Fourteen-Day Evolution of COVID-19 Symptoms during the Third Wave in Nonvaccinated Subjects and Effects of Hesperidin Therapy: A Randomized, Double-Blinded, Placebo-Controlled Study.

COVID-19 symptoms can cause substantial disability, yet no therapy can currently reduce their frequency or duration. We conducted a double-blind placebo-controlled trial of hesperidin 1000 mg once daily for 14 days in 216 symptomatic nonvaccinated COVID-19 subjects. Thirteen symptoms were recorded after 3, 7, 10, and 14 days. The primary endpoint was the proportion of subjects with any of four cardinal (group A) symptoms: fever, cough, shortness of breath, or anosmia. At the baseline, symptoms in decreasing frequency were as follows: cough (53.2%), weakness (44.9%), headache (42.6%), pain (35.2%), sore throat (28.7%), runny nose (26.9%), chills (22.7%), shortness of breath (22.2%), anosmia (18.5%), fever (16.2%), diarrhea (6.9%), nausea/vomiting (6.5%), and irritability/confusion (3.2%). Group A symptoms in the placebo vs. hesperidin group were 88.8% vs. 88.5% (day 1) and reduced to 58.5 vs. 49.4% at day 14 (OR 0.69, 95% CI 0.38-1.27, p = 0.23). At day 14, 15 subjects in the placebo group and 28 in the hesperidin group failed to report their symptoms. In an attrition bias analysis imputing "no symptoms" to missing values, the hesperidin group showed reduction of 14.5% of group A symptoms from 50.9% to 36.4% (OR: 0.55, 0.32-0.96, p = 0.03). Anosmia, the most frequent persisting symptom (29.3%), was lowered by 7.3% to 25.3% in the hesperidin group vs. 32.6% in the placebo group (p = 0.29). The mean number of symptoms in the placebo and hesperidin groups was 5.10 (SD 2.26) vs. 5.48 (SD 2.35) (day 1) and 1.40 (SD 1.65) vs. 1.38 (SD 1.76) (day 14) (p = 0.92). In conclusion, most nonvaccinated COVID-19 infected subjects remain symptomatic after 14 days with anosmia being the most frequently persisting symptom. Hesperidin 1 g daily may help reduce group A symptoms. Earlier treatment of longer duration and/or higher dosage should be tested.

Phase 2 clinical trial of PBI-4050 in patients with idiopathic pulmonary fibrosis.

PBI-4050 is a novel orally active small-molecule compound with demonstrated anti-fibrotic activity in several models of fibrosis, including lung fibrosis. We present results from our first clinical study of PBI-4050 in patients with idiopathic pulmonary fibrosis (IPF).This 12-week open-label study explored the safety, efficacy and pharmacokinetics of daily oral doses of 800 mg PBI-4050 alone and in combination with nintedanib or pirfenidone in patients with predominantly mild or moderate IPF. Nine patients received PBI-4050 alone, 16 patients received PBI-4050 with nintedanib and 16 patients received PBI-4050 with pirfenidone.PBI-4050 alone or in combination with nintedanib or pirfenidone was well tolerated. Pharmacokinetic profiles for PBI-4050 were similar in the PBI-4050 alone and PBI-4050+nintedanib groups but reduced in the PBI-4050+pirfenidone group, suggesting a drug-drug interaction. There were no significant changes in forced vital capacity (FVC), either in % predicted or mL, from baseline to week 12 for PBI-4050 alone or PBI-4050+nintedanib. In contrast, a statistically significant reduction (p<0.024) in FVC % pred was seen for PBI-4050+pirfenidone after 12 weeks.There were no safety concerns with PBI-4050 alone or in combination with nintedanib or pirfenidone in IPF patients. The stability of FVC between baseline and week 12 looked encouraging for PBI-4050 alone and in combination with nintedanib.

Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency.

