Precordial electrocardiographic recording and QT measurement from a novel wearable ring device.

Background: The availability of portable and wearable electrocardiographic (ECG) devices has increased secondary to technological development. Single-lead ECG recordings have been shown to reliably detect and characterize cardiac rhythms such as atrial fibrillation. Acquisition of precordial electrodes for full 12-lead ECG reconstruction from bipolar recordings is complicated by the absence of a body ground/Wilson central terminal electrode. The extent of difference between standard precordial leads and those from a wearable bipolar ECG recorder has not been characterized. Objective: The purpose of this study was to characterize the precordial ECG lead set from sequential bipolar recordings from an ECG ring wearable device. Methods: In 70 patients who wore an ECG device on a right-hand finger, sequential precordial leads (CR1-CR6) were obtained along with chest electrodes (V1-V6). During acquisition of the modified precordial lead CR6, a full standardized 12-lead ECG capture was obtained. Signal quality was assessed using automated analysis software, and correlation values between the ring-derived ECG precordial leads and standard ECG leads were compared with regard to QRS duration, QT width, and RR interval. Results: High concordance in the morphologies of precordial ECG leads obtained in a standard fashion and those recorded through an ECG ring was observed. Morphologic alignment improved with increasing laterality of the precordial lead with chest to right arm ring recording (CR5, CR6) compared with anterior chest leads to right arm (CR1, CR2). Segmental measurements of QRS duration and QT segment were well aligned and of high correlation. Conclusion: Wearable ring-based ECG technology is capable of high-fidelity recordings of precordial leads for nonsimultaneous reconstruction of complete ECG sets. These recordings correlate highly with surface-obtained QRS and QT duration measurements and have significant implications for clinical applications. Uninterpretable tracings were primarily due to electrode noise from poor electrode contact.

Computer Simulations of Deep Eutectic Solvents: Challenges, Solutions, and Perspectives.

Deep eutectic solvents (DESs) are one of the most rapidly evolving types of solvents, appearing in a broad range of applications, such as nanotechnology, electrochemistry, biomass transformation, pharmaceuticals, membrane technology, biocomposite development, modern 3D-printing, and many others. The range of their applicability continues to expand, which demands the development of new DESs with improved properties. To do so requires an understanding of the fundamental relationship between the structure and properties of DESs. Computer simulation and machine learning techniques provide a fruitful approach as they can predict and reveal physical mechanisms and readily be linked to experiments. This review is devoted to the computational research of DESs and describes technical features of DES simulations and the corresponding perspectives on various DES applications. The aim is to demonstrate the current frontiers of computational research of DESs and discuss future perspectives.

Machine-learning-based data-driven discovery of nonlinear phase-field dynamics.

One of the main questions regarding complex systems at large scales concerns the effective interactions and driving forces that emerge from the detailed microscopic properties. Coarse-grained models aim to describe complex systems in terms of coarse-scale equations with a reduced number of degrees of freedom. Recent developments in machine-learning algorithms have significantly empowered the discovery process of governing equations directly from data. However, it remains difficult to discover partial differential equations (PDEs) with high-order derivatives. In this paper, we present data-driven architectures based on a multilayer perceptron, a convolutional neural network (CNN), and a combination of a CNN and long short-term memory structures for discovering the nonlinear equations of motion for phase-field models with nonconserved and conserved order parameters. The well-known Allen-Cahn, Cahn-Hilliard, and phase-field crystal models were used as test cases. Two conceptually different types of implementations were used: (a) guided by physical intuition (such as the local dependence of the derivatives) and (b) in the absence of any physical assumptions (black-box model). We show that not only can we effectively learn the time derivatives of the field in both scenarios, but we can also use the data-driven PDEs to propagate the field in time and achieve results in good agreement with the original PDEs.

Reengineering the Discharge Transition Process of COVID-19 Patients Using Telemedicine, Remote Patient Monitoring, and Around-the-Clock Remote Patient Monitoring from the Emergency Department and Inpatient Units.

