Directive 02-14: Tax Obligations of Persons Purchasing Cigarettes in Interstate Commerce for which the Massachusetts Cigarette Excise Has Not Been Paid

The development of accurate clinical biomarkers has been challenging in part due to the diversity between patients and diseases. One approach to account for the diversity is to use multiple markers to classify patients, based on the concept that each individual marker contributes information from its respective subclass of patients. Here we present a new strategy for developing biomarker panels that accounts for completely distinct patient subclasses. Marker State Space (MSS) defines "marker states" based on all possible patterns of high and low values among a panel of markers. Each marker state is defined as either a case state or a control state, and a sample is classified as case or control based on the state it occupies. MSS was used to define multi-marker panels that were robust in cross validation and training-set/test-set analyses and that yielded similar classification accuracy to several other classification algorithms. A three-marker panel for discriminating pancreatic cancer patients from control subjects revealed subclasses of patients based on distinct marker states. MSS provides a straightforward approach for modeling highly divergent subclasses of patients, which may be adaptable for diverse applications.</p

A Reappraisal of the U.S. Clinical Trials of Post-Treatment Lyme Disease Syndrome

Four federally funded randomized placebo-controlled treatment trials of post-treatment Lyme syndrome in the United States have been conducted. Most international treatment guidelines summarize these trials as having shown no acute or sustained benefit to repeated antibiotic therapy. The goal of this paper is to determine whether this summary conclusion is supported by the evidence. Methods: The methods and results of the 4 U.S. treatment trials are described and their critiques evaluated. Results: 2 of the 4 U.S. treatment trials demonstrated efficacy of IV ceftriaxone on primary and/or secondary outcome measures. Conclusions: Future treatment guidelines should clarify that efficacy of IV ceftriaxone for post-treatment Lyme fatigue was demonstrated in one RCT and supported by a second RCT, but that its use was not recommended primarily due to adverse events stemming from the IV route of treatment. While repeated IV antibiotic therapy can be effective, safer modes of delivery are needed

A pilot study of disulfiram for individuals with persistent symptoms despite prior antibiotic treatment for Lyme disease

IntroductionIn vitro studies report that disulfiram is effective in killing Borrelia burgdorferi. Case series suggest disulfiram may help to reduce the symptoms of patients with persistent symptoms despite prior antibiotic treatment for Lyme disease. This pilot study assessed safety, tolerability, and signs of clinical response.Materials and methodsParticipants with a history of previously treated Lyme disease and persistent fatigue were randomly assigned in a double-blinded fashion to either Group A (disulfiram for 4 weeks and placebo for 4 weeks) or Group B (disulfiram for 8 weeks). Primary outcome endpoint was at 10 weeks with a follow-up at 14 weeks. The primary aim was to assess safety and tolerability. A clinical aim assessed signs of clinical improvement using well-validated measures, focusing on improvement in fatigue and quality of life. Target enrollment was 24 participants.Results940 individuals were screened, 11 were enrolled and nine participated in the trial. Dosing started low and increased based on response and tolerance to a maximum of 500 mg daily. Safety. Two participants discontinued medication due to clinical worsening, one of whom was briefly hospitalized. Three additional participants were withdrawn from treatment due to lab test abnormalities. Tolerability. Only three of nine participants completed the full course of treatment (two in Group A and one in Group B). Lower doses were better tolerated than the highest dose. Clinical response. Of nine participants, clinically meaningful improvement was noted in fatigue for six and in quality of life for four. Among the six fatigue responders, improvement was also noted on a multiple domain symptom index (six of six), overall symptom burden (five of six), and functional impairment (four of six). The study was terminated early due to end of project funding, higher than expected adverse events, and recognition that sufficient information was gathered to inform future studies.Conclusions and relevanceThis study reveals the risks associated with disulfiram, especially at higher doses, while suggesting potential clinical benefits among some participants. Efficacy could not be assessed given the small sample size and the lack of a placebo-control group.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT03891667?cond=Lyme%20Disease&amp;intr=disulfiram&amp;rank=1, NCT03891667

Randomized sham-controlled trial of repetitive transcranial magnetic stimulation in treatment-resistant obsessive–compulsive disorder

