Long-Lived Electronic Coherences in Molecules.

We demonstrate long-lived electronic coherences in molecules using a combination of measurements with shaped octave spanning ultrafast laser pulses and calculations of the light matter interaction. Our pump-probe measurements prepare and interrogate entangled nuclear-electronic wave packets whose electronic phase remains well defined despite vibrational motion along many degrees of freedom. The experiments and calculations illustrate how coherences between excited states can survive, even when coherence with the ground state is lost, and may have important implications for many areas of attosecond science and photochemistry.

Iatrogenic haemoperitoneum requiring transfusion after ventriculoperitoneal shunt placement: case report.

Cerebrospinal fluid (CSF) diversion for hydrocephalus via ventriculoperitoneal (VP) shunting is one of the most commonly performed neurosurgical procedures. Unfortunately, VP shunting also carries a high complication rate. While long-term complications of VP shunting are generally well-described, the literature on more acute, iatrogenic injury during shunt placement is essentially limited to easily identifiable intracranial bleeds. Herein is presented the first reported case of iatrogenic abdominal wall vessel injury as a consequence of blind distal VP shunt catheter placement causing a critical haemoperitoneum that necessitated multiple transfusions. Presentation and recognition of this bleed was delayed as it occurred over a number of days. Injury to the inferior epigastric artery, or potentially a distal branch of the superficial epigastric artery, is suspected to have occurred during either blind subcutaneous tunnelling of the shunt catheter passage or during penetration of the peritoneum. Haemoperitoneum as a potential complication of procedures involving manipulation or penetration of the abdominal wall (i.e. paracentesis) is well-described in the medical and general surgical literature, and ultrasound-guidance has been widely adopted to mitigate bleeding in these cases. Familiarity with intra-abdominal haemorrhage as a potential complication of VP shunting and an understanding of its presentation is critical for timely identification of this phenomenon. Furthermore, the use of real-time ultrasound-guidance for tunnelling and distal shunt catheter placement may decrease the incidence of intrabdominal complications after shunt placement more generally and should be considered an area of future study.

Investigational New Drug Enabling Nonclinical Safety Pharmacology Assessment of the Iminosugar UV-4, a Broad-Spectrum Host-Targeted Antiviral Agent.

UV-4 (N-(9-methoxynonyl)-1-deoxynojirimycin) is a broad-spectrum antiviral drug candidate with demonstrated activity in vitro and in vivo against multiple, diverse viruses. Nonclinical safety pharmacology studies were conducted to support the filing of an Investigational New Drug (IND) application. Preliminary in vitro pharmacology testing evaluating potential for binding to "off-target" receptors and enzymes indicated no significant liability for advanced development of UV-4. The safety pharmacology of UV-4 was evaluated in the in vitro human ether-à-go-go-related gene (hERG) assay, in a central nervous system (CNS) study in the mouse (modified Irwin test), in a respiratory safety study in conscious mice using whole body plethysmography, and in a cardiovascular safety study in conscious, radiotelemetry-instrumented beagle dogs. There were no observed adverse treatment-related effects following administration of UV-4 as the hydrochloride salt in the hERG potassium channel assay, on respiratory function, in the CNS study, or in the cardiovascular assessment. Treatment-related cardiovascular effect of decreased arterial pulse pressure after 50 or 200 mg of UV-4/kg was the only change outside the normal range, and all hemodynamic parameters returned to control levels by the end of the telemetry recording period. These nonclinical safety pharmacology assessments support the evaluation of this host-targeted broad-spectrum antiviral drug candidate in clinical studies.

Investigational New Drug Enabling Nonclinical Safety Assessment of the Iminosugar UV-4, a Broad-Spectrum Host-Targeted Antiviral Agent.

The iminosugar UV-4 is a broad-spectrum antiviral drug candidate with activity in vitro and in vivo against multiple, diverse viruses. The toxicological profile of UV-4, dosed as the hydrochloride salt, was evaluated in single-dose and repeat-dose oral toxicity studies in mice, rats, dogs, and non-human primates (NHP). No moribundity or deaths were associated with the drug up to the maximum tolerated dose. No treatment-related adverse effects were observed following single oral doses in dogs, rats, and mice up to 250, 400, 1000 mg/kg, respectively, and in NHP up to 180 mg/kg administered three times daily for 10 days. UV-4-related findings were generally seen at higher doses after 7- or 14-day exposure. The most common clinical pathology findings (increase in aspartate aminotransferase and decreased platelet count) were consistently found across species and each appeared dose related. The kidney, mesenteric lymph nodes, stomach including gastrointestinal tract, and thymus were identified as target organs in mice, rats, and dogs. In 14-day repeat-dose toxicology studies in mice and dogs conducted in compliance with Good Laboratory Practice regulations, the dog was considered to be the most sensitive species to UV-4 exposure based on the treatment-related adverse effects noted in the identified target organs. The results of these studies demonstrate the safety profile of UV-4 hydrochloride and supported the selection of starting and maximal doses for a single ascending dose first-in-human clinical study.

