The question of whether influenza is transmitted to a significant degree by aerosols remains controversial, in part, because little is known about the quantity and size of potentially infectious ...airborne particles produced by people with influenza. In this study, the size and amount of aerosol particles produced by nine subjects during coughing were measured while they had influenza and after they had recovered, using a laser aerosol particle spectrometer with a size range of 0.35 to 10 μm. Individuals with influenza produce a significantly greater volume of aerosol when ill compared with afterward (p = 0.0143). When the patients had influenza, their average cough aerosol volume was 38.3 picoliters (pL) of particles per cough (SD 43.7); after patients recovered, the average volume was 26.4 pL per cough (SD 45.6). The number of particles produced per cough was also higher when subjects had influenza (average 75,400 particles/cough, SD 97,300) compared with afterward (average 52,200, SD 98,600), although the difference did not reach statistical significance (p = 0.1042). The average number of particles expelled per cough varied widely from patient to patient, ranging from 900 to 302,200 particles/cough while subjects had influenza and 1100 to 308,600 particles/cough after recovery. When the subjects had influenza, an average of 63% of each subject's cough aerosol particle volume in the detection range was in the respirable size fraction (SD 22%), indicating that these particles could reach the alveolar region of the lungs if inhaled by another person. This enhancement in aerosol generation during illness may play an important role in influenza transmission and suggests that a better understanding of this phenomenon is needed to predict the production and dissemination of influenza-laden aerosols by people infected with this virus.
Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resources: a PDF file of demographic information, influenza test results, and volume and peak flow rate during each cough and a PDF file containing number and size of aerosol particles produced.
The development of biomarkers to predict the progression of Parkinson’s disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The ...Parkinson’s Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ
1-42
), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ
1-42
, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ
1-42
, or highest t-tau/Aβ
1-42
and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance.
APOE
ε4 genotype was associated with lower levels of Aβ
1-42
, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.
Dropouts and missing data are nearly-ubiquitous in obesity randomized controlled trails, threatening validity and generalizability of conclusions. Herein, we meta-analytically evaluate the extent of ...missing data, the frequency with which various analytic methods are employed to accommodate dropouts, and the performance of multiple statistical methods.
We searched PubMed and Cochrane databases (2000-2006) for articles published in English and manually searched bibliographic references. Articles of pharmaceutical randomized controlled trials with weight loss or weight gain prevention as major endpoints were included. Two authors independently reviewed each publication for inclusion. 121 articles met the inclusion criteria. Two authors independently extracted treatment, sample size, drop-out rates, study duration, and statistical method used to handle missing data from all articles and resolved disagreements by consensus. In the meta-analysis, drop-out rates were substantial with the survival (non-dropout) rates being approximated by an exponential decay curve (e(-lambdat)) where lambda was estimated to be .0088 (95% bootstrap confidence interval: .0076 to .0100) and t represents time in weeks. The estimated drop-out rate at 1 year was 37%. Most studies used last observation carried forward as the primary analytic method to handle missing data. We also obtained 12 raw obesity randomized controlled trial datasets for empirical analyses. Analyses of raw randomized controlled trial data suggested that both mixed models and multiple imputation performed well, but that multiple imputation may be more robust when missing data are extensive.
Our analysis offers an equation for predictions of dropout rates useful for future study planning. Our raw data analyses suggests that multiple imputation is better than other methods for handling missing data in obesity randomized controlled trials, followed closely by mixed models. We suggest these methods supplant last observation carried forward as the primary method of analysis.
