Case-Based Learning in Surgery: Lessons Learned

Background  

The aim of the study was to obtain a deepened understanding of the implementation process of case-based learning (CBL) during a surgical semester at the Undergraduate Medical Program at Karolinska Institutet. The objectives are to identify the level of success of the implementation and to identify practical and theoretical implications of importance in connection to the process.     

Physical training increases osteoprotegerin in postmenopausal women

The purpose of this study was to explore whether mechanical loading by exercise over a 1–year period in postmenopausal women had an effect on the receptor activator for nuclear factor kappa B ligand/osteoprotegerin (RANKL/OPG) system or the levels of the Wnt-signaling antagonist sclerostin. A total of 112 postmenopausal were randomized to either sedentary life (controls) or physical activity (training group). Ninety-two women fulfilled the study protocol. The training program consisted of three fast 30-min walks and one or two 1-h aerobic training sessions per week. The effect on the bone mineral density of the hip assessed with dual X-ray absorptiometry was positive as reported earlier. Blood samples were taken from participants at baseline and after 1 year and serum levels of OPG, RANKL and sclerostin were quantified together with the bone metabolism markers C-terminal telopeptide of collagen type I (CTX) and bone-specific alkaline phosphatase (BALP). The results were analyzed using an analysis of covariance model using baseline values as the covariate. The training group displayed a clear mean increase of OPG +7.55 pg/ml compared to controls (p = 0.007). The mean changes for RANKL +0.19 pg/ml (square-root transformed data) and sclerostin +0.62 pmol/l were non-significant (p = 0.13 and p = 0.34). The changes in bone turnover markers CTX and BALP showed a tendency to decrease in the training group versus controls but the changes were small and non-significant. Although our study is limited in number of participating women, we have been able to show an OPG-associated, and RANKL- and sclerostin-independent, training-induced inhibition of postmenopausal bone loss.     

Multiple brown tumours of the upper extremity in a patient with secondary hyperparathyroidism as a result of chronic renal failure

A man with chronic renal failure was referred to the hand clinic because of massive osteolytic tumours in his right arm. Secondary hyperparathyroidism and brown tumours were suggested, and he was treated by subtotal parathyroidectomy. Rapid reduction of the vast tumours was noted postoperatively.     

High-flow nasal cannula (HFNC) support in interhospital transport of critically ill children

Purpose

Optimal respiratory support for interhospital transport of critically ill children is challenging and has been scarcely investigated. High-flow nasal cannula (HFNC) therapy has emerged as a promising support mode in the paediatric intensive care unit (PICU), but no data are available on HFNC used during interhospital transport. We aimed to assess the safety of HFNC during retrievals of critically ill children and its impact on the need for invasive ventilation (IV).

Methods

This was a retrospective, single-centre study of children under 2 years old transported by a specialized paediatric retrieval team to PICU. We compared IV rates before (2005–2008) and after introduction of HFNC therapy (2009–2012).

Results

A total of 793 infants were transported. The mean transport duration was 1.4 h (range 0.25–8), with a mean distance of 205 km (2–2,856). Before introduction of HFNC, 7 % (n = 23) were retrieved on non-invasive ventilation (NIV) and 49 % (n = 163) on IV. After introduction of HFNC, 33 % (n = 150) were retrieved on HFNC, 2 % (n = 10) on NIV, whereas IV decreased to 35 % (n = 162, p < 0.001). No patients retrieved on HFNC required intubation during retrieval, or developed pneumothorax or cardiac arrest. Using HFNC was associated with a significant reduction in IV initiated by the retrieval team (multivariate OR 0.51; 95 % CI 0.27–0.95; p = 0.032).

Conclusions

We report on a major change of practice in transport of critically ill children in our retrieval system. HFNC therapy was increasingly used and was not inferior to low-flow oxygen or NIV. Randomized trials are needed to assess whether HFNC can reduce the need for IV in interhospital transport of critically ill children.     

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Therapies to prevent transmission of malaria parasites to the mosquito vector are a vital part of the global malaria elimination agenda. Primaquine is currently the only drug with such activity; however, its use is limited by side effects. The development of transmission-blocking strategies requires an understanding of sexual stage malaria parasite (gametocyte) biology and the identification of new drug leads. Lysine acetylation is an important posttranslational modification involved in regulating eukaryotic gene expression and other essential processes. Interfering with this process with histone deacetylase (HDAC) inhibitors is a validated strategy for cancer and other diseases, including asexual stage malaria parasites. Here we confirm the expression of at least one HDAC protein in Plasmodium falciparum gametocytes and show that histone and nonhistone protein acetylation occurs in this life cycle stage. The activity of the canonical HDAC inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; Vorinostat) and a panel of novel HDAC inhibitors on early/late-stage gametocytes and on gamete formation was examined. Several compounds displayed early/late-stage gametocytocidal activity, with TSA being the most potent (50% inhibitory concentration, 70 to 90 nM). In contrast, no inhibitory activity was observed in P. falciparum gametocyte exflagellation experiments. Gametocytocidal HDAC inhibitors caused hyperacetylation of gametocyte histones, consistent with a mode of action targeting HDAC activity. Our data identify HDAC inhibitors as being among a limited number of compounds that target both asexual and sexual stage malaria parasites, making them a potential new starting point for gametocytocidal drug leads and valuable tools for dissecting gametocyte biology.     