Congenital plasminogen deficiency is caused by mutations in PLG, the gene coding for production of the zymogen plasminogen, and is an ultrarare disorder associated with abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes. Left untreated, these lesions may impair organ function and impact quality of life. Plasminogen replacement therapy should provide an effective treatment of the manifestations of congenital plasminogen deficiency. An open-label phase 2/3 study of human Glu-plasminogen administered IV at 6.6 mg/kg every 2 to 4 days in 15 patients with congenital plasminogen deficiency is ongoing. Reported here are data on 14 patients who completed at least 12 weeks of treatment. The primary end point was an increase in trough plasminogen activity levels by at least an absolute 10% above baseline. The secondary end point was clinical success, defined as ≥50% improvement in lesion number/size or functionality impact from baseline. All patients achieved at least an absolute 10% increase in trough plasminogen activity above baseline. Clinical success was observed in all patients with clinically visible (conjunctiva and gingiva), nonvisible (nasopharynx, bronchus, colon, kidney, cervix, and vagina), and wound-healing manifestations of the disease. Therapeutic effects were rapid, as all but 2 lesions resolved or improved after 4 weeks of treatment. Human Glu-plasminogen was well tolerated in both children and adults. This study provides critical first evidence of the clinical utility of ongoing replacement therapy with human Glu-plasminogen for the treatment of children and adults with congenital plasminogen deficiency. This trial was registered at www.clinicaltrials.gov as #NCT02690714.

Patterns of altered neural synchrony in the default mode network in autism spectrum disorder revealed with magnetoencephalography (MEG): Relationship to clinical symptomatology.

Disrupted neural synchrony may be a primary electrophysiological abnormality in autism spectrum disorders (ASD), altering communication between discrete brain regions and contributing to abnormalities in patterns of connectivity within identified neural networks. Studies exploring brain dynamics to comprehensively characterize and link connectivity to large-scale cortical networks and clinical symptoms are lagging considerably. Patterns of neural coherence within the Default Mode Network (DMN) and Salience Network (SN) during resting state were investigated in 12 children with ASD (MAge = 9.2) and 13 age and gender-matched neurotypicals (NT) (MAge = 9.3) with magnetoencephalography. Coherence between 231 brain region pairs within four frequency bands (theta (4-7 Hz), alpha, (8-12 Hz), beta (13-30 Hz), and gamma (30-80 Hz)) was calculated. Relationships between neural coherence and social functioning were examined. ASD was characterized by lower synchronization across all frequencies, reaching clinical significance in the gamma band. Lower gamma synchrony between fronto-temporo-parietal regions was observed, partially consistent with diminished default mode network (DMN) connectivity. Lower gamma coherence in ASD was evident in cross-hemispheric connections between: angular with inferior/middle frontal; middle temporal with middle/inferior frontal; and within right-hemispheric connections between angular, middle temporal, and inferior/middle frontal cortices. Lower gamma coherence between left angular and left superior frontal, right inferior/middle frontal, and right precuneus and between right angular and inferior/middle frontal cortices was related to lower social/social-communication functioning. Results suggest a pattern of lower gamma band coherence in a subset of regions within the DMN in ASD (angular and middle temporal cortical areas) related to lower social/social-communicative functioning. Autism Res 2018, 11: 434-449. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Communication between different areas of the brain was observed in children with ASD and neurotypical children while awake, but not working on a task. Magnetoencephalography was used to measure tiny magnetic fields naturally generated via brain activity. The brains of children with ASD showed less communication between areas that are important for social information processing compared to the brains of neurotypical children. The amount of communication between these areas was associated with social and social communication difficulties.

Periodic Discharges: Insight From Magnetoencephalography.

