Molecular pharmacodynamics of meropenem for nosocomial pneumonia caused by Pseudomonas aeruginosa.

Hospital-acquired pneumonia (HAP) is a leading cause of morbidity and mortality, commonly caused by Pseudomonas aeruginosa. Meropenem is a commonly used therapeutic agent, although emergent resistance occurs during treatment. We used a rabbit HAP infection model to assess the bacterial kill and resistance pharmacodynamics of meropenem. Meropenem 5 mg/kg administered subcutaneously (s.c.) q8h (±amikacin 3.33-5 mg/kg q8h administered intravenously[i.v.]) or meropenem 30 mg/kg s.c. q8h regimens were assessed in a rabbit lung infection model infected with P. aeruginosa, with bacterial quantification and phenotypic/genotypic characterization of emergent resistant isolates. The pharmacokinetic/pharmacodynamic output was fitted to a mathematical model, and human-like regimens were simulated to predict outcomes in a clinical context. Increasing meropenem monotherapy demonstrated a dose-response effect to bacterial kill and an inverted U relationship with emergent resistance. The addition of amikacin to meropenem suppressed the emergence of resistance. A network of porin loss, efflux upregulation, and increased expression of AmpC was identified as the mechanism of this emergent resistance. A bridging simulation using human pharmacokinetics identified meropenem 2 g i.v. q8h as the licensed clinical regimen most likely to suppress resistance. We demonstrate an innovative experimental platform to phenotypically and genotypically characterize bacterial emergent resistance pharmacodynamics in HAP. For meropenem, we have demonstrated the risk of resistance emergence during therapy and identified two mitigating strategies: (i) regimen intensification and (ii) use of combination therapy. This platform will allow pre-clinical assessment of emergent resistance risk during treatment of HAP for other antimicrobials, to allow construction of clinical regimens that mitigate this risk.IMPORTANCEThe emergence of antimicrobial resistance (AMR) during antimicrobial treatment for hospital-acquired pneumonia (HAP) is a well-documented problem (particularly in pneumonia caused by Pseudomonas aeruginosa) that contributes to the wider global antimicrobial resistance crisis. During drug development, regimens are typically determined by their sufficiency to achieve bactericidal effect. Prevention of the emergence of resistance pharmacodynamics is usually not characterized or used to determine the regimen. The innovative experimental platform described here allows characterization of the emergence of AMR during the treatment of HAP and the development of strategies to mitigate this. We have demonstrated this specifically for meropenem-a broad-spectrum antibiotic commonly used to treat HAP. We have characterized the antimicrobial resistance pharmacodynamics of meropenem when used to treat HAP, caused by initially meropenem-susceptible P. aeruginosa, phenotypically and genotypically. We have also shown that intensifying the regimen and using combination therapy are both strategies that can both treat HAP and suppress the emergence of resistance.

Learning from failure: how eliminating required attendance sparked the beginning of a medical school transformation.

Concern about medical student attendance has been rising over the last decade. Thinking a required attendance policy would fix things, we instituted such a mandate in 2010 only to find that although students were present at lecture and other learning sessions they were disengaged. In addition, we experienced growing distrust between faculty and students and tensions between the Student Affairs and Curriculum offices. After five years, we dismantled the policy in favor of encouraged attendance. We discuss both positive and negative surprising consequences that followed this new approach to attendance which has reshaped our vision for the medical school learning experience. It has been transformative and has afforded us the opportunity to redefine our results in accord with the culture in which we aspire to live and work.

A Novel Presentation of Littoral Cell Angioma and Lymphatic Malformations in a Neonate.

This case report describes a novel presentation of littoral cell angioma (LCA) and lymphatic malformations involving the omentum and mesentery. To our knowledge, these 2 entities have not been reported in the same patient. A 1-month term infant male presented with chylous ascites. During his workup, imaging detected splenic nodules. Biopsies revealed that the nodules were LCA and the chylous ascites was secondary to microscopic mesenteric and omental lymphatic malformations. Evaluation for a secondary malignancy, an underlying immunologic defect, and genetic causes were unrevealing. The presence of LCA and lymphatic malformations in the same patient suggests a genetic link between these 2 rare vascular disorders and may help elucidate the etiopathogenesis of these 2 poorly understood anomalies.