Background: At the beginning of the COVID-19 pandemic, New York City quickly became the epicenter with hospitals at full capacity needing to care for patients. At New York Presbyterian Brooklyn Methodist Hospital, we needed to develop an innovative system of how to safely discharge the massive influx of patients. Inundation of patient care with limited manpower and resources forced us to align with a third-party vendor, around-the-clock alert, to make remote patient monitoring (RPM) possible. Each patient was prescribed a pulse oximeter and nurses were assigned to monitor vital signs, speak to patients, and escalate to physicians if required. Results: We enrolled 50 patients, of whom 13 were escalated resulting in 3 emergency room visits and 1 readmission. We had a high compliance rate with high patient satisfaction in postsurveys. Discussion: Our program was unique in that it utilized telemedicine for regular patient follow-up, along with RPM through a third-party vendor. Patients were able to be safely discharged home with close follow-up through regularly obtained vitals with access to a 24/7 hotline for any emergencies, possibly preventing readmissions. Limitations include a small sample size population. Conclusions: Our experience shows that in a short period despite lack of resources, telehealth and RPM's concurrent use with a third-party vendor could be successfully utilized for safe discharges with high patient satisfaction.

Oral Antiplatelet Therapy Administered Upstream to Patients With NSTEMI.

OBJECTIVE: To describe from a noninterventional registry (Utilization of Ticagrelor in the Upstream Setting for Non-ST-Segment Elevation Acute Coronary Syndrome), the short-term ischemic and hemorrhagic outcomes in patients with non-ST elevation myocardial infarction (MI) are managed with a loading dose (LD) of a P2Y12 inhibitor (P2Y12i) given at least 4 hours before diagnostic angiography and delineation of coronary anatomy. Prior data on the effects of such "upstream loading" have been inconsistent. METHODS: In 53 US hospitals, we evaluated the in-hospital care and outcomes of patients with confirmed non-ST elevation MI managed with an interventional strategy and loaded upstream (at least 4 h before diagnostic angiography) with oral P2Y12i therapy. Patients entered into the database were grouped into 1 of 4 cohorts for analysis: (1) overall cohort, (2) thienopyridine (clopidogrel or prasugrel) load, (3) ticagrelor load, and (4) ticagrelor-consistent. The fourth cohort is a subset of cohort 3 that received ticagrelor throughout the index hospital stay and at discharge. We evaluated in-hospital clinical course and ischemic and bleeding outcomes in all patients and also 30-day outcomes in the ticagrelor-consistent cohort. RESULTS: A total of 3355 patients were enrolled, of whom 1087 had 30-day follow-up. The mean (±SD) age was 63.3 ± 12.5 years, and 62.6% were male. Thrombolysis in MI and Global Registry of Acute Coronary Events scores placed these patients in the intermediate risk range, and CRUSADE scores were in the moderate risk range. The LD in Utilization of Ticagrelor in the Upstream Setting for Non-ST-Segment Elevation Acute Coronary Syndrome was clopidogrel in 45.6%, ticagrelor in 53.6%, and prasugrel in 0.8%. The median upstream interval (LD to angiography) was 17:27 hours and did not change appreciably over the course of the data collection period (2/15-10/19). Access was radial in 48.6% and femoral in 51.4%. Postangiography management was medical only in 32.3%, percutaneous coronary intervention in 59.4%, and coronary artery bypass grafting in 8.3%. Median length of stay was 2.7 days, and median time from angiography to coronary artery bypass grafting was 3.6 days. In-hospital mortality was 0.51%, and major bleeding (thrombolysis in MI) was 0.24%; the in-hospital major adverse cardiovascular events rate was 0.7%, and stent thrombosis occurred in 0.18%. No significant differences were seen between the ticagrelor and clopidogrel cohorts in hospital, but 16% received more than 1 P2Y12i in-hospital. On follow-up (93.2% response), 86.7% of patients reported taking ticagrelor as directed. CONCLUSIONS: Upstream loading of P2Y12i was associated with very low rates of bleeding and short length of stay in a large cohort of non-ST elevation MI (NSTEMI) patients managed invasively.

The safety of oral anticoagulants registry (SOAR): A national, ED-based study of the evaluation and management of bleeding and bleeding concerns due to the use of oral anticoagulants.