In open trials, 1-Hz repetitive transcranial magnetic stimulation (rTMS) to the supplementary motor area (SMA) improved symptoms and normalized cortical hyper-excitability of patients with obsessive–compulsive disorder (OCD). Here we present the results of a randomized sham-controlled double-blind study. Medication-resistant OCD patients (n=21) were assigned 4 wk either active or sham rTMS to the SMA bilaterally. rTMS parameters consisted of 1200 pulses/d, at 1 Hz and 100% of motor threshold (MT). Eighteen patients completed the study. Response to treatment was defined as a ≽25% decrease on the Yale–Brown Obsessive Compulsive Scale (YBOCS). Non-responders to sham and responders to active or sham rTMS were offered four additional weeks of open active rTMS. After 4 wk, the response rate in the completer sample was 67% (6/9) with active and 22% (2/9) with sham rTMS. At 4 wk, patients receiving active rTMS showed on average a 25% reduction in the YBOCS compared to a 12% reduction in those receiving sham. In those who received 8-wk active rTMS, OCD symptoms improved from 28.2±5.8 to 14.5±3.6. In patients randomized to active rTMS, MT measures on the right hemisphere increased significantly over time. At the end of 4-wk rTMS the abnormal hemispheric laterality found in the group randomized to active rTMS normalized. The results of the first randomized sham-controlled trial of SMA stimulation in the treatment of resistant OCD support further investigation into the potential therapeutic applications of rTMS in this disabling condition

The Marker State Space (MSS) Method for Classifying Clinical Samples

The development of accurate clinical biomarkers has been challenging in part due to the diversity between patients and diseases. One approach to account for the diversity is to use multiple markers to classify patients, based on the concept that each individual marker contributes information from its respective subclass of patients. Here we present a new strategy for developing biomarker panels that accounts for completely distinct patient subclasses. Marker State Space (MSS) defines "marker states" based on all possible patterns of high and low values among a panel of markers. Each marker state is defined as either a case state or a control state, and a sample is classified as case or control based on the state it occupies. MSS was used to define multi-marker panels that were robust in cross validation and training-set/test-set analyses and that yielded similar classification accuracy to several other classification algorithms. A three-marker panel for discriminating pancreatic cancer patients from control subjects revealed subclasses of patients based on distinct marker states. MSS provides a straightforward approach for modeling highly divergent subclasses of patients, which may be adaptable for diverse applications. © 2013 Fallon et al

WAIS-III and WMS-III performance in chronic Lyme disease

There is controversy regarding the nature and degree of intellectual and memory deficits in chronic Lyme disease. In this study, 81 participants with rigorously diagnosed chronic Lyme disease were administered the newest revisions of the Wechsler Adult Intelligence Scale (WAIS-III) and Wechsler Memory Scale (WMS-III), and compared to 39 nonpatients. On the WAIS-III, Lyme disease participants had poorer Full Scale and Performance IQ's. At the subtest level, differences were restricted to Information and the Processing Speed subtests. On the WMS-III, Lyme disease participants performed more poorly on Auditory Immediate, Immediate, Auditory Delayed, Auditory Recognition Delayed, and General Memory indices. Among WMS-III subtests, however, differences were restricted to Logical Memory (immediate and delayed) and Family Pictures (delayed only), a Visual Memory subtest. Discriminant analyses suggest deficits in chronic Lyme are best characterized as a combination of memory difficulty and diminished processing speed. Deficits were modest, between one-third and two-thirds of a standard deviation, consistent with earlier studies. Depression severity had a weak relationship to processing speed, but little other association to test performance. Deficits in chronic Lyme disease are consistent with a subtle neuropathological process affecting multiple performance tasks, although further work is needed to definitively rule out nonspecific illness effects

Psychiatric Aspects of Lyme Disease in Children and Adolescents: A Community Epidemiologic Study in Westchester, New York

To date, no community study has examined the psychiatric aspects and or sequelae of Lyme disease (LO) among children. As part of a community epidemiologic study of psychiatric disorders among children ages 9 through 17 in a Lyme endemic county, parents were asked whether their child had ever been diagnosed as having LD, and 10.1% (36/357) responded yes to the LO question. Of the 36, 29 also agreed to take part in a follow-up interview. Sixteen of the 29 children had had physician-diagnosed LO as well as either an erythema migrans rash or a positive serology. Fifteen of these 16 received treatment within I month of symptom onset; none of these 15 children were symptomatic longer than 4 months. Only one child had physical symptoms at the time of the interview; she was not treated until 4 month~ after symptom onset. This child experienced 5 years of mtermittent arthritis, cognitive deficits, emotional problems, severe fatigue, and a deterioration in school performance. Courses of oral antibiotics were at first associated with a good response, followed by a resurgence of symptoms month<; later. The lifetime prevalence of LD by history among children ages 9 through 17 in an endemic area may be at least 44.8/1000. In general, when LD is diagnosed early, it responds well to treatment. Delayed diagnosis and treatment may lead to a chronic course