Coherent Control of Internal Conversion in Strong-Field Molecular Ionization.

We demonstrate coherent control over internal conversion during strong-field molecular ionization with shaped, few-cycle laser pulses. The control is driven by interference in different neutral states, which are coupled via non-Born-Oppenheimer terms in the molecular Hamiltonian. Our measurements highlight the preservation of electronic coherence in nonadiabatic transitions between electronic states.

What's New in the Management of Foot Deformities in Children With Cerebral Palsy.

BACKGROUND: Foot deformities have been frequently reported in cerebral palsy (CP), and numerous diagnostic modalities and treatment options have recently been developed to achieve a better level of management for children with CP. METHODS: A thorough search of the English literature, published between January 2013 and March 2016, was performed. A summary of the new findings that had not previously described was reported. The review included recent advances regarding clinical and gait evaluation, orthotic management, botulinum toxin A treatment, and surgical correction. RESULTS: The review summarized new findings reported in 46 articles and abstracts that were published between January 2013 and March 2016. Older articles were included and cited when an original description was mentioned, or when a change or development of some findings was discussed. CONCLUSIONS: Foot deformity forms an essential part of evaluating children with CP. Dramatic advances have been achieved in gait assessment, conservative management, and surgical correction. Promising results have been reported with the goal to reach a higher level of orthopaedic care and optimize the functional potentials for children with CP. LEVEL OF EVIDENCE: Level IV-literature review.

The Utility of High-Fidelity Simulation for Training Critical Care Fellows in the Management of Extracorporeal Membrane Oxygenation Emergencies: A Randomized Controlled Trial.

OBJECTIVE: Although extracorporeal membrane oxygenation volume has increased, proficiency in the technology requires extensive training. We compared traditional water-drill-based extracorporeal membrane oxygenation training with simulation-based extracorporeal membrane oxygenation training with the hypothesis that simulation-based training is superior. DESIGN: Randomized controlled trial. SETTING: Academic medical center. SUBJECTS: Pulmonary/critical care fellows. INTERVENTIONS: Participants had a preintervention simulated extracorporeal membrane oxygenation emergency (Sim1-recirculation) then randomized into simulation and traditional groups. Each group participated in three teaching scenarios, via high-fidelity simulation or via water-drills. After 6 weeks and after 1 year, participants returned for two simulated extracorporeal membrane oxygenation emergencies (Sim2-pump failure and Sim3-access insufficiency). Sim2 was a case encountered during teaching, whereas Sim3 was novel. A critical action, necessary for resolution of each scenario, was preidentified for timing. MEASUREMENTS AND MAIN RESULTS: Primary outcome was time required to perform critical actions. Twenty-one fellows participated in the study (simulation, 10; traditional, 11). Groups had similar scenario scores (p = 0.4) and times to critical action (p = 0.8) on Sim1. At 6 weeks, both groups had similar scenario scores on Sim2 (p = 0.5), but the simulation group scored higher on Sim3 (p = 0.03). Times to critical actions were shorter in the simulation group during Sim2 (127 vs 174 s, p = 0.004) and Sim3 (159 vs 300 s; p = 0.04). These findings persisted at 1 year. CONCLUSIONS: In novice critical care fellows, simulation-based extracorporeal membrane oxygenation training is superior to traditional training. Benefits transfer to novel scenarios and are maintained over the long term. Further studies evaluating the utility of simulation in other learner groups and for maintenance of proficiency are required.

Chest Intensive Care Unit Imaging: Pearls and Pitfalls.

Imaging plays a major role in the care of the intensive care unit (ICU) patients. An understanding of the monitoring devices is essential for the interpretation of imaging studies. An awareness of their expected locations aids in identifying complications in a timely manner. This review describes the imaging of ICU monitoring and support catheters, tubes, and pulmonary and cardiac devices, some more commonly encountered and others that have been introduced into clinical patient care more recently. Special focus will be placed on chest radiography and potential pitfalls encountered.

Treatment of proximal tibial buckle fractures: removable knee immobilizer versus long leg cast.

