The Headache Handbook: Diagnosis and Treatment helps both generalist and specialist clinicians, including family practitioners, chiropractors, and neurologists, to understand headache, possibly the ...most ubiquitous symptom in medicine. This comprehensive work covers the myriad of differences among headache patients and the need for accurate fact gathering and physical and neurological examinations. Topics include anatomy and physiology of headache; evaluation and treatment of various headache types; interventional procedures; and manual medicine consultations.
Focal malformations of cortical development, including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are important causes of intractable childhood epilepsy. Using targeted and exome ...sequencing on DNA from resected brain samples and nonbrain samples from 53 patients with FCD or HME, we identified pathogenic germline and mosaic mutations in multiple PI3K/AKT pathway genes in 9 patients, and a likely pathogenic variant in 1 additional patient. Our data confirm the association of DEPDC5 with sporadic FCD but also implicate this gene for the first time in HME. Our findings suggest that modulation of the mammalian target of rapamycin pathway may hold promise for malformation‐associated epilepsy. Ann Neurol 2015;77:720–725
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Inhibition of fatty acid amide hydrolase‐1 (FAAH1) and the subsequent elevation of fatty acid amides has been proposed as a strategy to induce the analgesic ...properties of cannabinoids without the accompanying negative side effects such as impairment in cognition, motor control and predisposition to psychoses. PF‐04457845 is a potent and selective irreversible FAAH1 inhibitor which has been shown to elevate fatty acid amide concentrations in animal models and induce responses in behavioural models suggestive of analgesia.
WHAT THIS STUDY ADDS
• This study is the first to investigate a FAAH1 inhibitor in humans. PF‐04457845 is well tolerated following single and multiple dosing to healthy volunteers and has pharmacokinetic and pharmacodynamic properties that make nearly complete inhibition of FAAH1 possible with once daily dosing.
AIMS To evaluate the pharmacology and tolerability of PF‐04457845, an orally available fatty acid amide hydrolase‐1 (FAAH1) inhibitor, in healthy subjects.
METHODS
Double‐blind, randomized, placebo‐controlled single and multiple rising dose studies and an open‐label, randomized, food effect study were conducted. Plasma and urine PF‐04457845 concentrations, plasma fatty acid amide concentrations and FAAH1 activity in human leucocytes were measured. Tolerability, including effects on cognitive function, were assessed.
RESULTS
PF‐04457845 was rapidly absorbed (median tmax 0.5–1.2 h). Exposure increased supraproportionally to dose from 0.1 to 10 mg and proportionally between 10 and 40 mg single doses. The pharmacokinetics appeared dose proportional following 14 days once daily dosing between 0.5 and 8 mg. Steady‐state was achieved by day 7. Less than 0.1% of the dose was excreted in urine. Food had no effect on PF‐04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (>97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF‐04457845. Mean fatty acid amide concentrations increased (3.5‐ to 10‐fold) to a plateau and then were maintained following PF‐04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF‐04457845 on cognitive function. PF‐04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated.
CONCLUSIONS
PF‐04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.
Abstract
Objectives
Comparative assessments of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) molecular assays that have been operationalized through the US Food and Drug ...Administration’s Emergency Use Authorization process are warranted to assess real-world performance. Characteristics such as sensitivity, specificity, and false-negative rate are important to inform clinical use.
Methods
We compared five SARS-CoV-2 assays using nasopharyngeal and nasal swab specimens submitted in transport media; we enriched this cohort for positive specimens, since we were particularly interested in the sensitivity and false-negative rate. Performance of each test was compared with a composite standard.
Results
The sensitivities and false-negative rates of the 239 specimens that met inclusion criteria were, respectively, as follows: Centers for Disease Control and Prevention 2019 nCoV Real-Time RT-PCR Diagnostic Panel, 100% and 0%; TIB MOLBIOL/Roche z 480 Assay, 96.5% and 3.5%; Xpert Xpress SARS-CoV-2 (Cepheid), 97.6% and 2.4%; Simplexa COVID-19 Direct Kit (DiaSorin), 88.1% and 11.9%; and ID Now COVID-19 (Abbott), 83.3% and 16.7%.
