A Proposal to Increase Value and Equity in the Development and Distribution of New Pharmaceuticals.

The process of developing and marketing new pharmaceuticals in the United States is driven by a need to maximize returns to shareholders. This results all too often in the production of new medications that are expensive and of marginal value to patients and society. In line with our heightened awareness of the importance of social justice and public health-and in light of our government's alliance with private companies in bringing us COVID-19 vaccines-we need to reconsider how new pharmaceuticals are developed and distributed. Accordingly, we propose the creation of a new agency of the Food and Drug Administration (FDA) that would direct the whole process. This agency would fund the research and development of high-value medications, closely monitor the clinical studies of these new drugs, and manage their distribution at prices that are value-based, fair, and equitable.

Does Coaching Hospitalists in a Community Hospital Improve the Measured Experience of Care?

Hospitals initiate physician communication training programs expecting to improve patient experience measures. However, most efforts have relied on methods with limited attention to bedside physician-patient interactions. We conducted an intensive in-person hospitalist coaching program to improve patient experience in a community hospital. Full-time hospitalists were coached twice monthly by physician-coaches using a structured process featuring direct observation of care and immediate recommendations. Coach-observed care measures improved marginally. Difference-in-differences analysis of 1137 Hospital Consumer Assessment of Healthcare Providers and Systems surveys revealed no significant improvements by trained hospitalists in preintervention versus intervention comparisons, calling into question the strategy of using coaching programs to improve hospitals' doctor communication measures.

Percutaneous Interventions for Secondary Mitral Regurgitation.

Mitral regurgitation is frequently associated with ventricular dysfunction and carries a high mortality. Guideline-directed medical therapy, surgical mitral valve repair or replacement, and, in the setting of advanced heart failure, heart transplant and left ventricular assist devices have been the mainstay of treatment. However, rapid advancement in the field has resulted in approval of edge-to-edge mitral valve repair with the MitraClip, and there are several novel catheter-based percutaneous options in clinical trials. Percutaneous options, while promising, must be deployed in patients who are most likely to benefit, and thus, understanding the pathophysiology of specific subgroups of patients with functional mitral regurgitation (eg, disproportionate versus proportionate mitral regurgitation) is key to the success of new devices. We review the pathophysiology, percutaneous therapeutic treatment options, and ongoing clinical trials for functional mitral regurgitation.

Venous thrombosis after nitrous oxide abuse, a case report.

Nitrous oxide is a commonly abused inhalant by adolescents and young adults. There is limited data describing the adverse effects of nitrous oxide abuse, known colloquially as "whippets". We present a 21-year-old female with no medical history who presented to the emergency department for confusion, hallucinations, weakness, and falls. She was accompanied by her roommates, who endorsed significant nitrous oxide abuse. Imaging revealed a large cerebral sinus venous thrombus with extension into the transverse sinus, sigmoid sinus and internal jugular vein. She had no prior history of venous or arterial thrombosis. Hypercoagulability workup demonstrated an elevated homocysteine level, elevated methylmalonic acid level, and normal cobalamin and folate levels. Additionally, she was found to be 11 weeks pregnant, with no prior spontaneous abortions. Genetic testing was significant for methylenetetrahydrofolate reductase polymorphisms. She was managed with enoxaparin, cobalamin and folate supplementation. Homocysteine and methylmalonic acid levels normalized after cessation of nitrous oxide use, with no recurrence of venous thrombosis. This case represents the first reported patient with a venous thrombus associated with nitrous oxide abuse.

Stepping to an Auditory Metronome Improves Weight-Bearing Symmetry in Poststroke Hemiparesis.

Asymmetry in weight-bearing is a common feature in poststroke hemiparesis and is related to temporal asymmetry during walking. The aim of this study was to investigate the effect of an auditory cue for stepping in place on measures of temporal and weight-bearing asymmetry. A total of 10 community-dwelling adults (6 males and 4 females) with chronic poststroke hemiparesis performed 5 un-cued stepping trials and 5 stepping trials cued by an auditory metronome cue. A Vicon system was used to collect full body kinematic trajectories. Two force platforms were used to measure ground reaction forces. Step, swing, and stance times were used to calculate temporal symmetry ratios. Weight-bearing was assessed using the vertical component of the ground reaction force and center of mass-center of pressure separation at mid-stance. Weight-bearing asymmetry was significantly reduced during stepping with an auditory cue. Asymmetry values for step, swing, and stance times were also significantly reduced with auditory cueing. These findings show that auditory cueing when stepping in place produces immediate reductions in measures of temporal asymmetry and dynamic weight-bearing asymmetry.

Probability of phenotypically detectable protein damage by ENU-induced mutations in the Mutagenetix database.