The purpose of this study was to compare outcomes and management of patients with buckle fractures of the proximal tibia treated with either a knee immobilizer or a long leg cast (LLC). A retrospective review was performed of pediatric patients with a buckle fracture of the proximal tibia over a 5-year period. Two cohorts were included, those treated with a LLC versus a removable knee immobilizer. Data collected included immobilization type, fracture laterality, length of immobilization, number of clinic visits, fracture displacement, and complications. Differences in complications and management between the cohorts were evaluated. In total, 224 patients met inclusion criteria (58% female, mean age 3.1 years ± 1.7 years). Of these patients, 187 patients (83.5%) were treated with a LLC. No patients in either group were found to have interval fracture displacement during treatment. Seven patients (3.1%) demonstrated skin complications, all in the LLC cohort. Mean length of immobilization was shorter for those treated in a knee immobilizer at 25.9 days versus 27.9 days for the LLC cohort (P = 0.024). Total number of clinic visits was also less at 2.2 (SD ±â€…0.4 days) for the knee immobilizer and 2.6 (SD ±â€…0.7 days) for the LLC (P = 0.001) cohorts. Pediatric patients with proximal tibial buckle fractures can be safely managed with a knee immobilizer. This treatment method is associated with a shorter duration of immobilization and fewer clinic visits without incidence of fracture displacement. In addition, knee immobilizers can lessen skin issues associated with cast immobilization and cast-related office visits. This is a Level III evidence, retrospective comparative study.

A phase I/II study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B.

BackgroundSanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS levels, prevent brain atrophy, and potentially delay cognitive decline.MethodsIn this phase I/II open-label study, patients with MPS type IIIB (n = 22) were treated with tralesinidase alfa administered i.c.v. The patients were monitored for drug exposure; total HS and HS nonreducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma; anti-drug antibody response; brain, spleen, and liver volumes as measured by MRI; and cognitive development as measured by age-equivalent (AEq) scores.ResultsIn the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV.ConclusionAdministration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy.Trial registrationClinicaltrials.gov NCT02754076.FUNDINGBioMarin Pharmaceutical Inc. and Allievex Corporation.

A simple approach for characterizing the spatially varying sensitivity of microchannel plate detectors.

We present a simple approach to characterize the spatial variation of the gain in microchannel plate (MCP) coupled to phosphor detectors using single electron or photon hits. The technique is easy to implement and general enough to be extended to other kinds of detectors. We demonstrate the efficacy of the approach on both laboratory and Monte Carlo generated datasets. Furthermore, we use the approach to measure the variation in gain over time as the MCP is exposed to an increasing number of electrons.

Reproductive and developmental toxicology studies of iminosugar UV-4.

UV-4 (N-(9-methoxynonyl)-1-deoxynojirimycin) is a host-targeted antiviral agent, which targets mammalian proteins (endoplasmic reticulum glucosidases) rather than virally encoded proteins. This mechanism confers both broad-spectrum activity and low potential for generation of viral drug resistance mutations. Reproductive and developmental studies of UV-4 evaluated effects on fertility and early embryonic development in rats, embryo-fetal development in rats and rabbits, and pre- and postnatal development including maternal function in rats. All reproductive and developmental studies conducted achieved dose levels where parental toxicity (generally decreased body weight, decreased food consumption and adverse clinical signs) were observed. Toxicokinetic evaluations confirmed UV-4 crossed the placenta exposing fetal rats and rabbits in utero. Adverse findings in reproductive and developmental studies included decreases in sperm motility with histopathology correlates, visceral and skeletal malformations, changes in eye opening, air drop reflex, vaginal opening and preputial separation. The combined results of the fertility and early embryonic developmental study and pre- and postnatal study suggested that there may be an increased risk for male fertility. These effects are similar to those reported in pre-clinical studies of the structurally related drug Miglustat (N-butyl-1-deoxynojirimycin), therefore UV-4 may have risk of developmental or reproductive adverse outcomes in humans similar to existing approved agents in this drug class.

Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects.