PURPOSE: This study used magnetoencephalography (MEG) dipole localization and coherence measurement to evaluate the magnetic fields associated with periodic discharges. The primary goal of the study was to evaluate whether MEG could consistently localize quasiperiodic discharges that were observed on the EEG portion of the recording. The secondary objective was to evaluate whether coherence measurements would correlate with topographic maxima of epileptiform activity. METHODS: A total of 13 inpatients, whose electrographic records demonstrated lateralized periodic discharges (LPDs), were recruited from Henry Ford Hospital neurology and intensive care units. Nine patients were found clinically to be in status epilepticus before the EEG determination of LPDs. Spontaneous cortical brain activity was recorded with 148-channel MEG for 10 minutes. Data were sampled at 508 Hz and DC-100 Hz and filtered from 1 Hz to 40 Hz. Interictal events were imaged with single equivalent current dipole localization. Magnetoencephalography coherence source imaging analysis was performed and compared with the cortical topography of LPD patterns and with the focal lesions seen on the MRI (9 patients) or computed tomography (5 patients) imaging modalities. RESULTS: The morphology of periodic waveforms was similar between EEG and MEG portions of the study. In patients with substrate positivity on imaging studies, coherence analysis revealed a tendency for LPDs to arise from the interface between the lesion and the surrounding, uncompromised cortex rather than from the lesion itself. In nonlesional patients with recent status epilepticus, the localization of maximal coherence was in the temporal lobes. CONCLUSIONS: This study demonstrated that MEG is able to detect and localize LPDs arising from damaged and adjacent cortex. The MEG coherence source imaging measurements also suggest the presence of epileptogenic networks perilesionally in cases with focal lesions on imaging. In patients without acute anatomic abnormality, the MEG coherence identified the epileptogenic networks in temporal lobe structures. Magnetoencephalography coherence source imaging may provide physicians with markers for differentiating between LPDs arising from acute injury currents versus LPDs arising from prolonged status epilepticus.

MEG Coherence and DTI Connectivity in mTLE.

Magnetoencephalography (MEG) is a noninvasive imaging method for localization of focal epileptiform activity in patients with epilepsy. Diffusion tensor imaging (DTI) is a noninvasive imaging method for measuring the diffusion properties of the underlying white matter tracts through which epileptiform activity is propagated. This study investigates the relationship between the cerebral functional abnormalities quantified by MEG coherence and structural abnormalities quantified by DTI in mesial temporal lobe epilepsy (mTLE). Resting state MEG data was analyzed using MEG coherence source imaging (MEG-CSI) method to determine the coherence in 54 anatomical sites in 17 adult mTLE patients with surgical resection and Engel class I outcome, and 17 age- and gender- matched controls. DTI tractography identified the fiber tracts passing through these same anatomical sites of the same subjects. Then, DTI nodal degree and laterality index were calculated and compared with the corresponding MEG coherence and laterality index. MEG coherence laterality, after Bonferroni adjustment, showed significant differences for right versus left mTLE in insular cortex and both lateral orbitofrontal and superior temporal gyri (p < 0.017). Likewise, DTI nodal degree laterality, after Bonferroni adjustment, showed significant differences for right versus left mTLE in gyrus rectus, insular cortex, precuneus and superior temporal gyrus (p < 0.017). In insular cortex, MEG coherence laterality correlated with DTI nodal degree laterality ([Formula: see text] in the cases of mTLE. None of these anatomical sites showed statistically significant differences in coherence laterality between right and left sides of the controls. Coherence laterality was in agreement with the declared side of epileptogenicity in insular cortex (in 82 % of patients) and both lateral orbitofrontal (88 %) and superior temporal gyri (88 %). Nodal degree laterality was also in agreement with the declared side of epileptogenicity in gyrus rectus (in 88 % of patients), insular cortex (71 %), precuneus (82 %) and superior temporal gyrus (94 %). Combining all significant laterality indices improved the lateralization accuracy to 94 % and 100 % for the coherence and nodal degree laterality indices, respectively. The associated variations in diffusion properties of fiber tracts quantified by DTI and coherence measures quantified by MEG with respect to epileptogenicity possibly reflect the chronic microstructural cerebral changes associated with functional interictal activity. The proposed methodology for using MEG and DTI to investigate diffusion abnormalities related to focal epileptogenicity and propagation may provide a further means of noninvasive lateralization.

Application of MEG coherence in lateralization of mTLE.