OBJECTIVE: The Safety of Oral Anticoagulants Registry (SOAR) was designed to describe the evaluation and management of patients with oral anticoagulant (OAC)-related major bleeding or bleeding concerns who present to the emergency department (ED) with acute illness or injury. Patients in the ED are increasingly taking anticoagulants, which can cause bleeding-related complications as well as impact the acute management of related or unrelated clinical issues that prompt presentation. Modifications of emergency evaluation and management due to anticoagulation have not previously been studied. METHODS: This was a multicenter observational in-hospital study of patients who were judged to be experiencing an active OAC effect and had (a) an obvious bleeding event or (b) were deemed at risk for serious bleeding spontaneously, after injury, or during an indicated invasive procedure. Diagnostic testing, therapies employed, and clinical outcomes were collected. RESULTS: Thirty-one US hospitals contributed data to SOAR. Of 1513 subjects, acute hemorrhage (AH) qualified 78%, while 22% had a bleeding concern (BC). Warfarin was the index OAC in 37.3%, dabigatran in 13.3%, and an anti-Factor Xa in 49.4%. The most common sites of AH were gastrointestinal (51.0%) and intracranial (26.8%). In warfarin-treated patients, the mean (IQR) presenting INR was 3.1 (2.2, 4.8) in AH patients and 3.9 (2.4, 7.2) in BC patients. Three-fifths of SOAR patients were treated with factor repletion or specific reversal agents, and those patients had a longer length of stay. In addition, seven (0.76%) of the treated patients experienced an in-hospital thrombotic complication; two of these seven died on the index admission, both of fatal pulmonary embolism. Vitamin K was used and dosed inconsistently in both warfarin and NOAC cohorts. CONCLUSION: Care of anticoagulated patients in the acute care setting is inconsistent, reflecting the diversity of presentation. As the prevalence of OAC use increases with the aging of the US population, further study and targeted educational efforts are needed to drive more evidence-based care of these patients.

Flubendazole as a macrofilaricide: History and background.

Benzimidazole anthelmintics have long been employed for the control of soil-transmitted helminth infections. Flubendazole (FBZ) was approved in 1980 for the treatment of gastrointestinal nematode infections in both veterinary and human medicine. It has also long been known that parenteral administration of FBZ can lead to high macrofilaricidal efficacy in a variety of preclinical models and in humans. As part of an effort to stimulate the discovery and development of new macrofilaricides, particularly for onchocerciasis, research has recently been devoted to the development of new formulations that would afford high oral bioavailability of FBZ, paving the way for potential clinical development of this repurposed drug for the treatment of human filariases. This review summarizes the background information that led to this program and summarizes some of the lessons learned from it.

Efficacy and Safety of a Single-Dose Mebendazole 500 mg Chewable, Rapidly-Disintegrating Tablet for Ascaris lumbricoides and Trichuris trichiura Infection Treatment in Pediatric Patients: A Double-Blind, Randomized, Placebo-Controlled, Phase 3 Study.

This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of a new chewable, rapidly-disintegrating mebendazole (MBZ) 500 mg tablet for Ascaris lumbricoides and Trichuris trichiura infection treatment. Pediatric patients (1-15 years; N = 295; from Ethiopia and Rwanda) excreting A. lumbricoides and/or T. trichiura eggs were enrolled. The study had a screening phase (3 days), a double-blind treatment phase (DBP, 19 days), and an open-label phase (OLP, 7 days). Patients received MBZ or placebo on day 1 of DBP and open-label MBZ on day 19 ± 2 after stool sample collection. Cure rates (primary endpoint), defined as species-specific egg count of 0 at the end of DBP, were significantly higher in the MBZ group than placebo for A. lumbricoides (83.7% [72/86; 95% CI: 74.2%; 90.8%] versus 11.1% [9/81; 95% CI: 5.2%; 20.1%], P < 0.001) and for T. trichiura (33.9% [42/124; 95% CI: 25.6%; 42.9%] versus 7.6% [9/119; 95% CI: 3.5%; 13.9%], P < 0.001). Egg reduction rates (secondary endpoint) were significantly higher in the MBZ group than placebo for A. lumbricoides (97.9% [95% CI: 94.4; 99.9] versus 19.2% [95% CI: -5.9; 41.5]; P < 0.001) and T. trichiura (59.7% [95% CI: 33.9; 78.8] versus 10.5% [95% CI: -16.8; 32.9]; P = 0.003). Treatment-emergent adverse events (TEAEs) in MBZ group occurred in 6.3% (9/144) of patients during DBP and 2.5% (7/278) during OLP. No deaths, serious TEAEs, or TEAEs leading to discontinuations were reported. A 500 mg chewable MBZ tablet was more efficacious than placebo for the treatment of A. lumbricoides and T. trichiura infections in pediatric patients, and no safety concerns were identified.

