Citations

Background and purpose Onabotulinumtoxin A was effective and well tolerated for prophylaxis of headache in patients with chronic migraine ( CM ) in two randomized, double‐blind, placebo‐controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxin A in CM prophylaxis in adults, the pooled safety data from four double‐blind, placebo‐controlled trials were analyzed. Methods The pooled analysis included two phase 2 and two phase 3 double‐blind, placebo‐controlled trials. The safety population was 2436 patients, 1997 of whom received ≥1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events ( AE s), physical examination and clinical laboratory tests. Results Onabotulinumtoxin A was safe and well tolerated, with a low discontinuation rate (3.4%) due to AE s. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxin A injections, 1455 patients (72.9%) reported at least one AE . Neck pain (12.6%) was the most common onabotulinumtoxin A ‐associated AE , followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AE s were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxin A treatment and 3.0% of patients receiving placebo. AE s were consistent with the known tolerability profile of onabotulinumtoxin A . Conclusions Multiple treatments with onabotulinumtoxinA at doses of 75–260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM .

Background: Warfarin is still the most commonly used anticoagulant for the treatment of venous thromboembolism and other hypercoagulable states. Warfarin metabolism is affected by multiple factors, including diet, medications, and individual patient characteristics. As both underdosing and overdosing can increase risks to patients, several studies have attempted to develop dosing protocols. However, few have investigated how patient weight and body mass index (BMI) affect warfarin dosing. Objective: The objective of this study was to determine the association between BMI and the total weekly dose (TWD) of warfarin. Methods: In this retrospective study, we identified patients taking warfarin who had an international normalized ratio (INR) within the therapeutic range to assess if there was a significant correlation between TWD, that is, maintenance warfarin dosing, and BMI in obese and nonobese patients. Results: A total of 831 patients were studied, with a BMI range between 13.4 and 63.1 kg/m 2 . We found that BMI is positively correlated with the total weekly warfarin dose. Our study showed that for each 1-point increase in BMI, the weekly warfarin dose increased by 0.69 mg. We found that the average warfarin weekly dose in this population can be estimated using the formula: 12.34 + 0.69 × BMI. Conclusion: There is an association between BMI and the TWD of warfarin. This could have dosing implications for both patients and prescribers, as patients with a high BMI will be expected to require higher doses of warfarin to maintain a therapeutic INR.

BackgroundPostmenopausal hormone therapy (HT) increases the risk of venous thrombosis and ischemic stroke.ObjectivesWe postulated that HT might increase the risk of ischemic stroke by promoting venous clots that travel to the brain through a right to left shunt (RLS).MethodsA total of 2,389 records were studied. After eliminating the premenopausal patients, and those with TIAs and non‐ischemic strokes, the medical records of 1846 postmenopausal women hospitalized at four institutions for ischemic stroke were reviewed to identify those who had undergone an adequate study to assess for RLS. The proportion of women with a shunt in users and non‐users of HT was compared in stroke patients and in a reference population consisting of postmenopausal women undergoing elective cardiac catheterization.ResultsThere were 363 (20%) records that had complete data and were included in the analysis. A shunt was more prevalent in patients with a cryptogenic stroke than in patients with a stroke of known cause (55/88 (63%) vs. 53/275 (19%), P < 0.001). In patients with a stroke of known cause, the frequency of a shunt was similar to that in reference women 31/136 (23%), and the proportion of women with a shunt was similar in non‐users and current users of HT (14% vs. 20%, P = 0.40). However, among patients with a cryptogenic stroke, the prevalence of a shunt was 1.5 times higher in current users than non‐users of HT (82% vs. 56%, P = 0.04).ConclusionsApproximately 23% of older women have a RLS. HT in these women may increase the risk of ischemic stroke by promoting paradoxical embolism. © 2014 Wiley Periodicals, Inc.

Background The utility of longitudinal, circumferential, and radial strain and strain rate in determining prognosis in chronic heart failure is not well established. Methods and Results In 416 patients with chronic systolic heart failure, we performed speckle‐tracking analyses of left ventricular longitudinal, circumferential, and radial strain and strain rate on archived echocardiography images (30 frames per second). Cox regression models were used to determine the associations between strain and strain rate and risk of all‐cause mortality, cardiac transplantation, and ventricular‐assist device placement. The area under the time‐dependent ROC curve ( AUC ) was also calculated at 1 year and 5 years. Over a maximum follow‐up of 8.9 years, there were 138 events (33.2%). In unadjusted models, all strain and strain rate parameters were associated with adverse outcomes ( P <0.001). In multivariable models, all parameters with the exception of radial strain rate ( P =0.11) remained independently associated, with patients in the lowest tertile of strain or strain rate parameter having a ≈2‐fold increased risk of adverse outcomes compared with the reference group ( P <0.05). Addition of strain to ejection fraction ( EF ) led to a significantly improved AUC at 1 year (0.697 versus 0.633, P =0.032) and 5 years (0.700 versus 0.638, P =0.001). In contrast, strain rate did not provide incremental prognostic value to EF alone. Conclusions Longitudinal and circumferential strain and strain rate, and radial strain are associated with chronic heart failure prognosis. Strain provides incremental value to EF in the prediction of adverse outcomes, and with additional study may be a clinically relevant prognostic tool.