Magnetoencephalography (MEG) is a noninvasive imaging method for localization of focal epileptiform activity in patients with epilepsy. This study investigates the cerebral functional abnormalities quantified by MEG coherence laterality in mesial temporal lobe epilepsy (mTLE). Resting state MEG data was analyzed using MEG coherence source imaging (MEG-CSI) method to determine the coherence in 54 anatomical sites in 12 adult mTLE patients and 12 age- and gender-matched controls. MEG coherence laterality, after Bonferroni adjustment, showed significant differences for right versus left mTLE in insular cortex and both lateral orbitofrontal and superior temporal gyri (p<;0.025). None of these anatomical sites showed statistically significant differences in coherence laterality between right and left sides of controls. Coherence laterality was in agreement with the declared side of epileptogenicity in insular cortex (in 75% of patients) and both lateral orbitofrontal (83%) and superior temporal gyri (84%). Combining all significant laterality indices improved the lateralization accuracy to 92%. The proposed methodology for using MEG to investigate the abnormalities related to focal epileptogenicity and propagation can provide a further means of noninvasive lateralization.

Application of DTI connectivity in lateralization of mTLE.

Diffusion tensor imaging (DTI) is a noninvasive imaging method for measuring the diffusion properties of the underlying white matter tracts through which epileptiform activity is propagated. This study investigates the structural abnormalities quantified by DTI in mesial temporal lobe epilepsy (mTLE). Fiber tracts passing through 54 anatomical sites in 12 adult mTLE patients and 12 age- and gender-matched controls were identified using DTI tractography. DTI nodal degree (ND) and laterality index were then calculated. ND laterality, after Bonferroni adjustment, showed significant differences for right versus left mTLE in gyrus rectus, insular cortex, precuneus and superior temporal gyrus (p<;0.025). None of these anatomical sites showed statistically significant differences in ND laterality between right and left sides of the controls. Laterality models determined by logistic regression on the ND laterality data agreed with the side of epileptogenicity as it pertained to the gyrus rectus, insular cortex, precuneus and superior temporal gyrus for 89%, 72%, 83% and 92% of the patients, respectively. Combining the laterality measures in these four anatomical sites improved the results further with correct lateralization of 100% for all patients. The proposed methodology for using DTI connectivity to investigate diffusion abnormalities related to focal epileptogenicity and propagation can provide a further means of noninvasive lateralization.

Neural synchrony examined with magnetoencephalography (MEG) during eye gaze processing in autism spectrum disorders: preliminary findings.

BACKGROUND: Gaze processing deficits are a seminal, early, and enduring behavioral deficit in autism spectrum disorder (ASD); however, a comprehensive characterization of the neural processes mediating abnormal gaze processing in ASD has yet to be conducted. METHODS: This study investigated whole-brain patterns of neural synchrony during passive viewing of direct and averted eye gaze in ASD adolescents and young adults (M Age = 16.6) compared to neurotypicals (NT) (M Age = 17.5) while undergoing magnetoencephalography. Coherence between each pair of 54 brain regions within each of three frequency bands (low frequency (0 to 15 Hz), beta (15 to 30 Hz), and low gamma (30 to 45 Hz)) was calculated. RESULTS: Significantly higher coherence and synchronization in posterior brain regions (temporo-parietal-occipital) across all frequencies was evident in ASD, particularly within the low 0 to 15 Hz frequency range. Higher coherence in fronto-temporo-parietal regions was noted in NT. A significantly higher number of low frequency cross-hemispheric synchronous connections and a near absence of right intra-hemispheric coherence in the beta frequency band were noted in ASD. Significantly higher low frequency coherent activity in bilateral temporo-parieto-occipital cortical regions and higher gamma band coherence in right temporo-parieto-occipital brain regions during averted gaze was related to more severe symptomology as reported on the Autism Diagnostic Interview-Revised (ADI-R). CONCLUSIONS: The preliminary results suggest a pattern of aberrant connectivity that includes higher low frequency synchronization in posterior cortical regions, lack of long-range right hemispheric beta and gamma coherence, and decreased coherence in fronto-temporo-parietal regions necessary for orienting to shifts in eye gaze in ASD; a critical behavior essential for social communication.

Slow brain activity (ISA/DC) detected by MEG.