A Double-Masked, Placebo-Controlled Study of Fluoxetine for Hypochondriasis

This study assessed the efficacy, durability, and tolerability of fluoxetine for hypochondriasis, a disorder for which controlled pharmacological trials are scarce. Fifty-seven patients with hypochondriasis were enrolled: 12 discontinued during the placebo run-in, and 45 were randomized to either fluoxetine or placebo for 12 weeks (acute treatment). Responder status was defined as a Clinical Global Impression rating for hypochondriasis of much or very much improved. Secondary outcome measures included severity of hypochondriasis, somatization, anxiety, and depression. Responders to acute treatment entered a 12-week maintenance phase to week 24. Sustained responders at week 24 entered a 12-week double-masked discontinuation phase. Primary analysis used the intent-to-treat sample. More patients responded with improvement in hypochondriasis when given fluoxetine compared with placebo, starting at week 8 (50.0% vs 19.0%, P = 0.03) and continuing to week 12 (62.5% vs 33.3%, P = 0.05). Mean dose at week 12 dose was 51.4 mg (SD, T23 mg). The acute treatment response was maintained to week 24 with more responders in the fluoxetine compared with the placebo group (54.2% vs 23.8%, P = 0.04). Significant improvement was not noted on the continuous secondary outcomes measures of hypochondriasis, with the exception of the Clinical Global Impression hypochondriasis severity scale at week 24. Likelihood of response was not associated with severity of psychiatric comorbidity. Durability of response after controlled drug discontinuation could not be reasonably assessed, given the small sample size of patients who entered the discontinuation phase (n = 10). Fluoxetine was well tolerated, with no significant differences in discontinuation due to side effects between treatment groups. Fluoxetine is a moderately effective and well-tolerated treatment for hypochondriasis

Proposed research classification criteria for Lyme disease in infection associated chronic illness studies

BackgroundResearch on patients with persistent symptoms despite prior treatment for Lyme disease can be challenging to interpret given the diversity of criteria selected to characterize Lyme disease and to define the syndrome of those with persistent symptoms. Because most research studies only include patients with well-documented prior Lyme disease, the generalizability of the study results is limited, excluding the larger group of patients often seen in community practice who do not meet these stringent enrollment criteria. Researchers at the Lyme and other Tick-borne Diseases Clinical Trials Network (LTD-CTN) recognized early on that a research classification system was needed to facilitate the design of studies that are more inclusive. This paper presents a proposed research classification system.MethodsCriteria used in published clinical research on previously treated Lyme disease were reviewed. Clinical expertise was provided by principal investigators in the LTD-CTN. Further input was obtained from a diverse panel of stakeholders in the field, including clinicians, academic researchers, and patient advocates. This classification system was developed based on feedback collected from all these sources.ResultsThe new research classification system proposes criteria for Lyme disease at different levels of diagnostic certainty: well-defined, probable, possible, and uncertain. Criteria for ascertainment for each classification level and additional factors to be considered in patient selection for research are described.ConclusionThe proposed research classification system should improve the quality and generalizability of clinical research by providing clear case definitions for enrollment of a more diverse group of patients with sequelae from Lyme disease

Lignin nanoparticles as delivery systems to facilitate translocation of methoxyfenozide in soybean (Glycine max)

Nanoscale delivery systems have the potential to improve the effectiveness of agrochemicals while reducing their negative environmental impacts. Herein, we explore the use of lignin nanoparticles (LNPs) to enhance the translocation of methoxyfenozide (MFZ), a non-systemic pesticide, in soybean plants under hydroponic conditions. LNPs (113.8 ± 3.5 nm and zeta potential – 53.3 ± 6.9 mV) were synthesized by emulsion evaporation from lignin-graft-poly(lactic-co-glycolic) acid and MFZ was incorporated into the LNPs (2.7% w/w). Twenty eight day old soybeans were grown hydroponically and were treated with 0.01, 0.1 or 1 mg/ml of LNPs. Plants were harvested after 6, 12, and 24 h of continuous hydroponic exposure to the roots and the concentration of MFZ was quantified in root, stem, and leaf tissues. The results suggest effective and time dependent transfer of MFZ from the hydroponic suspension to the roots, and translocation from the roots to the leaves. MFZ concentrations in the 1 mg/ml treated-plants at 24 h were 519.30, 3.72 and 1.72 μg/g in the roots, stem, and leaves, at 24 h, respectively, as compared to only 28.52, 0.58, 0.39 μg/g in the plants under neat MFZ exposure. The translocation efficiency (TE) of nanodelivered MFZ ranged from 0.06 to 0.08 at 0.01 mg/ml TE, 0.01–0.05 at 0.1 mg/ml, and 0.01–0.006 at 1 mg/ml over 24 h. Even though TE was higher for free MFZ, the concentration and total amount of analyte translocated to the shoots by LNPs were higher than those of free MFZ. In conclusion, LNPs were able to significantly enhance the translocation of non-systemic MFZ from the roots to the soybean aerial tissues in 24 h. This work provides a new platform to enhance the accuracy and precision of pesticide delivery and will be a valuable tool in sustainable nano-enabled agriculture