Previous studies have demonstrated the cost-effectiveness of physician-pharmacist collaborations to improve hypertension control. However, most studies have limited generalizability, lacking minority ...and low-income populations. The Collaboration Among Pharmacist and Physicians to Improve Blood Pressure Now (CAPTION) trial randomized 625 patients from 32 medical offices in 15 states. Each office had an existing clinical pharmacist on staff. Pharmacists in intervention offices communicated with patients and made recommendations to physicians about changes in therapy. Demographic information, blood pressure (BP), medications, and physician visits were recorded. In addition, pharmacists tracked time spent with each patient. Costs were assigned to medications and pharmacist and physician time. Cost-effectiveness ratios were calculated based on changes in BP measurements and hypertension control rates. Thirty-eight percent of patients were black, 14% were Hispanic, and 49% had annual income <$25 000. At 9 months, average systolic BP was 6.1 mm Hg lower (±3.5), diastolic was 2.9 mm Hg lower (±1.9), and the percentage of patients with controlled hypertension was 43% in the intervention group and 34% in the control group. Total costs for the intervention group were $1462.87 (±132.51) and $1259.94 (±183.30) for the control group, a difference of $202.93. The cost to lower BP by 1 mm Hg was $33.27 for systolic BP and $69.98 for diastolic BP. The cost to increase the rate of hypertension control by 1 percentage point in the study population was $22.55. Our results highlight the cost-effectiveness of a clinical pharmacy intervention for hypertension control in primary care settings.
Abstract Objective To determine the frequency and stability over time of the subgroup characterization of the tremor dominant (TD) versus postural instability gait disorder dominant (PIGD) ...Parkinson's disease (PD) in de novo patients. Background There is a substantial body of literature on the clinical sub classification of PD into TD versus PIGD subtype. However, there are limited data on the stability of this classification especially in early disease. Methods Parkinson's Progression Markers Initiative (PPMI) is a longitudinal case control study of de novo, untreated PD participants at enrollment. Participants undergo a number of assessments including the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). TD versus PIGD subtype was defined based on the previously published formula. We report one-year analysis data. Results 320 of 423 PD recruited subjects had data on subtype classification at year 1 and were included in the analysis. 228 (71%) were classified as TD, 56 (18%) as PIGD and 36 (11%) as indeterminate at baseline. At 12 months, 39% PIGD and 18% TD shifted subtypes: 29% PIGD shifted to TD and 11% to Indeterminate; 10% TD shifted to PIGD and 8% to Indeterminate. The classification was not affected by the dopaminergic treatment (p = 0.59). Conclusions TD versus PIGD subtype classification has substantial variability over first year in PD de novo cohort specifically for PIGD subtype. Dopaminergic therapy does not impact the change of the PD subtype. This instability has to be taken into consideration specifically when establishing correlations with the biomarkers and for long term prognostication.
Background:
Sensitive and specific biomarkers for use in progressive multiple sclerosis (MS) have not been established. We investigate neurofilament light (NfL) as a treatment response biomarker in ...progressive MS.
Objective:
To evaluate whether ibudilast 100 mg/day alters serum and cerebrospinal fluid (CSF) levels of NfL in progressive MS.
Methods:
In a protocol-defined exploratory analysis from a 2-year, phase 2 clinical trial of ibudilast in progressive MS (NCT01982942), serum samples were collected from 239 subjects and a subset contributed CSF and assayed using single-molecule assay (SIMOA) immunoassay. A mixed model for repeated measurements yielded log(NfL) as the response variable.
Results:
The geometric mean baseline serum NfL was 31.9 and 28.8 pg/mL in placebo and ibudilast groups, respectively. The geometric mean baseline CSF NfL was 1150.8 and 1290.3 pg/mL in placebo and ibudilast groups, respectively. Serum and CSF NfL correlations were r = 0.52 and r = 0.78 at weeks 48 and 96, respectively. Over 96 weeks, there was no between-group difference in NfL in either serum (p = 0.76) or CSF (p = 0.46). After controlling for factors that may affect NfL, no effect of ibudilast on NfL in either serum or CSF was observed.
Conclusion:
Ibudilast treatment was not associated with a change in either serum or CSF NfL.
To assess the neurobiological substrate of initial cognitive decline in Parkinson's disease (PD) to inform patient management, clinical trial design, and development of treatments.
We longitudinally ...assessed, up to 3 years, 423 newly diagnosed patients with idiopathic PD, untreated at baseline, from 33 international movement disorder centers. Study outcomes were four determinations of cognitive impairment or decline, and biomarker predictors were baseline dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan, structural magnetic resonance imaging (MRI; volume and thickness), diffusion tensor imaging (mean diffusivity and fractional anisotropy), cerebrospinal fluid (CSF; amyloid beta Aβ, tau and alpha synuclein), and 11 single nucleotide polymorphisms (SNPs) previously associated with PD cognition. Additionally, longitudinal structural MRI and DAT scan data were included. Univariate analyses were run initially, with false discovery rate = 0.2, to select biomarker variables for inclusion in multivariable longitudinal mixed-effect models.