Infraslow activity (ISA), direct coupled (DC), and direct current (DC) are the terms used to describe brain activity that occurs in frequencies below 0.1 Hz. Infraslow activity amplitude increase is also associated with epilepsy, traumatic brain injuries, strokes, tumors, and migraines and has been studied since the early 90s at the Henry Ford Hospital MEG Laboratory. We have used a DC-based magnetoencephalography (MEG) system to validate and characterize the ISA from animal models of cortical spreading depression thought to be the underlying mechanism of migraine and other cortical spreading depression-like events seen during ischemia, anoxia, and epilepsy. Magnetoencephalography characterizes these slow shifts easier than electroencephalography because there is no attenuation of these signals by the skull. In the current study, we report on ISA MEG signals of 12 patients with epilepsy in the preictal and postictal states. In the minutes just before the onset of a seizure, large-amplitude ISA MEG waveforms were detected, signaling the onset of the seizure. It is suggested that MEG assessment of ISA, in addition to activity in the conventional frequency band, can at times be useful in the lateralization of epileptic seizures.

An assessment of MEG coherence imaging in the study of temporal lobe epilepsy.

PURPOSE: This study examines whether magnetoencephalographic (MEG) coherence imaging is more sensitive than the standard single equivalent dipole (ECD) model in lateralizing the site of epileptogenicity in patients with drug-resistant temporal lobe epilepsy (TLE). METHODS: An archival review of ECD MEG analyses of 30 presurgical patients with TLE was undertaken with data extracted subsequently for coherence analysis by a blinded reviewer for comparison of accuracy of lateralization. Postoperative outcome was assessed by Engel classification. MEG coherence images were generated from 10 min of spontaneous brain activity and compared to surgically resected brain areas outlined on each subject's magnetic resonance image (MRI). Coherence values were averaged independently for each hemisphere to ascertain the laterality of the epileptic network. Reliability between runs was established by calculating the correlation between epochs. Match rates compared the results of each of the two MEG analyses with optimal postoperative outcome. KEY FINDINGS: The ECD method provided an overall match rate of 50% (13/16 cases) for Engel class I outcomes, with 37% (11/30 cases) found to be indeterminate (i.e., no spikes identified on MEG). Coherence analysis provided an overall match rate of 77% (20/26 cases). Of 19 cases without evidence of mesial temporal sclerosis, coherence analysis correctly lateralized the side of TLE in 11 cases (58%). Sensitivity of the ECD method was 41% (indeterminate cases included) and that of the coherence method 73%, with a positive predictive value of 70% for an Engel class Ia outcome. Intrasubject coherence imaging reliability was consistent from run-to-run (correlation > 0.90) using three 10-min epochs. SIGNIFICANCE: MEG coherence analysis has greater sensitivity than the ECD method for lateralizing TLE and demonstrates reliable stability from run-to-run. It, therefore, improves upon the capability of MEG in providing further information of use in clinical decision-making where the laterality of TLE is questioned.

Cortical locations of maximal spindle activity: magnetoencephalography (MEG) study.

The aim of this study was to determine the main cortical regions related to maximal spindle activity of sleep stage 2 in healthy individual subjects during a brief morning nap using magnetoencephalography (MEG). Eight volunteers (mean age: 26.1 +/- 8.7, six women) all right handed, free of any medical psychiatric or sleep disorders were studied. Whole-head 148-channel MEG and a conventional polysomnography montage (EEG; C3, C4, O1 and O2 scalp electrodes and EOG, EMG and ECG electrodes) were used for data collection. Sleep MEG/EEG spindles were visually identified during 15 min of stage 2 sleep for each participant. The distribution of brain activity corresponding to each spindle was calculated using a combination of independent component analysis and a current source density technique superimposed upon individual MRIs. The absolute maximum of spindle activation was localized to frontal, temporal and parietal lobes. However, the most common cortical regions for maximal source spindle activity were precentral and/or postcentral areas across all individuals. The present study suggests that maximal spindle activity localized to these two regions may represent a single event for two types of spindle frequency: slow (at 12 Hz) and fast (at 14 Hz) within global thalamocortical coherence.

Conversation effects on neural mechanisms underlying reaction time to visual events while viewing a driving scene: fMRI analysis and asynchrony model.