Conclusions
The assays that included a nucleic acid extraction followed by reverse transcription polymerase chain reaction were more sensitive than assays that lacked a full extraction. Most false negatives were seen in patients with low viral loads, as extrapolated from crossing threshold values.
Acute exacerbations of idiopathic pulmonary fibrosis Collard, Harold R; Moore, Bethany B; Flaherty, Kevin R ...
American journal of respiratory and critical care medicine,
10/2007, Letnik:
176, Številka:
7
Journal Article
Recenzirano
Odprti dostop
The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may ...experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.
To report a case of neurotrophic keratopathy (NK) in a patient with complex regional pain syndrome (CRPS) with ipsilateral facial involvement.
Case report.
An 18-year old woman with a 5-year history ...of CRPS type I, a systemic disorder with a neuropathic component with associated limb and right facial involvement, presented with an insidious onset of blurred vision and pain in the right eye. Ocular examination revealed decreased corneal sensation, as measured by Cochet-Bonnet testing, associated with recurrent epithelial defects and whorl-like superficial corneal epitheliopathy. NK was suspected and confirmed by in vivo confocal microscopy (IVCM), which revealed rarefaction of the subbasal nerve plexus in the affected eye. To enhance corneal nerve health, plasma rich in growth factors drops were used. Persistence of NK prompted a superficial keratectomy with placement of an amniotic membrane graft and a course of cenegermin 0.002% (Oxervate; Dompé Farmaceutici SpA, Italy) in the postoperative period. This combination therapy resulted in successful epithelial closure and vision improvement after 8 weeks of therapy with no recurrence of disease for 11 months. Importantly, at that final visit, IVCM demonstrated growth of corneal nerves for the first time in this patient.
This is the first case report of NK occurring in the context of CRPS, a neuropathy with ipsilateral facial pain involvement. IVCM was important in the diagnosis of NK, which responded successfully to ocular surface treatments focused on nerve health stimulation that ultimately resulted in corneal nerve growth.
Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of ...preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.
Overabundant populations of feral equids are negatively affecting rangelands in the western United States. To better manage these populations, robust estimates of abundance and demographic rates and ...cost-effective methods of reducing abundance are necessary. From August 2015 to April 2017, we estimated the abundance of feral burros (Equus asinus) at the Fort Irwin National Training Center (NTC; California, USA) using a double-observer-sightability aerial survey method; captured, radio-collared, and inoculated female burros with porcine zona pellucida (PZP), an immunocontraceptive control agent; estimated female demographic rates; and used matrix population models to simulate how changes in demographic and PZP delivery rates would influence burro abundance. We estimated there were 690 (95% CI=618–752) feral burros within the surveyed area, but these are part of a much larger population that is not geographically isolated from those in the survey area. Sighting probabilities ranged from 0.19–0.98 and were most strongly influenced by distance from observer and group size. We estimated age-specific demographic rates at the NTC and compiled mean rates across burro populations in arid environments from the literature. Mean fecundity varied from 0.17 to 0.58 foals/adult female with younger females having lower fecundity. Mean survival was 0.90 for foals, 0.98 for yearlings, and 0.96 for adults. The PZP vaccine treatment strategies that suppressed fertility for up to 10 years predicted that burro abundance would be reduced by 67–88% after 15 years (compared with no treatment), but none of these strategies resulted in population extirpation. Population growth rates shifted from increasing to decreasing at adult survival rates below 0.84 and the population was predicted to become extirpated when adult survival declined to <0.60. In the absence of other methods to reduce burro numbers, our findings indicate that current formulations of PZP immunocontraception, which require multiple doses, would be inadequate for controlling population growth rates at the NTC. Our fieldwork also highlighted the difficulty of administering PZP vaccination to large, free-ranging animals. Development of longer-term fertility reduction agents or more efficient vaccine delivery techniques would likely improve the efficacy of fertility control for overabundant ungulate populations. Lack of geographic closure (physical barriers to migration) further complicated efforts to reduce burro numbers.
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