Corrigendum: Strong, tough and stiff bioinspired ceramics from brittle constituents.

This corrects the article DOI: 10.1038/nmat3915.

Linking Rheology and Printability for Dense and Strong Ceramics by Direct Ink Writing.

Direct ink writing of dense and strong ceramic objects remains an important open challenge. We develop a universal dimensionless criterion for printing such objects. Boehmite, an Al2O3 precursor, was used to assess the rheological properties leading to dense structures in ceramics manufactured by direct ink writing. Boehmite suspensions undergo time dependent gelation, thus providing a rheological laboratory of flow behaviours that can be correlated with printability requirements. We measured the evolution of rheological properties over several days and quantified the deformation of simple printed shapes at different aging times. We then identified the relevant physical parameters leading to printable suspensions. We defined a dimensionless number, Ξ, based on measured rheological properties, that predicts deformation of the printed object and determines the printability criterion. An important difference with this criterion is that Ξ necessarily accounts for capillary forces and gravitational slumping. We show that boehmite inks reach a printed shape fidelity > 90% when Ξ > 1, and that Al2O3 bars printed under these conditions can be sintered to 97% density, without printing defects, and have flexural strengths (500-600 MPa) competitive with commercial aluminas. Using Ξ, researchers can rationally design inks for printing dense materials by tailoring their rheological properties such that Ξ ≈ 1.

Shift Schedules and Intern Work Hours, Patient Numbers, Conference Attendance, and Sleep at a Single Pediatric Residency Program.

OBJECTIVE: The effects of 2011 Accreditation Council on Graduate Medical Education (ACGME) duty hour standards on intern work hours, patient load, conference attendance, and sleep have not been fully determined. We prospectively compared intern work hours, patient numbers, conference attendance, sleep duration, pattern, and quality in a 2011 ACGME duty hour-compliant shift schedule with a 2003 ACGME duty hour-compliant call schedule at a single pediatric residency program. METHODS: Interns were assigned to shift or call schedules during 4 alternate months in the winter of 2010-2011. Work hours, patient numbers, conference attendance, sleep duration, pattern, and quality were tracked. RESULTS: Interns worked significantly fewer hours per week on day (73.2 hours) or night (71.6 hours) shifts than during q4 call (79.6 hours; P < .01). During high census months, shift schedule interns cared for significantly more patients/day (8.1/day shift vs 6.2/call; P < .001) and attended significantly fewer conferences than call schedule interns. Night shift interns slept more hours per 24-hour period than call schedule interns (7.2 ± 0.5 vs 6.3 ± 0.9 hours; P < .05) and had more consistent sleep patterns. CONCLUSIONS: A shift schedule resulted in reduced intern work hours and improved sleep duration and pattern. Although intern didactic conference attendance declined significantly during high census months, opportunities for experiential learning remained robust with unchanged or increased intern patient numbers.

The effect of wall thickness distribution on mechanical reliability and strength in unidirectional porous ceramics.

Macroporous ceramics exhibit an intrinsic strength variability caused by the random distribution of defects in their structure. However, the precise role of microstructural features, other than pore volume, on reliability is still unknown. Here, we analyze the applicability of the Weibull analysis to unidirectional macroporous yttria-stabilized-zirconia (YSZ) prepared by ice-templating. First, we performed crush tests on samples with controlled microstructural features with the loading direction parallel to the porosity. The compressive strength data were fitted using two different fitting techniques, ordinary least squares and Bayesian Markov Chain Monte Carlo, to evaluate whether Weibull statistics are an adequate descriptor of the strength distribution. The statistical descriptors indicated that the strength data are well described by the Weibull statistical approach, for both fitting methods used. Furthermore, we assess the effect of different microstructural features (volume, size, densification of the walls, and morphology) on Weibull modulus and strength. We found that the key microstructural parameter controlling reliability is wall thickness. In contrast, pore volume is the main parameter controlling the strength. The highest Weibull modulus ([Formula: see text]) and mean strength (198.2 MPa) were obtained for the samples with the smallest and narrowest wall thickness distribution (3.1 [Formula: see text]m) and lower pore volume (54.5%).