BACKGROUND: UV-4 (N-(9'-methoxynonyl)-1-deoxynojirimycin, also called MON-DNJ) is an iminosugar small-molecule oral drug candidate with in vitro antiviral activity against diverse viruses including dengue, influenza, and filoviruses and demonstrated in vivo efficacy against both dengue and influenza viruses. The antiviral mechanism of action of UV-4 is through inhibition of the host endoplasmic reticulum-resident α-glucosidase 1 and α-glucosidase 2 enzymes. This inhibition prevents proper glycan processing and folding of virus glycoproteins, thereby impacting virus assembly, secretion, and the fitness of nascent virions. METHODOLOGY/PRINCIPAL FINDINGS: Here we report a first-in-human, single ascending dose Phase 1a study to evaluate the safety, tolerability, and pharmacokinetics of UV-4 hydrochloride (UV-4B) in healthy subjects (ClinicalTrials.gov Identifier NCT02061358). Sixty-four subjects received single oral doses of UV-4 as the hydrochloride salt equivalent to 3, 10, 30, 90, 180, 360, 720, or 1000 mg of UV-4 (6 subjects per cohort), or placebo (2 subjects per cohort). Single doses of UV-4 hydrochloride were well tolerated with no serious adverse events or dose-dependent increases in adverse events observed. Clinical laboratory results, vital signs, and physical examination data did not reveal any safety signals. Dose-limiting toxicity was not observed; the maximum tolerated dose of UV-4 hydrochloride in humans has not yet been determined (>1000 mg). UV-4 was rapidly absorbed and distributed after dosing with the oral solution formulation used in this study. Median time to reach maximum plasma concentration ranged from 0.5-1 hour and appeared to be independent of dose. Exposure increased approximately in proportion with dose over the 333-fold dose range. UV-4 was quantifiable in pooled urine over the entire collection interval for all doses. CONCLUSIONS/SIGNIFICANCE: UV-4 is a host-targeted broad-spectrum antiviral drug candidate. At doses in humans up to 1000 mg there were no serious adverse events reported and no subjects were withdrawn from the study due to treatment-emergent adverse events. These data suggest that therapeutically relevant drug levels of UV-4 can be safely administered to humans and support further clinical development of UV-4 hydrochloride or other candidate antivirals in the iminosugar class. TRIAL REGISTRATION: ClinicalTrials.gov NCT02061358 https://clinicaltrials.gov/ct2/show/NCT02061358.

Simulation-based uptraining improves provider comfort in the management of critically ill patients with COVID-19.

PURPOSE: The COVID-19 surge required the deployment of large numbers of non-intensive care providers to assist in the management of the critically ill. Institutions took a variety of approaches to "uptraining" such providers though studies describing methods and effectiveness are lacking. MATERIALS AND METHODS: One hundred and seventy-five providers underwent a 3 h simulation-based session focused on management of shock, mechanical ventilation, acute respiratory distress syndrome, and critical care ultrasound. All participants were sent surveys to assess their comfort with various aspects of critical care following return to their usual work environments. RESULTS: One hundred and eight providers of 175 (62%) completed the survey. Overall, 104/108 responders (96%) felt training either significantly or somewhat improved their knowledge in the management of ICU patients. Responders felt most comfortable in the management of hypoxemia in intubated patients and the management of ventilated patients with acute respiratory distress syndrome (93% strongly agree or agree, and 86% strongly agree or agree, respectively). Fewer responders felt more comfortable using focused echocardiography (70% strongly agree or agree) and lung ultrasonography in following progression of COVID-19 (76% strongly agree or agree). CONCLUSIONS: Simulation-based training improved provider comfort in the management of critically ill patients with COVID-19.

Simulation-Based Up-Training in Response to the COVID-19 Pandemic.

STATEMENT: The dramatic outbreak of COVID-19 placed unprecedented strain on the critical care workforce of New York City. The enhanced precautions required to safely care for COVID-19 patients impacted the performance of even routine critical care procedures. Meanwhile, staff were stretched to care for exponentially rising case volume as COVID intensive care units (ICUs) expanded. Simulation was used to bridge these gaps-first to familiarize personnel within the Division of Pulmonary and Critical Care with revised COVID-19 care procedures, then to orient noncritical care clinicians volunteering from other specialties for COVID ICU deployment to general critical care and COVID-19 care principles. Using mannequin-based simulation scenarios followed by comprehensive debriefing sessions, simulation participants received high-intensity, high-fidelity training in respiratory failure, circulatory failure, bedside ultrasound, bedside ICU procedures, and elements of COVID-19-specific care. More than 200 physicians and advanced practice practitioners completed simulation training in preparation for deployment, supplementing and enhancing the ICU workforce at a decisive time during the outbreak.

Development and Evaluation of a Cognitive Aid Booklet for Use in Rapid Response Scenarios.

