-up coincided with the level of bolus hold-up for 10/11 liquid and 27/28 solid boluses. CONCLUSIONS: In insulin-dependent diabetes, retarded esophageal transit usually reflects either peristaltic failure or focal low-amplitude pressure waves.

Motor events underlying gastro-oesophageal reflux in ambulant patients with reflux oesophagitis.

Information on the mechanism of gastro-oesophageal reflux in patients with reflux disease is limited largely to studies in resting recumbent subjects. Evidence exists that both posture and physical activity may influence reflux. The aim of this study was to investigate reflux mechanisms in ambulant patients with reflux oesophagitis. Concurrent ambulatory oesophageal manometry and pH monitoring were performed in 11 ambulant patients with erosive oesophagitis. Lower oesophageal sphincter (LOS) pressure was monitored with a perfused sleeve sensor. Recordings were made for 90 min before and 180 min after a meal. At set times patients sat in a chair or walked. LOS pressure was < or = 2 mmHg at the time of reflux for 98% of reflux episodes. Transient LOS relaxation was the most common pattern overall and the predominant pattern in seven patients, whilst persistently absent basal LOS pressure was the most common pattern in four patients. The pattern of LOS pressure was not altered by the presence of hiatus hernia or by walking. Straining occurred at the onset of 31% of acid reflux episodes but often followed the development of an oesophageal common cavity. The occurrence of straining was not influenced by walking. In ambulant patients with reflux oesophagitis: (1) LOS pressure is almost always absent at the time of reflux, usually because of transient LOS relaxation, (2) persistently absent basal LOS pressure is an important mechanism of reflux in a few patients, (3) straining may help to induce acid reflux in a variable proportion of occasions and may in some instances be a response to gas reflux, and (4) walking does not influence the occurrence of reflux or its mechanisms.

Effects of mediastinal irradiation on oesophageal function.

Although it is well recognised that oesophageal symptoms are common during therapeutic mediastinal irradiation of intrathoracic malignant diseases, the effects of mediastinal irradiation on oesophageal function are poorly defined. To clarify the pathogenesis of these sequelae a prospective study was performed to document comprehensively the effects of mediastinal irradiation on oesophageal function. Oesophageal symptoms, barium swallow, endoscopy, and combined radionuclide scintigraphy and oesophageal manometry were evaluated in eight patients with potentially curable intrathoracic malignant disease before treatment, during the last week of mediastinal irradiation, and six to eight weeks after its completion. Before irradiation, structural abnormalities were excluded by barium swallow and endoscopy. All but one patient experienced odynophagia or dysphagia, or both, during mediastinal irradiation (p < 0.001) but endoscopic abnormalities were observed in only three patients and there was no correlation between oesophageal symptoms and endoscopic changes. Irradiation, however, had no significant effect on oesophageal motility or transit. It is concluded that oesophageal symptoms which develop during mediastinal irradiation are not a result of altered oesophageal motility or transit and may reflect increased mucosal sensitivity.

Mechanisms of gastroesophageal reflux in ambulant healthy human subjects.

BACKGROUND/AIMS: Investigation of the motor events underlying gastroesophageal reflux has largely been confined to resting, recumbent subjects. The motor events associated with reflux during physical activity remain unknown. The aim of this study was to investigate the patterns of lower esophageal sphincter (LES) function underlying reflux in healthy subjects and the effect of exercise and physical activity on reflux mechanisms. METHODS: LES pressure was recorded with a perfused sleeve sensor in 10 healthy subjects; intraluminal transducers recorded pressure in the stomach, esophagus, and pharynx, and pH was recorded 5 cm above the LES. Signals were stored in a portable data-logger. Recordings were made for 24 hours, including moderate physical activity, periods of rest and sleep, standardized meals, and standardized exercise. RESULTS: Most reflux episodes (81 of 123; 66%) occurred in the 3 hours after food intake; only 2 episodes occurred during exercise. LES pressure was < or = 3 cm H2O in 79% of reflux episodes. Transient LES relaxation was the mechanism of reflux in 82% of episodes, irrespective of activity or body position, whereas swallow-related LES relaxations accounted for 13% and persistently absent LES pressure accounted for 1%. Straining occurred in only 20% of episodes. CONCLUSIONS: In ambulant healthy subjects, accurate continuous recording of LES function is possible, reflux usually occurs during transient LES relaxations, and straining is not a major factor in the induction of reflux.