Intrathecal 2-hydroxypropyl-ß-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.

BACKGROUND: Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-ß-cyclodextrins (HPßCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPßCD. METHODS: In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HPßCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPßCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPßCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range. FINDINGS: Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPßCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPßCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPßCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423). INTERPRETATION: Patients with NPC1 treated with intrathecal HPßCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPßCD. FUNDING: National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson.

Use of Electronic Clinical Decision Support and Hard Stops to Decrease Unnecessary Thyroid Function Testing.

NewYork-Presbyterian Brooklyn Methodist Hospital embarked on a Zero Unnecessary Study (ZEUS) initiative, whereby all aspects of clinical care were evaluated and strategies were implemented to mitigate waste. An opportunity was found in regards to thyroid function testing. It has been shown that certain TFTs are ordered far more often than clinically indicated. Free T3 (fT3) and Free T4 (fT4) are only indicated when the TSH is abnormal in the inpatient setting, with rare exceptions. Thus, a clinical algorithm for Clinical Decision Support (CDS) and Hard Stops (HS) were incorporated into the Electronic Medical Record (EMR) to prevent fT3 or fT4 to be ordered without an abnormal TSH, with certain predefined exceptions. In addition, a reflex rule was built which automatically orders (reflex) fT3 and fT4 if the TSH is abnormal. The pre and post-intervention ratios of fT3 and fT4 orders per total TSH orders were analyzed. Pre-intervention data revealed that fT4 was the most frequently ordered TFT laboratory test on admission, after TSH. Post-Intervention, there was a decrease in the ratio of fT4 to TSH orders (fT4/TSH) of 35.2%, from 44.6% to 28.9%. The percentage of fT4 ordered due to abnormal TSH increased by 126.1%, from 36.8% to 83.2%. The fT3 to TSH ordering ratio similarly decreased by 55.2%, from 6.2% to 2.9%. The decreases in both fT3/TSH and fT4/TSH ratios were statistically significant. Any unnecessary orders are a burden on healthcare. It is now possible to achieve goals that were not previously thought to be possible because of advancement in medicine and technology. By making small changes and saving costs, we can target our energy and resources toward effectively treating patients.

Evaluation of the diagnostic potential of urinary N-Acetyltyramine-O,ß-glucuronide (NATOG) as diagnostic biomarker for Onchocerca volvulus infection.

BACKGROUND: Onchocerciasis, also known as river blindness is one of the neglected tropical diseases affecting millions of people, mainly in sub-Saharan Africa and is caused by the filarial nematode Onchocerca volvulus. Efforts to eliminate this disease are ongoing and are based on mass drug administration programs with the microfilaricide ivermectin. In order to monitor the efficacy of these programs, there is an unmet need for diagnostic tools capable of identifying infected patients. We have investigated the diagnostic potential of urinary N-acetyltyramine-O,ß-glucuronide (NATOG), which is a promising O. volvulus specific biomarker previously identified by urine metabolome analysis. METHODS: A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was used to assess the stability characteristics of NATOG and to evaluate the levels of NATOG in study samples. An LC-fluorescence method was also developed. RESULTS: Stability characteristics of NATOG were investigated and shown to be ideally suited for use in tropical settings. Also, an easy and more accessible method based on liquid chromatography coupled to fluorescence detection was developed and shown to have the necessary sensitivity (limit of quantification 1 µM). Furthermore, we have evaluated the levels of NATOG in a population of 98 nodule-positive individuals from Ghana with no or low levels of microfilaria in the skin and compared them with the levels observed in different control groups (endemic controls (n = 50), non-endemic controls (n = 18) and lymphatic filariasis (n = 51). Only a few (5 %) of nodule-positive individuals showed an increased level (> 10 µM) of NATOG and there was no statistical difference between the nodule-positive individuals and the control groups (P > 0.05). CONCLUSIONS: Results of the present study indicate the limited potential of NATOG as a diagnostic biomarker for O. volvulus infection in amicrofilaridermic individuals.

