Clinicians' Perspectives on Providing Emergency-Only Hemodialysis to Undocumented Immigrants: A Qualitative Study.

Background: In the United States, nearly half of undocumented immigrants with end-stage kidney disease receive hemodialysis only when they are evaluated in an emergency department and are found to have life-threatening renal failure ("emergency-only hemodialysis" [EOHD]). These patients experience psychosocial distress and much higher mortality than patients receiving regularly scheduled hemodialysis, but little is known about how providing EOHD affects the clinicians involved. Objective: To understand clinicians' experiences providing EOHD. Design: Qualitative study using semistructured interviews. Setting: A safety-net hospital in Denver, Colorado, and a safety-net system in Houston, Texas. Participants: Fifty interdisciplinary clinicians experienced in providing EOHD. Measurements: Interviews were analyzed using thematic analysis. Outcomes included themes and subthemes. Results: Four themes and 13 subthemes (in parentheses) were identified: 1) drivers of professional burnout (emotional exhaustion from witnessing needless suffering and high mortality, jeopardizing patient trust, detaching from patients, perceived lack of control over EOHD criteria, and physical exhaustion from overextending to bridge care), 2) moral distress from propagating injustice (altered care based on nonmedical factors, focus on volume at the expense of quality, and need to game the system), 3) confusing and perverse financial incentives (wasting resources, confusing financial incentives, and concerns about sustainability), and 4) inspiration toward advocacy (deriving inspiration from patients and strengthened altruism). Limitation: Whether the findings apply to other settings is unknown, and social desirability response bias might have reduced reporting of negative perceptions and experiences. Conclusion: Clinicians in safety-net settings who provide EOHD to undocumented patients describe experiencing moral distress and being driven toward professional burnout. The burden of EOHD on clinicians should inform discussions of systemic approaches to support provision of adequate care based on medical need. Primary Funding Source: Robert Wood Johnson Foundation and Doris Duke Charitable Foundation.

Lower-limb muscle function during gait in varus mal-aligned osteoarthritis patients.

This study quantified the contributions by muscular, gravitational and inertial forces to the ground reaction force (GRF) and external knee adduction moment (EKAM) for knee osteoarthritis (OA) patients and controls walking at similar speeds. Gait data for 39 varus mal-aligned medial knee OA patients and 15 controls were input into musculoskeletal models to calculate the contributions of individual muscles and gravity to the fore-aft (progression), vertical (support), and mediolateral (balance) GRF, and the EKAM. The temporal patterns of contributions to GRF and EKAM were similar between the groups. Magnitude differences in GRF contributions were small but some reached significance. Peak GRF contributions were lower in patients except hamstrings in early-stance progression (p < 0.001) and gastrocnemius in late-stance progression (p < 0.001). Both EKAM peaks were higher in patients, due mainly to greater adduction contribution from gravity (p < 0.001) at the first peak, and lower abduction contributions from soleus (p < 0.001) and gastrocnemius (p < 0.001) at the second peak. Gluteus medius contributed most to EKAM in both groups, but was higher in patients during mid-stance only (p < 0.001). Differences in GRF contributions were attributed to altered quadriceps-hamstrings action as well as compensatory adaptation of the ankle plantarflexors to reduced gluteus medius action. The large effect of varus mal-alignment on the frontal-plane moment arms of the gravity, soleus, and gastrocnemius GRF contributions about the knee explained greater patient EKAM. Our results shed further light on how the EKAM contributes to altered knee-joint loads in OA and why some interventions may affect different portions of the EKAM waveform. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Using Time-Referenced Data to Assess Medication Administration Performance and Quality.

OBJECTIVE: This study tests the feasibility of using a large (big) clinical data set to test the ability to extract time-referenced data related to medication administration to identify late doses and as-needed (PRN) administration patterns by RNs in an inpatient setting. METHODS: The study is a secondary analysis of a set of data using bar-code medication administration time stamps (n = 3043812) for 50883 patients admitted to a single, urban, 525-bed hospital in 11 inpatient units by 714 nurses between April 1, 2013, and March 31, 2015. RESULTS: The large majority of scheduled medications (43.3%) were administered between 9 to 10 AM and 9 to 10 PM accounting for the most amount of delayed doses. On average, patients received 8.9 medications per day, and nurses administered 19.7 medications per shift. The average full-time nurse administered 3414 medications per year. CONCLUSIONS: The findings support use of time-referenced data to identify clinical processes and performance in administering scheduled and PRN medications.

In Vitro and In Vivo Modeling of Hydroxypropyl Methylcellulose (HPMC) Matrix Tablet Erosion Under Fasting and Postprandial Status.