This neuroimaging study investigated the neural mechanisms of the effect of conversation on visual event detection during a driving-like scenario. The static load paradigm, established as predictive of visual reaction time in on-road driving, measured reaction times to visual events while subjects watched a real-world driving video. Behavioral testing with twenty-eight healthy volunteers determined the reaction time effects from overt and covert conversation tasks in this paradigm. Overt and covert conversation gave rise to longer visual event reaction times in the surrogate driving paradigm compared to just driving with no conversation, with negligible effect on miss rates. The covert conversation task was then undertaken by ten right-handed healthy adults in a 4-Tesla fMRI magnet. We identified a frontal-parietal network that maintained event detection performance during the conversation task while watching the driving video. Increased brain activations for conversation vs. no conversation during such simulated driving was found not only in language regions (Broca's and Wernicke's areas), but also specific regions in bilateral inferior frontal gyrus, bilateral anterior insula and orbitofrontal cortex, bilateral lateral prefrontal cortex (right middle frontal gyrus and left frontal eye field), supplementary motor cortex, anterior and posterior cingulate gyrus, right superior parietal lobe, right intraparietal sulcus, right precuneus, and right cuneus. We propose an Asynchrony Model in which the frontal regions have a top-down influence on the synchrony of neural processes within the superior parietal lobe and extrastriate visual cortex that in turn modulate the reaction time to visual events during conversation while driving.

Conversation effects on neural mechanisms underlying reaction time to visual events while viewing a driving scene using MEG.

Magnetoencephalography (MEG) imaging examined the neural mechanisms that modulate reaction times to visual events while viewing a driving video, with and without a conversation. Twenty-four subjects ages 18-65 were monitored by whole-head MEG. The primary tasks were to monitor a driving video and to depress a foot pedal in response to a small red light presented to the left or below the driving scene at unpredictable times. The behavioral reaction time (RT) to the lights was recorded. The secondary task was a hands-free conversation. The subject pressed a button to answer a ring tone, and then covertly answered pre-recorded non-emotional questions such as "What is your birth date?" RTs for the conversation task (1043 ms, SE=65 ms) were slightly longer than for the primary task (baseline no conversation (944 ms, SE=48 ms)). During the primary task RTs were inversely related to the amount of brain activity detected by MEG in the right superior parietal lobe (Brodmann's Area 7). Brain activity was seen in the 200 to 300 ms range after the onset of the red light and in the visual cortex (BA 19) about 85 ms after the red light. Conversation reduced the strengths of these regression relationships and increased mean RT. Conversation may contribute to increased reaction times by (1) damping brain activation in specific regions during specific time windows, or (2) reducing facilitation from attention inputs into those areas or (3) increasing temporal variability of the neural response to visual events. These laboratory findings should not be interpreted as indicative of real-world driving, without on-road validation, and comparison to other in-vehicle tasks.

Locking solutions for hemodialysis catheters; heparin and citrate--a position paper by ASDIN.

There is wide variation in the use of solutions to "lock" or fill tunneled central venous catheters for dialysis. Some centers use undiluted heparin concentrations ranging from 1000 to 10,000 U/ml and other centers place from 1000 to 10,000 U per lumen. Based on available evidence, it appears that heparin 1000 U/ml, or 4% sodium citrate are suitable choices for lock solution to maintain patency of tunneled central venous catheters for dialysis. Risks from systemic anticoagulation are lower with heparin 1000 U/ml and 4% sodium citrate, compared with higher concentrations of heparin (5000 and 10,000 U/ml). The need for use of tissue plasminogen activator for maintaining catheter patency is increased by using heparin lock at 1000 U/ml, vs. higher concentrations. Higher concentrations of heparin lock should be reserved for patients who have evidence of catheter occlusion or thrombosis when heparin is used at 1000 U/ml. Similar choices for lock solution are sensible for acute hemodialysis catheters. When heparin is used for catheter lock, the injected volume should not exceed the internal volume of the catheter.

Integrated MEG/fMRI model validated using real auditory data.