Collaborative development of 2-hydroxypropyl-ß-cyclodextrin for the treatment of Niemann-Pick type C1 disease.

In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Sciences (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-ß-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-ß-CD for the benefit of the NPC patient community.

Maintenance of efficacy and safety of rabeprazole in children with endoscopically proven GERD.

OBJECTIVE: The aim of the present study was to evaluate 24-week maintenance of efficacy and safety of rabeprazole in children with endoscopically proven gastroesophageal reflux disease (GERD). METHODS: Children ages 1 to 11 years who achieved endoscopic/histologic healing (defined as grade 0 of the Hetzel-Dent Classification scale and/or grade 0 of the Histological Features of Reflux Esophagitis scale) in a 12-week treatment phase were continued on the same dose for an additional 24 weeks during the maintenance phase. The dose was determined by weight: children weighing 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children weighing ≥ 15 kg (high-weight cohort) received 10 or 20 mg. RESULTS: Healing was maintained in 90% of children (100% [low-weight cohort]; 89% [10 mg, high-weight cohort]; 85% [20 mg, high-weight cohort]). The Total GERD Symptom and Severity score continued to improve slightly in all of the children across all dose groups (P = 0.026) during the maintenance phase, except the 10-mg dose group (low-weight cohort), which experienced a slight worsening of 3.6 points. Overall, 71% children felt better on the GERD Symptom Relief score (P < 0.001); 95% of investigators and 92% of parent/caregivers rated "Good to Excellent" on the Global Treatment Satisfaction scale and Clinical Global Impressions Improvement scale, respectively. Overall incidence of treatment-emergent adverse events was 63%; upper respiratory tract infections (13%) and vomiting (11%) were the most commonly reported (>10%). CONCLUSIONS: Rabeprazole was effective in maintaining endoscopic/histologic healing during a 24-week maintenance period in children with endoscopically proven GERD. The clinical effect and safety profile were largely similar across dose groups.

CaseBook challenges: Managing gout, hyperuricemia and comorbidities -- dialogue with the experts.

The prevalence of gout and hyperuricemia are on the rise in the United States corresponding with an increase in risk factors for these conditions, such as obesity, metabolic syndrome, and the use of diuretics. A progressive disorder, untreated gout can be debilitating and result in tophi, chronic arthropathy, and recurrent kidney stones. Although joint aspiration is needed for a definitive diagnosis, the majority of patients are diagnosed presumptively based on medical history and presentation with characteristic signs and symptoms. Patients with gout also often have multiple comorbidities, and there is an increasing body of evidence that shows hyperuricemia is associated with incidence hypertension, diabetes, chronic kidney disease, and heart failure. Clinical strategies for the management of gout and hyperuricemia must include considerations for these and other common cardiometabolic and renal conditions. In addition to acute flare therapy and prophylaxis, the treatment of gout involves lowering serum uric acid (SUA) levels with the urate-lowering therapies (ULTs) allopurinol or febuxostat. Once begun, treatment with ULT is lifelong. However, inadequate dosing and patient nonadherence or intolerance to therapy often lead to treatment failure. Recent guidelines from the American College of Rheumatology stress tailoring therapy and target SUA level (traditionally <6 mg/dL, but lower levels may be needed for certain patients) based on gout severity and the presence of comorbid conditions. Because painful acute gout flares may result in trips to the emergency department and because the majority of gout cases are managed in primary care, it is important for clinicians practicing in these settings to be able to diagnose and treat this condition and communicate with patients to improve their understanding of the disease process and adherence to treatment.

Efficacy and safety of rabeprazole in children (1-11 years) with gastroesophageal reflux disease.