PURPOSE: To develop a model linking in vitro and in vivo erosion of extended release tablets under fasting and postprandial status. METHODS: A nonlinear mixed-effects model was developed from the in vitro erosion profiles of four hydroxypropyl methylcellulose (HPMC) matrix tablets studied under a range of experimental conditions. The model was used to predict in vivo erosion of the HPMC matrix tablets in different locations of the gastrointestinal tract, determined by magnetic marker monitoring. In each gastrointestinal segment the pH was set to physiological values and mechanical stress was estimated in USP2 apparatus rotation speed equivalent. RESULTS: Erosion was best described by a Michaelis-Menten type model. The maximal HPMC release rate (VMAX) was affected by pH, mechanical stress, HPMC and calcium hydrogen phosphate content. The amount of HPMC left at which the release rate is half of VMAX depended on pH and calcium hydrogen phosphate. Mechanical stress was estimated for stomach (39.5 rpm), proximal (93.3 rpm) and distal (31.1 rpm) small intestine and colon (9.99 rpm). CONCLUSIONS: The in silico model accurately predicted the erosion profiles of HPMC matrix tablets under fasting and postprandial status and can be used to facilitate future development of extended release tablets.

Musculoskeletal loading in the symptomatic and asymptomatic knees of middle-aged osteoarthritis patients.

This study quantified the contributions by muscles, gravity, and inertia to the tibiofemoral compartment forces in the symptomatic (SYM) and asymptomatic (ASYM) limbs of varus mal-aligned medial knee osteoarthritis (OA) patients, and compared the results with healthy controls (CON). Muscle forces and tibiofemoral compartment loads were calculated using gait data from 39 OA patients and 15 controls aged 49 ± 7 years. Patients exhibited lower knee flexion angle, higher hip abduction, and knee adduction angles, lower internal knee flexion torque but higher external knee adduction moment. Muscle forces were highest in CON except hamstrings, which was highest in SYM. ASYM muscle forces were lowest for biceps femoris short head and gastrocnemius but otherwise intermediate between SYM and CON. In all subjects, vasti, hamstrings, gastrocnemius, soleus, gluteus medius, gluteus maximus, and gravity were the largest contributors to medial compartment force (MCF). Inertial contributions were negligible. Highest MCF was found in SYM throughout stance. Small increases in contributions from hamstrings, gluteus maximus, gastrocnemius, and gravity at the first peak; soleus and rectus femoris at the second peak; and soleus, gluteus maximus, gluteus medius, and gravity during mid-stance summed to produce significantly higher total MCF. Compared to CON, the ASYM limb exhibited similar peak MCF but higher mid-stance MCF. In patients, diminished non-knee-spanning muscle forces did not produce correspondingly diminished MCF contributions due to the influence of mal-alignment. Our findings emphasize consideration of muscle function, lower-limb alignment, and mid-stance loads in developing interventions for OA, and inclusion of the asymptomatic limb in clinical assessments. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:321-330, 2017.

A solid-state NMR method to determine domain sizes in multi-component polymer formulations.

Polymer domain sizes are related to many of the physical properties of polymers. Here we present a solid-state NMR experiment that is capable of measuring domain sizes in multi-component mixtures. The method combines selective excitation of carbon magnetization to isolate a specific component with proton spin diffusion to report on domain size. We demonstrate the method in the context of controlled release formulations, which represents one of today's challenges in pharmaceutical science. We show that we can measure domain sizes of interest in the different components of industrial pharmaceutical formulations at natural isotopic abundance containing various (modified) cellulose derivatives, such as microcrystalline cellulose matrixes that are film-coated with a mixture of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC).

Nanostructure of Materials Determined by Relayed Paramagnetic Relaxation Enhancement.

Particle and domain sizes strongly influence the properties of materials. Here we present an NMR approach based on paramagnetic relaxation enhancement (PRE) relayed by spin diffusion (SD), which allows us to determine lengths in the nm-µm range. We demonstrate the method on multicomponent organic polymer mixtures by selectively doping one component with a paramagnetic center in order to measure the domain size in a second component. Using this approach we determine domain sizes in ethyl cellulose/hydroxypropyl cellulose film coatings in pharmaceutical controlled release formulations. Here we measure particle sizes ranging from around 50 to 200 nm.

The influence of hydroxypropyl methylcellulose (HPMC) molecular weight, concentration and effect of food on in vivo erosion behavior of HPMC matrix tablets.

Four different hydrophilic matrix formulations based on hydroxypropyl methylcellulose (HPMC) were investigated for erosion properties in vivo. Three formulations contained a fixed amount of HPMC (40%) with varying proportions of two HPMC grades with different molecular weights (Methocel K100LV and K4M), and a fourth formulation contained a lower amount of the HPMC of lower molecular weight (20%). The effect of food on the in vivo erosion behavior was investigated on two formulations containing different contents of the same HPMC grade. The in vivo erosion behavior and gastrointestinal transit were investigated using magnetic marker monitoring (MMM). The in vitro and in vivo erosion-time profiles show that the erosion was strongly dependent on the composition of the formulation. The formulations containing a larger proportion of high molecular weight HPMC or higher content of HPMC exhibit relatively slower erosion rate and vice versa. In vivo erosion rates were significantly higher under postprandial administration as compared to fasted state administration. No rapid disintegration of any of the formulations (i.e. formulation failure that can potentially cause dose dumping) was observed.