By year 3, cognitive impairment was diagnosed in 15-38% participants depending on the criteria applied. Biomarkers, some longitudinal, predicting cognitive impairment in multivariable models were: (1) dopamine deficiency (decreased caudate and putamen DAT availability); (2) diffuse, cortical decreased brain volume or thickness (frontal, temporal, parietal, and occipital lobe regions); (3) co-morbid Alzheimer's disease Aβ amyloid pathology (lower CSF Aβ 1-42); and (4) genes (COMT val/val and BDNF val/val genotypes).
Cognitive impairment in PD increases in frequency 50-200% in the first several years of disease, and is independently predicted by biomarker changes related to nigrostriatal or cortical dopaminergic deficits, global atrophy due to possible widespread effects of neurodegenerative disease, co-morbid Alzheimer's disease plaque pathology, and genetic factors.
The purpose of this study was to evaluate if a physician/pharmacist collaborative model would be implemented as determined by improved blood pressure (BP) control in primary care medical offices with ...diverse geographic and patient characteristics and whether long-term BP control could be sustained.
Prospective, cluster-randomized trial of 32 primary care offices stratified and randomized to control, 9-month intervention (brief), and 24-month intervention (sustained). We enrolled 625 subjects with uncontrolled hypertension; 54% from racial/ethnic minority groups and 50% with diabetes mellitus or chronic kidney disease. The primary outcome of BP control at 9 months was 43% in intervention offices (n=401) compared with 34% in the control group (n=224; adjusted odds ratio, 1.57 95% confidence interval, 0.99-2.50; P=0.059). The adjusted difference in mean systolic/diastolic BP between the intervention and control groups for all subjects at 9 months was -6.1/-2.9 mm Hg (P=0.002 and P=0.005, respectively), and it was -6.4/-2.9 mm Hg (P=0.009 and P=0.044, respectively) in subjects from racial or ethnic minorities. BP control and mean BP were significantly improved in subjects from racial minorities in intervention offices at 18 and 24 months (P=0.048 to P<0.001) compared with the control group.
Although the results of the primary outcome (BP control) were negative, the key secondary end point (mean BP) was significantly improved in the intervention group. Thus, the findings for secondary end points suggest that team-based care using clinical pharmacists was implemented in diverse primary care offices and BP was reduced in subjects from racial minority groups.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00935077.
BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted ...treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.
To analyze longitudinal levels of CSF biomarkers in drug-naive patients with Parkinson disease (PD) and healthy controls (HC), examine the extent to which these biomarker changes relate to clinical ...measures of PD, and identify what may influence them.
CSF α-synuclein (α-syn), total and phosphorylated tau (t- and p-tau), and β-amyloid 1-42 (Aβ42) were measured at baseline and 6 and 12 months in 173 patients with PD and 112 matched HC in the international multicenter Parkinson's Progression Marker Initiative. Baseline clinical and demographic variables, PD medications, neuroimaging, and genetic variables were evaluated as potential predictors of CSF biomarker changes.
CSF biomarkers were stable over 6 and 12 months, and there was a small but significant increase in CSF Aβ42 in both patients with patients with PD and HC from baseline to 12 months. The t-tau remained stable. The p-tau increased marginally more in patients with PD than in HC. α-syn remained relatively stable in patients with PD and HC. Ratios of p-tau/t-tau increased, while t-tau/Aβ42 decreased over 12 months in patients with PD. CSF biomarker changes did not correlate with changes in Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale motor scores or dopamine imaging. CSF α-syn levels at 12 months were lower in patients with PD treated with dopamine replacement therapy, especially dopamine agonists.
These core CSF biomarkers remained stable over 6 and 12 months in patients with early PD and HC. PD medication use may influence CSF α-syn. Novel biomarkers are needed to better profile progressive neurodegeneration in PD.
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