Computational inference of mutation effects is necessary for genetic studies in which many mutations must be considered as etiologic candidates. Programs such as PolyPhen-2 predict the relative severity of damage caused by missense mutations, but not the actual probability that a mutation will reduce/eliminate protein function. Based on genotype and phenotype data for 116,330 ENU-induced mutations in the Mutagenetix database, we calculate that putative null mutations, and PolyPhen-2-classified "probably damaging", "possibly damaging", or "probably benign" mutations have, respectively, 61%, 17%, 9.8%, and 4.5% probabilities of causing phenotypically detectable damage in the homozygous state. We use these probabilities in the estimation of genome saturation and the probability that individual proteins have been adequately tested for function in specific genetic screens. We estimate the proportion of essential autosomal genes in Mus musculus (C57BL/6J) and show that viable mutations in essential genes are more likely to induce phenotype than mutations in non-essential genes.

Chiral Imprinting in the Gas Phase.

Undoing the twist: Recent successful attempts to change the relative populations of two otherwise identical enantiomers of a large gas-phase molecule using resonant microwave fields are highlighted. Specifically, the population of a specific enantiomer of a chiral terpene could be enhanced relative to the other enantiomer by the application of a sequence of microwave pulses in a phase- and polarization-controlled manner.

Stepping to the Beat: Feasibility and Potential Efficacy of a Home-Based Auditory-Cued Step Training Program in Chronic Stroke.

BACKGROUND: Hemiparesis after stroke typically results in a reduced walking speed, an asymmetrical gait pattern and a reduced ability to make gait adjustments. The purpose of this pilot study was to investigate the feasibility and preliminary efficacy of home-based training involving auditory cueing of stepping in place. METHODS: Twelve community-dwelling participants with chronic hemiparesis completed two 3-week blocks of home-based stepping to music overlaid with an auditory metronome. Tempo of the metronome was increased 5% each week. One 3-week block used a regular metronome, whereas the other 3-week block had phase shift perturbations randomly inserted to cue stepping adjustments. RESULTS: All participants reported that they enjoyed training, with 75% completing all training blocks. No adverse events were reported. Walking speed, Timed Up and Go (TUG) time and Dynamic Gait Index (DGI) scores (median [inter-quartile range]) significantly improved between baseline (speed = 0.61 [0.32, 0.85] m⋅s-1; TUG = 20.0 [16.0, 39.9] s; DGI = 14.5 [11.3, 15.8]) and post stepping training (speed = 0.76 [0.39, 1.03] m⋅s-1; TUG = 16.3 [13.3, 35.1] s; DGI = 16.0 [14.0, 19.0]) and was maintained at follow-up (speed = 0.75 [0.41, 1.03] m⋅s-1; TUG = 16.5 [12.9, 34.1] s; DGI = 16.5 [13.5, 19.8]). CONCLUSION: This pilot study suggests that auditory-cued stepping conducted at home was feasible and well-tolerated by participants post-stroke, with improvements in walking and functional mobility. No differences were detected between regular and phase-shift training with the metronome at each assessment point.

Rotationally resolved electronic spectroscopy of the rotamers of 1,3-dimethoxybenzene.

Conformational assignments in molecular beam experiments are often based on relative energies, although there are many other relevant parameters, such as conformer-dependent oscillator strengths, Franck-Condon factors, quantum yields and vibronic couplings. In the present contribution, we investigate the conformational landscape of 1,3-dimethoxybenzene using a combination of rotationally resolved electronic spectroscopy and high level ab initio calculations. The electronic origin of one of the three possible planar rotamers (rotamer (0,180) with both substituents pointing at each other) has not been found. Based on the calculated potential energy surface of 1,3-dimethoxybenzene in the electronic ground and lowest excited state, we show that this can be explained by a distorted non-planar geometry of rotamer (0,180) in the S1 state.

Community-based asthma education.

OBJECTIVES: Objectives: The authors studied the impact a community hospital-based asthma education (AE) program had on asthma understanding, healthcare utilization, and estimated costs. STUDY DESIGN: Prospective observational study. METHODS: Every self-selected enrollee in Ellis Hospital's AE program from April 1, 2011, to December 31, 2015, was captured using quality assurance data. Significant changes comparing individual progress were evaluated using 2-tailed paired t tests using SPSS software. Care utilization was measured 1 year before and after AE. Asthma control was evaluated with Asthma Control Test (ACT) scores. The average charges for emergency department (ED) visits and asthma admissions were used to estimate cost impact. RESULTS: In total, 574 patients of all ages (mean age = 30 years) were seen over the study period. Participants reported better controlled asthma (mean pre-AE ACT score = 14; mean post-AE ACT score = 19; P <.001). Individuals also demonstrated increased asthma knowledge (mean pre-AE knowledge score = 10; mean post-AE score = 13; P <.001). In the 12 months prior to education, there was a mean of 1.1 ED visits and 0.16 inpatient admissions per AE participant. In the 12 months following education, ED visits dropped to a mean of 0.4 visits and admissions to 0.06 per individual (P <.001). We estimated that the program decreased ED charges for this study cohort by about $600,000 and inpatient charges by about $230,000. CONCLUSIONS: Our data suggest that patient AE efforts at the community level are associated with better knowledge of asthma, decreased symptoms, and increased quality of life. The use of expensive resources also was favorably impacted.