Appetite Response among Those Susceptible or Resistant to Obesity.

An alternative approach in determining cause, treatment, and prevention of obesity is to study those who appear resistant to the obesogenic environment. We examined appetite responses in 33 obesity resistant individuals (ORI) versus 28 obesity susceptible individuals (OSI). Fingerprick blood samples to measure ghrelin, total peptide YY (PYY), leptin, glucose, and insulin along with appetite ratings were collected at baseline and 15, 30, 60, 120, and 180 min following consumption of a standardized meal. Fasting, area under the curve (AUC), peak/nadir, and time to peak/nadir were compared. Participants completed the three factor eating questionnaire (TFEQ). No significant differences were observed for ghrelin or PYY. Higher leptin concentrations in the OSI disappeared after controlling for percent body fat (%BF). Significant differences in appetite ratings included a lower hunger nadir among OSI compared with ORI (P = 0.017). Dietary restraint (P < 0.001) and disinhibition (P < 0.001) were lower in ORI compared with OSI, with and without adjustment for %BF. Given the differential body weight of the study groups, similar observed ghrelin concentrations were unexpected, perhaps indicating OSI and ORI respond differently to the same ghrelin concentration. Also ORI response to hunger appears different as they exhibit lower levels of dietary restraint and disinhibition compared with OSI.

The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment.

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic 'fashions', and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts.

Cardiovascular adaptations, fluid shifts, and countermeasures related to space flight.

Significant progress has been made related to understanding cardiovascular adaptations to microgravity and development of countermeasures to improve crew re-adaptation to gravity. The primary ongoing issues are orthostatic intolerance after flight, reduced exercise capacity, the effect of vascular-smooth muscle loss on other physiologic systems, development of efficient and low-cost countermeasures to counteract these losses, and an understanding of fluid shift mechanisms. Previous animal studies of cardiovascular adaptations offer evidence that prolonged microgravity remodels walls of blood vessels, which in turn, is important for deconditioning of the cardiovascular system and other functions of the body. Over the past 10 years, our studies have documented that treadmill exercise within lower body negative pressure counteracts most physiologic decrements with bed rest in both women and men. Future studies should improve hardware and protocols to protect crew members during prolonged missions. Finally, it is proposed that transcapillary fluid shifts in microgravity may be related to the loss of tissue weight and external compression of blood vessels.

Substituent distribution and clouding behavior of hydroxypropyl methyl cellulose analyzed using enzymatic degradation.

The distribution of substituents along the polymer backbone will have a strong influence on the properties of modified cellulose. Endoglucanases were used to degrade three different batches of hydroxypropyl methyl cellulose (HPMC) derivatives with similar chemical properties. The phase separation of the HPMCs as a function of temperature, i.e., the clouding behavior, was analyzed prior to degradation. The total amount of unsubstituted glucose was determined using total acid hydrolysis followed by high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD). The products after enzymatic degradation were analyzed with size-exclusion chromatography with online multiangle light scattering and refractive index detection and also with reducing end determination. To further characterize the formed products, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was employed for analysis of short-chained oligosaccharides. The different endoglucanases showed varying degradation capability of HPMC derivatives, depending on structure of the active site. The investigated HPMCs had different susceptibility to degradation by the endoglucanases. The results showed a difference in substituent distribution between HPMC batches, which could explain the differing clouding behaviors. The batch with the lowest cloud point was shown to contain a higher number of non-degradable, highly substituted regions.

NMR, cloud-point measurements and enzymatic depolymerization: complementary tools to investigate substituent patterns in modified celluloses.

The substituent patterns of some chemically modified celluloses were characterized as a function of their size distribution, using size-exclusion chromatography coupled to both nuclear magnetic resonance spectroscopy (NMR) and cloud-point measurements. Intact and enzymatically hydrolyzed methyl cellulose (MC) was fractionated according to size, and the level of substitution of the fractions was measured off-line using NMR. Clouding behavior was also measured as a function of size. Clear differences between hydrolyzed and nonhydrolyzed samples were observed using both techniques. For samples that had been selectively hydrolyzed using cellulose-degrading enzymes, NMR data showed a direct link between the degree of degradation and the level of substitution. Differences in the clouding behavior highlighted changes in substituent levels and substituent patterns across the size distribution. The techniques gave valuable and somewhat complementary information on the substituent distributions of the samples before and after enzymatic hydrolysis.