OBJECTIVE: Evaluate the efficacy and safety of rabeprazole in children, 1 to 11 years old, with endoscopically/histologically proven gastroesophageal reflux disease (GERD). METHODS: Children were randomized to 0.5- or 1.0-mg/kg rabeprazole granule formulation for 12 weeks. The dose was further determined by weight: children 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children ≥15 kg (high-weight cohort) received 10 or 20 mg. The primary endpoint was endoscopic/histologic healing at week 12 (defined as grade 0 on the Hetzel-Dent classification scale and/or grade 0 on the Histological Features of Reflux Esophagitis scale). RESULTS: Overall, 81% (87/108) achieved endoscopic/histologic healing at week 12 with higher healing in the low-weight cohort (82% [5-mg dose], 94% [10-mg dose]) compared with high-weight cohort (76% [10-mg dose], 78% [20-mg dose]). There was a significant (P < 0.001) decrease in the mean Total GERD Symptoms and Severity score from 19.7 points (baseline) to 8.6 points (week 12), with 26% fewer children reporting GERD symptoms at week 12. The average frequency of symptoms per child decreased from 7.7 (week 1) to 4.7 (week 12). The GERD Symptom Relief score showed that 71% of children felt better, 81% were rated "good to excellent" on the Global Treatment Satisfaction scale by the investigator; 77% were rated "good to excellent" on the Clinical Global Impressions-Improvement scale by the parent/caregiver. The most common (>10%) treatment-emergent adverse events included cough and vomiting (14% each), abdominal pain (12%), and diarrhea (11%). CONCLUSIONS: Rabeprazole was effective and safe in 1- to 11-year-old children with GERD.

Burn disaster response planning in New York City: updated recommendations for best practices.

Since its inception in 2006, the New York City (NYC) Task Force for Patients with Burns has continued to develop a city-wide and regional response plan that addressed the triage, treatment, transportation of 50/million (400) adult and pediatric victims for 3 to 5 days after a large-scale burn disaster within NYC until such time that a burn center bed and transportation could be secured. The following presents updated recommendations on these planning efforts. Previously published literature, project deliverables, and meeting documents for the period of 2009-2010 were reviewed. A numerical simulation was designed to evaluate the triage algorithm developed for this plan. A new, secondary triage scoring algorithm, based on co-morbidities and predicted outcomes, was created to prioritize multiple patients within a given acuity and predicted survivability cohort. Recommendations for a centralized patient and resource tracking database, plan operations, activation thresholds, mass triage, communications, data flow, staffing, resource utilization, provider indemnification, and stakeholder roles and responsibilities were specified. Educational modules for prehospital providers and nonburn center nurses and physicians who would provide interim care to burn injured disaster victims were created and pilot tested. These updated best practice recommendations provide a strong foundation for further planning efforts, and as of February 2011, serve as the frame work for the NYC Burn Surge Response Plan that has been incorporated into the New York State Burn Plan.

Efficacy and safety of PANCREAZE® for treatment of exocrine pancreatic insufficiency due to cystic fibrosis.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) is critical for correction of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF). METHODS: This was a randomized, placebo-controlled PERT withdrawal study evaluating the efficacy and safety of PANCREAZE® (pancrelipase) in CF patients with EPI. Participants (n=49) entered an open-label, ≤ 14 day run-in phase, maintained a high-fat diet (100 ± 15 g/day), and received PANCREAZE® (10.5 or 21). Participants with a coefficient of fat absorption (CFA)≥ 80% (n=40) were then randomized (1:1) to receive either PANCREAZE® or placebo during a double-blind, ≤ 7 day withdrawal phase. RESULTS: PANCREAZE® improved fat absorption as shown by significantly lower mean ± SD change in CFA between open-label and double-blind phases for PANCREAZE® (-1.5 ± 5.88%; p<0.001) compared to placebo (-34.1 ± 23.03%). Protein absorption was similarly improved. No unexpected adverse events were reported. CONCLUSIONS: This study demonstrated PANCREAZE® was effective in treating EPI due to CF and was safe and well tolerated.

Enhancing the diagnostic performance of troponins in the acute care setting.