The main objective of this paper is to present methods and results for the estimation of parameters of our proposed integrated magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) model. We use real auditory MEG and fMRI datasets from 7 normal subjects to estimate the parameters of the model. The MEG and fMRI data were acquired at different times, but the stimulus profile was the same for both techniques. We use independent component analysis (ICA) to extract activation-related signal from the MEG data. The stimulus-correlated ICA component is used to estimate MEG parameters of the model. The temporal and spatial information of the fMRI datasets are used to estimate fMRI parameters of the model. The estimated parameters have reasonable means and standard deviations for all subjects. Goodness of fit of the real data to our model shows the possibility of using the proposed model to simulate realistic datasets for evaluation of integrated MEG/fMRI analysis methods.

Assessing intermittent pesticide exposure from flea control collars containing the organophosphorus insecticide tetrachlorvinphos.

Fleas are a persistent problem for pets that require implementation of control measures. Consequently, pesticide use by homeowners for flea control is common and may increase pesticide exposure for adults and children. Fifty-five pet dogs (23 in study 1; 22 in study 2) of different breeds and weights were treated with over-the-counter flea collars containing tetrachlorvinphos (TCVP). During study 1, fur of treated dogs was monitored for transferable TCVP residues using cotton gloves to pet the dogs during 5-min rubbings post-collar application. Plasma cholinesterase (ChE) activity was also measured in treated dogs. Average amounts of TCVP transferred from the fur of the neck (rubbing over the collar) and from the back to gloves at 3 days post-collar application were 23,700+/-2100 and 260+/-50 microg/glove, respectively. No inhibition of plasma ChE was observed. During study 2, transferable TCVP residues to cotton gloves were monitored during 5-min rubbings post-collar application. Transferable residues were also monitored on cotton tee shirts worn by children and in the first morning urine samples obtained from adults and children. Average amounts of TCVP transferred to gloves at 5 days post-collar application from the neck (over the collar) and from the back were 22,400+/-2900 and 80+/-20 microg/glove, respectively. Tee shirts worn by children on days 7-11 contained 1.8+/-0.8 microg TCVP/g shirt. No significant differences were observed between adults and children in urinary 2,4,5-trichloromandelic acid (TCMA) levels; however, all TCMA residues (adults and children) were significantly greater than pretreatment concentrations (alpha=0.05). The lack of ChE inhibition in dogs and the low acute toxicity level of TCVP (rat oral LD(50) of 4-5 g/kg) strongly suggest that TCVP is rapidly detoxified and excreted and therefore poses a very low toxicological risk, despite these high residues.

Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA).

BACKGROUND: Conventional treatment with epoetin to manage anaemia in chronic kidney disease needs frequent administrations, changes of dose, and close monitoring of haemoglobin concentrations. We aimed to compare the effectiveness of methoxy polyethylene glycol-epoetin beta, given intravenously at 2-week or 4-week intervals, with epoetin treatment one to three times per week for haemoglobin control in haemodialysis patients. METHODS: We screened 1115 adult patients from 96 centres who had stable chronic renal anaemia and were on dialysis treatment and intravenous maintenance epoetin. We did an open-label, parallel-group, non-inferiority trial to compare two dosing intervals of methoxy polyethylene glycol-epoetin beta with standard epoetin treatment. We established baseline haemoglobin concentration and eligibility over a 4-week run-in period. 223 patients were randomly assigned to receive methoxy polyethylene glycol-epoetin beta every 2 weeks, and 224 to receive it every 4 weeks. The initial dose was based on the average epoetin dose given during the week before the switch. The primary endpoint was change in haemoglobin concentration between baseline and the assessment period. We analysed patients both by intention to treat and per protocol. This study is registered with ClinicalTrials.gov, number NCT00077610. FINDINGS: We excluded 133 of the 673 randomised patients from the per-protocol analysis because they had inadequate iron status or fewer than five haemoglobin measurements during the assessment period or needed red blood cell transfusions. The mean change from baseline haemoglobin for patients who had switched to intravenous methoxy polyethylene glycol-epoetin beta every 2 weeks (-0.71 g/L, 95% CI -2.20 to 0.77) or every 4 weeks (-0.25 g/L, -1.79 to 1.29) was non-inferior to the mean change for patients who continued treatment with epoetin (-0.75 g/L, -2.26 to 0.75) (p<0.0001 for both comparisons). Of the 666 patients who received at least one dose of study drug, the incidence of adverse events or serious adverse events did not differ between groups (p=0.30 and p=0.40, respectively). INTERPRETATION: This long-acting erythropoiesis-stimulating agent is as safe as conventional epoetin treatment, and can maintain anaemia management in haemodialysis patients when given intravenously at 4-week dosing intervals.