First-Year Analysis of a New, Home-Based Palliative Care Program Offered Jointly by a Community Hospital and Local Visiting Nurse Service.

BACKGROUND: There is a growing need for home-based palliative care services, especially for seriously ill individuals who want to avoid hospitalizations and remain with their regular outside care providers. AIM: To evaluate the effectiveness of Care Choices, a new in-home palliative care program provided by the Visiting Nurse Services of Northeastern New York and Ellis Medicine's community hospital serving New York's Capital District. METHODS: This prospective cohort study assessed patient outcomes over the course of 1 year for 123 patients (49 men and 74 women) with serious illnesses who were new enrollees in the program. Quality of life was assessed at baseline and after 1 month on service. Satisfaction with care was measured after 1 and 3 months on service. The number of emergency department visits and inpatient hospitalizations pre- and postenrollment was measured for all enrollees. RESULTS: Patients were highly satisfied (72.7%-100%) with their initial care and reported greater satisfaction ( P < .05) and stable symptom management over time. Fewer emergency department ( P < .001) and inpatient hospital admissions ( P < .001) occurred among enrollees while on the palliative care service. CONCLUSION: An in-home palliative care program offered jointly through a visiting nurse service and community hospital may be a successful model for providing quality care that satisfies chronically ill patients' desire to remain at home and avoid hospital admissions.

Metronome Cueing of Walking Reduces Gait Variability after a Cerebellar Stroke.

Cerebellar stroke typically results in increased variability during walking. Previous research has suggested that auditory cueing reduces excessive variability in conditions such as Parkinson's disease and post-stroke hemiparesis. The aim of this case report was to investigate whether the use of a metronome cue during walking could reduce excessive variability in gait parameters after a cerebellar stroke. An elderly female with a history of cerebellar stroke and recurrent falling undertook three standard gait trials and three gait trials with an auditory metronome. A Vicon system was used to collect 3-D marker trajectory data. The coefficient of variation was calculated for temporal and spatial gait parameters. SDs of the joint angles were calculated and used to give a measure of joint kinematic variability. Step time, stance time, and double support time variability were reduced with metronome cueing. Variability in the sagittal hip, knee, and ankle angles were reduced to normal values when walking to the metronome. In summary, metronome cueing resulted in a decrease in variability for step, stance, and double support times and joint kinematics. Further research is needed to establish whether a metronome may be useful in gait rehabilitation after cerebellar stroke and whether this leads to a decreased risk of falling.

Electronic spectra of 2- and 3-tolunitrile in the gas phase. II. Geometry changes from Franck-Condon fits of fluorescence emission spectra.

We determined the changes of the geometries of 2- and 3-tolunitrile upon excitation to the lowest excited singlet states from Franck-Condon fits of the vibronic intensities in several fluorescence emission spectra and of the rotational constant changes upon excitation. These structural changes can be connected to the altered electron distribution in the molecules and are compared to the results of ab initio calculations. We show how the torsional barriers of the methyl groups in both components are used as probe of the molecular changes upon electronic excitation.

Electronic spectra of 2- and 3-tolunitrile in the gas phase. I. A study of methyl group internal rotation via rovibronically resolved spectroscopy.

Rotationally resolved fluorescence excitation spectra of the origin bands in the S1 ← S0 transition of 2-tolunitrile (2TN) and 3-tolunitrile (3TN) have been recorded in the collision-free environment of a molecular beam. Analyses of these data provide the rotational constants of each molecule and the potential energy curves governing the internal rotation of the attached methyl groups in both electronic states. 2TN exhibits much larger barriers along this coordinate than 3TN. Interestingly, the electronic transition dipole moment in both molecules is markedly influenced by the position of the attached methyl group rather than the position of the cyano group; possible reasons for this intriguing behavior are discussed.

NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component.

The NLRP3 inflammasome responds to microbes and danger signals by processing and activating proinflammatory cytokines, including interleukin 1ß (IL-1ß) and IL-18. We found here that activation of the NLRP3 inflammasome was restricted to interphase of the cell cycle by NEK7, a serine-threonine kinase previously linked to mitosis. Activation of the NLRP3 inflammasome required NEK7, which bound to the leucine-rich repeat domain of NLRP3 in a kinase-independent manner downstream of the induction of mitochondrial reactive oxygen species (ROS). This interaction was necessary for the formation of a complex containing NLRP3 and the adaptor ASC, oligomerization of ASC and activation of caspase-1. NEK7 promoted the NLRP3-dependent cellular inflammatory response to intraperitoneal challenge with monosodium urate and the development of experimental autoimmune encephalitis in mice. Our findings suggest that NEK7 serves as a cellular switch that enforces mutual exclusivity of the inflammasome response and cell division.