BACKGROUND: Current guidelines define cardiac troponin I (TnI) as an indicator of necrosis when the concentration exceeds the 99% upper limit of a healthy reference population, a reference value near the assay's lowest detectable level. We assessed the utility of a modified TnI cutoff point derived from a population at low risk for coronary artery disease (CAD) and evaluated its utility in determining acute myocardial infarction (MI). METHODS: A modified TnI cutoff point was derived by the receiver operating characteristic (ROC) curve from 737 consecutive patients who underwent serial TnI measurements for exclusion of MI. Creatinine kinase isoenzyme MB (CK-MB) evolutionary change was used to define MI. The new derived cutoff point was validated using another subset of 320 patients who were evaluated for MI. RESULTS: ROC-derived TnI cutoff point (A) was 0.65 µg/L, and its performance was compared to the recommended cutoff point ([B] 0.15 µg/L). Cutoff point A had greater specificity (94.5% vs. 86.9%, p < 0.001) but slightly lower sensitivity (96.5% vs. 100%, p < 0.01). Cutoff point A provided significantly greater positive predictive value (PPV) for MI (74.1% vs. 55.5%, p < 0.0001) and fewer false-positive errors, while preserving comparable negative predictive value (NPV) (98.9% vs. 100%). CONCLUSION: A higher cutoff point derived from a reference population of patients at low risk for CAD may improve the TnI performance assay. The PPV for diagnosis of MI was significantly higher and false-positive values were fewer without affecting the NPV. The more reliable diagnosis of MI may have resulted, which, in turn, may have significant clinical and economic implications.

Burn disaster response planning: an urban region's approach.

The objective of this study was to describe a draft response plan for the tiered triage, treatment, or transportation of 400 adult and pediatric victims (50/million population) of a burn disaster for the first 3 to 5 days after injury using regional resources. Review of meeting minutes and the 11 deliverables of the draft response plan was performed. The draft burn disaster response plan developed for NYC recommended: 1) City hospitals or regional burn centers within a 60-mile distance be designated as tiered Burn Disaster Receiving Hospitals (BDRH); 2) these hospitals be divided into a four-tier system, based on clinical resources; and 3) burn care supplies be provided to Tier 3 nonburn centers. Existing burn center referral guidelines were modified into a hierarchical BDRH matrix, which would vector certain patients to local or regional burn centers for initial care until capacity is reached; the remainder would be cared for in nonburn center facilities for up to 3 to 5 days until a city, regional, or national burn bed becomes available. Interfacility triage would be coordinated by a central team. Although recommendations for patient transportation, educational initiatives for prehospital and hospital providers, city-wide, interfacility or interagency communication strategies and coordination at the State or Federal levels were outlined, future initiatives will expound on these issues. An incident resulting in critically injured burn victims exceeding the capacity of local and regional burn center beds may be a reality within any community and warrants a planned response. To address this possibility within New York City, an initial draft of a burn disaster response has been created. A scaleable plan using local, state, regional, or federal health care and governmental institutions was developed.

Assessment of pharmacokinetics and pharmacodynamic effects related to abuse potential of a unique oral osmotic-controlled extended-release methylphenidate formulation in humans.

This was a double-blind, placebo-controlled, randomized, 5-period crossover study in 49 healthy subjects with a history of light (occasional) recreational stimulant use, to evaluate the abuse-related subjective effects of oral osmotic-controlled extended-release methylphenidate with comparable doses of immediate-release methylphenidate. Healthy subjects with a history of light recreational stimulant use were enrolled in the study if they demonstrated a positive response to a 20-mg dose of d-amphetamine and a negative placebo response. Enrolled subjects received single doses of placebo, 54 and 108 mg osmotic-controlled extended-release methylphenidate, and 50 and 90 mg immediate-release methylphenidate. For each treatment, pharmacokinetics, pharmacodynamics, and safety were assessed for 24 hours. Subjective data were collected through standard questionnaires and visual analog scales for positive, stimulant, negative, and other effects. Immediate-release and osmotic-controlled extended-release methylphenidate produced expected plasma concentration-time profiles of d-methylphenidate. Both doses of immediate-release methylphenidate (50 and 90 mg) produced statistically significantly higher subjective effects (eg, positive, stimulant) with respect to placebo for all measures. The higher osmotic-controlled extended-release methylphenidate dose of 108 mg also produced statistically significant differences from placebo for most measures. However, the most commonly prescribed therapeutic dose of osmotic-controlled extended-release methylphenidate (54 mg) did not produce significant differences from placebo for most measures. In addition, for comparable dose levels, osmotic-controlled extended-release methylphenidate produced lower positive and stimulant subjective effects than immediate-release methylphenidate, and low-dose immediate-release methylphenidate (50 mg) produced greater subjective effects than high-dose osmotic-controlled extended-release methylphenidate, with many effects demonstrating statistically significant differences. These data support the hypothesis that a formulation can modulate abuse potential by controlling the rate and extent of drug delivery.