Characterization of chemical substitution of hydroxypropyl cellulose using enzymatic degradation.

The distribution of substituents along the polymer backbone will have a strong influence on the properties of modified cellulose. Endoglucanases were used to degrade a series of hydroxypropyl cellulose (HPC) derivatives with a high degree of substitution. The HPCs were characterized with cloud-point analysis prior to degradation. The extent of enzymatic degradation was determined with size-exclusion chromatography with online multi-angle light scattering and refractive index detection and also with high-pH anion exchange chromatography with pulsed amperometric detection. To further characterize the formed products, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was employed for analysis of short-chained oligosaccharides. The different endoglucanases showed varying degradation capability depending on structure of the active site. The highly substituted HPCs had different susceptibility to degradation by the endoglucanases. The results show a difference in substituent distribution between HPCs, which would explain the differing cloud-point behaviors. Increased number of regions with low substitution could be correlated with lower polymer cloud point. The study shows the usefulness of enzymatic degradation to study the distribution of substituents in soluble biopolymer derivates.

Enzyme-aided investigation of the substituent distribution in cationic potato amylopectin starch.

The distribution of substituents along the polymer chain in cationic potato amylopectin starch, modified in solution, granular slurry, or dry state, was investigated. The starch derivatives were successively hydrolyzed by different enzymes, followed by characterization of the hydrolysis products obtained by means of electrospray mass spectrometry (ESI-MS) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). ESI-MS and MALDI-MS were proved to be appropriate techniques for identification of the substituted hydrolysis products, for which there are no standard compounds available. No highly substituted oligomers were found in the hydrolysates, which was taken as an indication of a more or less homogeneous distribution of cationic groups in the amylopectin molecules. Furthermore, from the results obtained it was suggested that the enzymes cleave glucosidic linkages only between unsubstituted glucose units and, preferentially, linkages in sequences containing more than two adjacent unsubstituted units. The determination of the amount of unsubstituted glucose produced from every successive hydrolysis step revealed slight differences between the different starch samples with respect to the homogeneity of the substitution pattern. Among the three samples under investigation, starch cationized in solution was found to have the most and dry-cationized starch the least homogeneous distribution of substituents.

Analytical approaches to improved characterization of substitution in hydroxypropyl cellulose.

Chemical characterization of cellulose derivatives is of high importance as it provides information about the often inhomogeneous substitution that may seriously affect the properties of these polymers in various applications. A detailed mapping of the chemical structure of these derivatives requires several advanced techniques to be employed. In this study, the average substitution and the substitution heterogeneity in two hydroxypropyl cellulose (HPC) samples from different suppliers were studied by means of NMR spectroscopy, MALDI-TOF MS, and HPAEC-PAD. (1)H and (13)C NMR provided information on the molar substitution, a parameter that could be analyzed by MALDI-TOF MS as well. In addition, the latter technique was used for determination of the distribution of the number of hydroxypropyl groups per glucose unit present in the two polymers. The heterogeneity of the substitution was studied by determining the amount of unsubstituted glucose units in the HPC samples, which was accomplished by HPAEC-PAD analysis. The results obtained suggest that the two HPC samples differ in both hydroxypropoxy content and distribution of the hydroxypropyl groups. Further, the benefits and importance of employing several analytical methods when investigating the cellulose ether substitution are demonstrated, as each method provides different kinds of information on the chemical content.

Initial characterization of ethyl(hydroxyethyl) cellulose using enzymic degradation and chromatographic methods.

Two different ethyl(hydroxyethyl) cellulose (EHEC) samples were characterized by size-exclusion chromatography (SEC) with multiangle light scattering (MALS) detection and high-performance anion-exchange chromatography (HPAEC) with pulsed amperometric detection (PAD). The aim of the study was to investigate the molar mass distribution and the heterogeneity of the substituent distribution, factors that are thought to affect the functional properties of EHEC. The presence of blocks of unsubstituted glucose units was studied by enzymic degradation of EHEC by two different endoglucanases from Trichoderma reesei. The SEC-MALS analysis of the hydrolysis products showed that both enzymes were strongly inhibited by the large number of substituents along the cellulose chain. However, as the weight-average molar mass was reduced from approximately 360,000 to 80,000 g/mol in one of the polymers and from 770,000 to 60,000 g/mol in the other polymer, it was suggested that both samples were composed of some unsubstituted regions where the enzymes got access to the glucosidic bonds. The amount of glucose released upon endoglucanase hydrolysis was determined by HPAEC-PAD, which gave information on the homogeneity of the substituent distribution. The production of unsubstituted glucose units indicated that one of the polymers had a more uneven distribution compared with the other. It was demonstrated that chemical characterization of EHEC is a complex task, which requires an analytical approach involving numerous different methods and techniques.