Intramolecular structure and dynamics of mequinol and guaiacol in the gas phase: Rotationally resolved electronic spectra of their S1 states.

The molecular structures of guaiacol (2-methoxyphenol) and mequinol (4-methoxyphenol) have been studied using high resolution electronic spectroscopy in a molecular beam and contrasted with ab initio computations. Mequinol exhibits two low frequency bands that have been assigned to electronic origins of two possible conformers of the molecule, trans and cis. Guaiacol also shows low frequency bands, but in this case, the bands have been assigned to the electronic origin and vibrational modes of a single conformer of the isolated molecule. A detailed study of these bands indicates that guaiacol has a vibrationally averaged planar structure in the ground state, but it is distorted along both in-plane and out-of-plane coordinates in the first electronically excited state. An intramolecular hydrogen bond involving the adjacent -OH and -OCH3 groups plays a major role in these dynamics.

Real-time resolution of point mutations that cause phenovariance in mice.

With the wide availability of massively parallel sequencing technologies, genetic mapping has become the rate limiting step in mammalian forward genetics. Here we introduce a method for real-time identification of N-ethyl-N-nitrosourea-induced mutations that cause phenotypes in mice. All mutations are identified by whole exome G1 progenitor sequencing and their zygosity is established in G2/G3 mice before phenotypic assessment. Quantitative and qualitative traits, including lethal effects, in single or multiple combined pedigrees are then analyzed with Linkage Analyzer, a software program that detects significant linkage between individual mutations and aberrant phenotypic scores and presents processed data as Manhattan plots. As multiple alleles of genes are acquired through mutagenesis, pooled "superpedigrees" are created to analyze the effects. Our method is distinguished from conventional forward genetic methods because it permits (1) unbiased declaration of mappable phenotypes, including those that are incompletely penetrant (2), automated identification of causative mutations concurrent with phenotypic screening, without the need to outcross mutant mice to another strain and backcross them, and (3) exclusion of genes not involved in phenotypes of interest. We validated our approach and Linkage Analyzer for the identification of 47 mutations in 45 previously known genes causative for adaptive immune phenotypes; our analysis also implicated 474 genes not previously associated with immune function. The method described here permits forward genetic analysis in mice, limited only by the rates of mutant production and screening.

Seasonal influenza vaccination and technologies.

Seasonal influenza is a serious respiratory illness that causes annual worldwide epidemics resulting in significant morbidity and mortality. Influenza pandemics occur about every 40 yrs, and may carry a greater burden of illness and death than seasonal influenza. Both seasonal influenza and pandemic influenza have profound economic consequences. The combination of current vaccine efficacy and viral antigenic drifts and shifts necessitates annual vaccination. New manufacturing technologies in influenza vaccine development employ cell culture and recombinant techniques. Both allow more rapid vaccine creation and production. In the past 5 years, brisk, highly creative activity in influenza vaccine research and development has begun. New vaccine technologies and vaccination strategies are addressing the need for viable alternatives to egg production methods and improved efficacy. At present, stubborn problems of sub-optimal efficacy and the need for annual immunization persist. There is an obvious need for more efficacious vaccines and improved vaccination strategies to make immunization easier for providers and patients. Mitigating this serious annual health threat remains an important public health priority.

Delicate balance of hydrogen bonding forces in D-threoninol.

The seven most stable conformers of D-threoninol (2(S)-amino-1,3(S)-butanediol), a template used for the synthesis of artificial nucleic acids, have been identified and characterized from their pure rotational transitions in the gas phase using chirped-pulse Fourier transform microwave spectroscopy. D-Threoninol is a close analogue of glycerol, differing by substitution of an NH2 group for OH on the C(ß) carbon and by the presence of a terminal CH3 group that breaks the symmetry of the carbon framework. Of the seven observed structures, two are H-bonded cycles containing three H-bonds that differ in the direction of the H-bonds in the cycle. The other five are H-bonded chains containing OH···NH···OH H-bonds with different directions along the carbon framework and different dihedral angles along the chain. The two structural types (cycles and chains of H-bonds) are in surprisingly close energetic proximity. Comparison of the rotational constants with the calculated structures at the MP2/6-311++G(d,p) level of theory reveals systematic changes in the H-bond distances that reflect NH2 as a better H-bond acceptor and poorer donor, shrinking the H-bond distances by ∼0.2 Å in the former case and lengthening them by a corresponding amount in the latter. Thus revealed is the subtle effect of asymmetric substitution on the energy landscape of a simple molecule, likely to be important in living systems.