Key Points Eosinophils recruited to the airways in response to A fumigatus sensitization and challenge degranulate in response to virus infection. Activated eosinophils are antiviral and promote survival from an otherwise lethal respiratory virus infection.

To determine the effects of acute metabolic acidosis and alkalosis on leucine metabolism in vivo, mongrel dogs were infused with [1-14C] leucine for 8 h, along with NaCI, HCI, or NaHCO3 over the last 4 h. Arterial pH did not change from the basal value during NaCI infusion but decreased (P &lt;.01) and increased (P &lt;.01) during HCI and NaHCO3 infusions, respectively. Total leucine carbon entry did not change from the basal value during saline infusion but increased (P &lt;.01) with acidosis and decreased (P &lt;.05) with alkalosis. Compared with saline controls, acidosis increased (P &lt;.01) leucine oxidation, whereas alkalosis decreased (P &lt;.01) leucine oxidation. During acidosis, total plasma essential and nonessential amino acid concentrations increased (P &lt;.05), whereas during alkalosis, total plasma essential and nonessential amino acid concentrations decreased (P &lt;.05). These studies suggest that acute alterations in arterial pH may affect the regulation of protein metabolism in vivo and must be considered in the interpretation of results from experiments in which alterations of acid-base homeostasis may have occurred.

To determine the role insulin resistance may play in the catabolic effect of high-dose prednisone therapy, healthy volunteers were studied on four occasions with the hormone-clamp technique at two insulin infusion rates. Subjects were studied after 5 days of prednisone (60 mg/day) or no steroid treatment and were infused with somatostatin, glucagon, growth hormone, [3H]glucose, [14C]leucine, and insulin (0.1 or 0.2 mil · kg1 · min1). At each rate of insulin infusion, the rate of leucine oxidation was increased (P &lt; .001) after steroid treatment. Leucine flux, an indicator of whole-body proteolysis, was similar in the presence or absence of steroid treatment (2.26 ± 0.08 vs. 2.13 ± 0.04 μmol · kg1 · min1 respectively) at the lower rate of insulin infusion but was higher during steroid treatment (2.18 ± 0.06 vs. 1.84 ± 0.13 μmol · kg1 · min1) at the 0.2-mU · kg1 · min1 insulin infusion. Steroid pretreatment had no significant effect on the nonoxidative rates of leucine disappearance. These data provide strong evidence that the protein wasting associated with glucocorticosteroid therapy is in part the result of steroid-induced resistance to the antiproteolytic effect of insulin and an increase in the oxidation (and thus wasting) of one essential amino acid, leucine.

ABSTRACT Diagnosis of yeast infection is typically accomplished by fungal smear and culture, histopathologic examination, and/or serologic studies. Newer assays based on mass spectrometry may be useful for yeast identification when histologic examination is inconclusive, fungal cultures are not ordered, or cultures fail to yield a causative agent. The purpose of this study was to evaluate the ability of the PLEX-ID broad fungal assay to accurately detect and identify yeasts in formalin-fixed paraffin-embedded (FFPE) tissues. Tissue samples from 78 FFPE specimens with both histopathology and corresponding culture results for a variety of yeasts were tested using the PLEX-ID broad fungal assay. A 40-μm FFPE tissue section from each specimen was digested with proteinase K followed by nucleic acid extraction and PCR using broad-range fungal primers. Yeast DNA in amplified products was identified using electrospray ionization mass spectrometry. Discordant results were resolved by D2 rRNA gene sequencing. PLEX-ID analysis detected yeast DNA in 78.2% (61/78) of the cases, of which 91.8% (56/61) were concordant with culture results. Of the 5 discordant positive results, 4 PLEX-ID results were considered to result from environmental contaminants, while 1 clinically important discrepancy was observed ( Blastomyces dermatitidis by culture and Cryptococcus neoformans by PLEX-ID). Sequencing of the discordant sample was unsuccessful. The majority of histopathology results (89.7% [70/78]) correlated with culture results. The PLEX-ID broad fungal assay identifies fungi directly from FFPE tissues and can be a useful adjunct to traditional culture and histopathology tests.