Assessing transferable residues from intermittent exposure to flea control collars containing the organophosphate insecticide chlorpyrifos.

Children can be exposed to pesticides from numerous residential sources such as carpet, house dust, toys and clothing from treated homes, and flea control remedies on pets. In the present studies, 48 pet dogs (24 in each of two studies) of different breeds and weights were treated with over-the-counter flea collars containing chlorpyrifos (CP), an organophosphorus insecticide. Transferable insecticide residues were quantified on cotton gloves used to rub the dogs for 5 min and on cotton tee shirts worn by a child (Study 2 only). First morning urine samples were also obtained from adults and children in both studies for metabolite (3,5,6-trichloro-2-pyridinol) quantification. Blood samples were obtained from treated dogs in Study 1 and plasma cholinesterase (ChE) activity was monitored. Transferable residues on gloves for all compounds were highest near the neck of the dogs and were lowest in areas most distant from the neck. Rubbing samples (over the collar) at two weeks post-collar application contained 447+/-57 microg CP/glove while samples from the fur of the back contained 8+/-2 microg CP/glove. In Study 2, cotton tee shirts worn by children at 15 days post-collar application for 4 h showed CP levels of 134+/-66 ng/g shirt. There were significant differences between adults and children in the levels of urinary metabolites with children generally having higher urinary levels of metabolites than adults (grand mean+/-SE; 11.6+/-1.1 and 7.9+/-0.74 ng/mg creatinine for children and adults, respectively, compared to 9.4+/-0.8 and 6.9+/-0.5 ng/mg creatinine before collar placement). Therefore, there was little evidence that the use of this flea collar contributed to enhanced CP exposure of either children or adults.

Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) Study.

Few data exist to guide treatment of anemic hemodialysis patients with high ferritin and low transferrin saturation (TSAT). The Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) trial was designed to evaluate the efficacy of intravenous ferric gluconate in such patients. Inclusion criteria were hemoglobin or=225 IU/kg per wk or >or=22,500 IU/wk. Patients with known infections or recent significant blood loss were excluded. Participants (n=134) were randomly assigned to no iron (control) or to ferric gluconate 125 mg intravenously with eight consecutive hemodialysis sessions (intravenous iron). At randomization, epoetin was increased 25% in both groups; further dosage changes were prohibited. At 6 wk, hemoglobin increased significantly more (P=0.028) in the intravenous iron group (1.6 +/- 1.3 g/dl) than in the control group (1.1 +/- 1.4 g/dl). Hemoglobin response occurred faster (P=0.035) and more patients responded after intravenous iron than in the control group (P=0.041). Ferritin 800 ng/ml had no relationship to the magnitude or likelihood of responsiveness to intravenous iron relative to the control group. Similarly, the superiority of intravenous iron compared with no iron was similar whether baseline TSAT was above or below the study median of 19%. Ferritin decreased in control subjects (-174 +/- 225 ng/ml) and increased after intravenous iron (173 +/- 272 ng/ml; P<0.001). Intravenous iron resulted in a greater increase in TSAT than in control subjects (7.5 +/- 7.4 versus 1.8 +/- 5.2%; P<0.001). Reticulocyte hemoglobin content fell only in control subjects, suggesting worsening iron deficiency. Administration of ferric gluconate (125 mg for eight treatments) is superior to no iron therapy in anemic dialysis patients receiving adequate epoetin dosages and have a ferritin 500 to 1200 ng/ml and TSAT