INTRODUCTION: Rapid response teams (RRTs) have become ubiquitous among hospitals in North America, despite lack of robust evidence supporting their effectiveness. Many RRTs do not yet use cognitive aids during these high-stakes, low-frequency scenarios, and there are no standardized cognitive aids that are widely available for RRTs on medicine patients. We sought to design an emergency manual to improve resident performance in common RRT calls. METHODS: Residents from the New York University School of Medicine Internal Medicine Residency Program were asked to volunteer for the study. The intervention group was provided with a 2-minute scripted informational session on cognitive aids as well as access to a cognitive aid booklet, which they were allowed to use during the simulation. RESULTS: Resident performance was recorded and scored by a physician who was blinded to the purpose of the study using a predefined scoring card. Residents in the intervention group performed significantly better in the simulated RRT, by overall score (mean score = 7.33/10 and 6.26/10, respectively, P = 0.02), and by performance on the two critical interventions, giving the correct dose of naloxone (89% and 39%, respectively, P < 0.001) and checking the patient's blood glucose level (93% and 52%, respectively, P = 0.001). CONCLUSIONS: In a simulated scenario of opiate overdose, internal medicine residents who used a cognitive aid performed better on critical tasks than those residents who did not have a cognitive aid. The use of an appropriately designed cognitive aid with sufficient education could improve performance in critical scenarios.

The prognostic significance of horizontal plane QRS axis in elderly heart failure.

In order to investigate whether horizontal plane QRS axis predicts the prognosis in elderly heart failure, we studied 80 consecutive patients by clinical assessment, ECG, Doppler and echocardiography. All patients were followed up for 2 years, 12 died and 68 survived. Age, gender distribution, blood pressure, co-existing diagnoses and medication were all similar between those who died and those who survived. The NYHA classification was significantly worse, left ventricular (LV) cavity size was greater, LV systolic function was lower in those who died than in survivors, despite similar LV wall thickness. On ECG, heart rate, PR interval, QT interval and frontal QRS axis did not differ between the two groups. The QRS duration was significantly longer and the horizontal QRS axis projected to a substantially more posterior direction in those who died than in survivors. The sensitivity and specificity of a horizontal QRS axis < or =-30 degrees for predicting death in 2 years were 75% and 62%, respectively. The former is above the sensitivity of a NYHA > or =3 and the latter is above the specificity of a LV shortening fraction < or =20%. The combination of a QRS horizontal axis < or =-30 degrees and NYHA > or =3 predicted 2 year mortality with a sensitivity of 75% and specificity of 91%. In conclusion, a left posterior QRS axis of the horizontal plane in elderly heart failure indicates an adverse prognosis, particularly when combined with NYHA classification and echocardiographic assessment.

Goal-Directed Transthoracic Echocardiography During Advanced Cardiac Life Support: A Pilot Study Using Simulation to Assess Ability.

INTRODUCTION: Goal-directed echocardiography (GDE) is used to answer specific clinical questions that provide invaluable information to physicians managing a hemodynamically unstable patient. We studied perception and ability of house staff previously trained in GDE to accurately diagnose common causes of cardiac arrest during simulated advanced cardiac life support (ACLS); we compared their results with those of expert echocardiographers. METHODS: Eleven pulmonary and critical care medicine fellows, 7 emergency medicine residents, and 5 cardiologists board certified in echocardiography were enrolled. Baseline ability to acquire 4 transthoracic echocardiography views was assessed, and participants were exposed to 6 simulated cardiac arrests and were asked to perform a GDE during ACLS. House staff performance was compared with the performance of 5 expert echocardiographers. RESULTS: Average baseline and scenario views by house staff were of good or excellent quality 89% and 83% of the time, respectively. Expert average baseline and scenario views were always of good or excellent quality. House staff and experts made the correct diagnosis in 68% and 77% of cases, respectively. On average, participants required 1.5 pulse checks to make the correct diagnosis. Of house staff, 94% perceived this study as an accurate assessment of ability. CONCLUSIONS: In an ACLS-compliant manner, house staff are capable of diagnosing management-altering pathologies the majority of the time, and they reach similar diagnostic conclusions in the same amount of time as expert echocardiographers in a simulated cardiac arrest scenario.

Compliance issues in manufacturing of drugs.

The therapeutic process relies on the assumption that the prescription written by the clinician is what is dispensed to the patient. In this article, we review the many factors involved in the manufacture of pharmaceutical products so that they consistently meet quality standards as approved by regulatory agencies. Industry and government agencies have developed procedures and laws to assure quality in Chemistry, Manufacturing and Controls (CMC) for pharmaceuticals, addressing conditions that may be harmful to patient health. This includes procedures for receipt of materials, production, packaging, labeling, quality control, release, storage and distribution, known as current Good Manufacturing Practice. Special control considerations for ophthalmic products include foreign particulate matter control, preservative effectiveness tests, sterility and leaching of chemicals from the packaging into the product. We also describe the "form, fill and seal" manufacture process as used in unit-dose, non-preserved ophthalmic products; product expiration dates; stages of drug development; and financial considerations for pharmaceutical companies.