Gas permeability of ice-templated, unidirectional porous ceramics.

We investigate the gas flow behavior of unidirectional porous ceramics processed by ice-templating. The pore volume ranged between 54% and 72% and pore size between 2.9 [Formula: see text]m and 19.1 [Formula: see text]m. The maximum permeability ([Formula: see text] [Formula: see text] m[Formula: see text]) was measured in samples with the highest total pore volume (72%) and pore size (19.1 [Formula: see text]m). However, we demonstrate that it is possible to achieve a similar permeability ([Formula: see text] [Formula: see text] m[Formula: see text]) at 54% pore volume by modification of the pore shape. These results were compared with those reported and measured for isotropic porous materials processed by conventional techniques. In unidirectional porous materials tortuosity ([Formula: see text]) is mainly controlled by pore size, unlike in isotropic porous structures where [Formula: see text] is linked to pore volume. Furthermore, we assessed the applicability of Ergun and capillary model in the prediction of permeability and we found that the capillary model accurately describes the gas flow behavior of unidirectional porous materials. Finally, we combined the permeability data obtained here with strength data for these materials to establish links between strength and permeability of ice-templated materials.

What's in a Transition? An Integrative Perspective on Transitions in Medical Education.

This Conversation Starters article presents a selected research abstract from the 2016 Association of American Medical Colleges Western Region Group on Educational Affairs annual spring meeting. The abstract is paired with the integrative commentary of three experts who shared their thoughts stimulated by the needs assessment study. These thoughts explore how the general theoretical mechanisms of transition may be integrated with cognitive load theory in order to design interventions and environments that foster transition.

Mechanical properties and failure behavior of unidirectional porous ceramics.

We show that the honeycomb out-of-plane model derived by Gibson and Ashby can be applied to describe the compressive behavior of unidirectional porous materials. Ice-templating allowed us to process samples with accurate control over pore volume, size, and morphology. These samples allowed us to evaluate the effect of this microstructural variations on the compressive strength in a porosity range of 45-80%. The maximum strength of 286 MPa was achieved in the least porous ice-templated sample (P(%) = 49.9), with the smallest pore size (3 µm). We found that the out-of-plane model only holds when buckling is the dominant failure mode, as should be expected. Furthermore, we controlled total pore volume by adjusting solids loading and sintering temperature. This strategy allows us to independently control macroporosity and densification of walls, and the compressive strength of ice-templated materials is exclusively dependent on total pore volume.

Changes in medical errors after implementation of a handoff program.

BACKGROUND: Miscommunications are a leading cause of serious medical errors. Data from multicenter studies assessing programs designed to improve handoff of information about patient care are lacking. METHODS: We conducted a prospective intervention study of a resident handoff-improvement program in nine hospitals, measuring rates of medical errors, preventable adverse events, and miscommunications, as well as resident workflow. The intervention included a mnemonic to standardize oral and written handoffs, handoff and communication training, a faculty development and observation program, and a sustainability campaign. Error rates were measured through active surveillance. Handoffs were assessed by means of evaluation of printed handoff documents and audio recordings. Workflow was assessed through time-motion observations. The primary outcome had two components: medical errors and preventable adverse events. RESULTS: In 10,740 patient admissions, the medical-error rate decreased by 23% from the preintervention period to the postintervention period (24.5 vs. 18.8 per 100 admissions, P<0.001), and the rate of preventable adverse events decreased by 30% (4.7 vs. 3.3 events per 100 admissions, P<0.001). The rate of nonpreventable adverse events did not change significantly (3.0 and 2.8 events per 100 admissions, P=0.79). Site-level analyses showed significant error reductions at six of nine sites. Across sites, significant increases were observed in the inclusion of all prespecified key elements in written documents and oral communication during handoff (nine written and five oral elements; P<0.001 for all 14 comparisons). There were no significant changes from the preintervention period to the postintervention period in the duration of oral handoffs (2.4 and 2.5 minutes per patient, respectively; P=0.55) or in resident workflow, including patient-family contact and computer time. CONCLUSIONS: Implementation of the handoff program was associated with reductions in medical errors and in preventable adverse events and with improvements in communication, without a negative effect on workflow. (Funded by the Office of the Assistant Secretary for Planning and Evaluation, U.S. Department of Health and Human Services, and others.).

Changes to pediatric clerkships' nighttime structure after introduction of the 2011 ACGME resident duty hour standards.

OBJECTIVE: To report changes in pediatric clerkship nighttime clinical structures before and after implementation of the 2011 Accreditation Council for Graduate Medical Education (ACGME) resident duty hour standards. METHODS: As part of the 2011 Council on Medical Student Education in Pediatrics (COMSEP) member annual survey, we surveyed leaders of pediatric undergraduate medical education on their medical school's current nighttime clinical structure, changes in nighttime structure between 2010 and 2011, and their school's student duty hour standards. RESULTS: Fifty-six percent (n = 83) of Liaison Committee for Medical Education (LCME)-accredited medical schools responded to the survey. Of received responses, 98% of pediatric clerkships have some form of nighttime clinical experience; 49% of clerkships have medical students stay late, 24% of clerkships utilize night shifts, and 16% use a traditional call structure. Forty-five percent of clerkships report changing their nighttime clinical experience after implementation of the 2011 ACGME duty hour standards; 46% of clerkships that changed had previously used traditional call. Seventy-six percent of clerkships report having medical student duty hour standards at their medical school. CONCLUSIONS: The majority of pediatric clerkships in our survey include nighttime clinical experiences in their curriculum, although variability exists in the type of structure. Additionally, the new ACGME duty hour standards appear to affect clerkships directors' choice of structure.

Strong, tough and stiff bioinspired ceramics from brittle constituents.

High strength and high toughness are usually mutually exclusive in engineering materials. In ceramics, improving toughness usually relies on the introduction of a metallic or polymeric ductile phase, but this decreases the material's strength and stiffness as well as its high-temperature stability. Although natural materials that are both strong and tough rely on a combination of mechanisms operating at different length scales, the relevant structures have been extremely difficult to replicate. Here, we report a bioinspired approach based on widespread ceramic processing techniques for the fabrication of bulk ceramics without a ductile phase and with a unique combination of high strength (470 MPa), high toughness (22 MPa m(1/2)), and high stiffness (290 GPa). Because only mineral constituents are needed, these ceramics retain their mechanical properties at high temperatures (600 °C). Our bioinspired, material-independent approach should find uses in the design and processing of materials for structural, transportation and energy-related applications.

Binocular shape constancy from novel views: the role of a priori constraints.

We tested shape constancy from novel views in the case of binocular viewing, using a variety of stimuli, including polyhedra, polygonal lines, and points in 3-D. The results of the psychophysical experiments show that constraints such as planarity of surface contours and symmetry are critical for reliable shape constancy. These results are consistent with the results obtained in our previous psychophysical experiments on shape constancy from novel views in the presence of a kinetic depth effect (Pizlo & Stevenson, 1999). On the basis of these results, we developed a new model of binocular shape reconstruction. The model is based on the assumption that binocular reconstruction is a difficult inverse problem, whose solution requires imposing a priori constraints on the family of possible interpretations. In the model, binocular disparity is used to correct monocularly reconstructed shape. The new model was tested on the same shapes as those used in the psychophysical experiments. The reconstructions produced by this model are substantially more reliable than the reconstructions produced by models that do not use constraints. Interestingly, monocular (but not binocular) reconstructions produced by this model correlate well with both monocular and binocular performance of human subjects. This fact suggests that binocular and monocular reconstructions of shapes in the human visual system involve similar mechanisms based on monocular shape constraints.