A three-dimensional finite element model of human atrial anatomy: New methods for cubic Hermite meshes with extraordinary vertices

High-order cubic Hermite finite elements have been valuable in modeling cardiac geometry, fiber orientations, biomechanics, and electrophysiology, but their use in solving three-dimensional problems has been limited to ventricular models with simple topologies. Here, we utilized a subdivision surface scheme and derived a generalization of the “local-to-global” derivative mapping scheme of cubic Hermite finite elements to construct bicubic and tricubic Hermite models of the human atria with extraordinary vertices from computed tomography images of a patient with atrial fibrillation. To an accuracy of 0.6 mm, we were able to capture the left atrial geometry with only 142 bicubic Hermite finite elements, and the right atrial geometry with only 90. The left and right atrial bicubic Hermite meshes were G1 continuous everywhere except in the one-neighborhood of extraordinary vertices, where the mean dot products of normals at adjacent elements were 0.928 and 0.925. We also constructed two biatrial tricubic Hermite models and defined fiber orientation fields in agreement with diagrammatic data from the literature using only 42 angle parameters. The meshes all have good quality metrics, uniform element sizes, and elements with aspect ratios near unity, and are shared with the public. These new methods will allow for more compact and efficient patient-specific models of human atrial and whole heart physiology.     

From the Cover: Electronic resonance with anticorrelated pigment vibrations drives photosynthetic energy transfer outside the adiabatic framework

The delocalized, anticorrelated component of pigment vibrations can drive nonadiabatic electronic energy transfer in photosynthetic light-harvesting antennas. In femtosecond experiments, this energy transfer mechanism leads to excitation of delocalized, anticorrelated vibrational wavepackets on the ground electronic state that exhibit not only 2D spectroscopic signatures attributed to electronic coherence and oscillatory quantum energy transport but also a cross-peak asymmetry not previously explained by theory. A number of antennas have electronic energy gaps matching a pigment vibrational frequency with a small vibrational coordinate change on electronic excitation. Such photosynthetic energy transfer steps resemble molecular internal conversion through a nested intermolecular funnel.     

Integrated view of genome structure and sequence of a single DNA molecule in a nanofluidic device

We show how a bird’s-eye view of genomic structure can be obtained at ∼1-kb resolution from long (∼2 Mb) DNA molecules extracted from whole chromosomes in a nanofluidic laboratory-on-a-chip. We use an improved single-molecule denaturation mapping approach to detect repetitive elements and known as well as unique structural variation. Following its mapping, a molecule of interest was rescued from the chip; amplified and localized to a chromosome by FISH; and interrogated down to 1-bp resolution with a commercial sequencer, thereby reconciling haplotype-phased chromosome substructure with sequence.Despite the sequencing of thousands of genomes (1), no human genome—reference or individual—has been described to completion (2): gaps remain in the genome reference sequence and there is a discontinuity between the resolution of next-generation sequencing and the resolution of cytogenetics. This gap leaves structure in the kilobase-to-megabase range partly unmapped. The nature and extent of highly repetitive regions—the centromeres, rDNA on the short arms of acrocentric chromosomes, the long arm of the Y chromosome—remain to be fully delineated, as do the sequences embedded in these regions. Sequencing of individual genomes (3) has also revealed that chromosome-scale amounts of sequence do not align to the human reference genome (4, 5), suggesting that substantial levels of sequence insertions are specific to individuals or subpopulations. Structural variation (SV) comprising rearrangement, loss, or gain of genomic regions is increasingly linked to phenotype and disease (6, 7). In cancer genomes, SV can be extreme (8) and difficult to deconvolve.All types and scales of SV pervade the human genome, but a single approach cannot capture them all (9). For example, though unbalanced SV can be readily ascertained by array technology, balanced SV cannot; a comprehensive analysis by paired-end sequencing is challenging and cost-prohibitive. Single-molecule optical mapping (10–13) facilitates assembly of genomes and detects SV, but haplotype phase is not preserved, because it requires construction of a consensus map from many molecules. These molecules cannot be recovered for further analysis, requiring larger amounts of sample for analysis, which may not be available, e.g., single-cell sequencing and clinical samples. An attempt to combine haplotyping and sequencing on Illumina flow cells was limited to sequencing only at the ends of short fragments (≤8 kb) (14).Microfluidic laboratory-on-a-chip devices have been used to separate individual chromosomes and extract genomic DNA (15, 16), enabling haplotype-phased genotype and sequence to be obtained. Meanwhile, laboratory-on-a-chip systems incorporating nanofluidics have been used to stretch and map DNA (17–19), but their application to detecting SV has remained theoretical due to technical limitations of the designs used. Existing platforms either do not stretch and hold DNA well enough to consistently produce accurate maps from a single molecule (20, 21), or they use inefficient labeling chemistry (22) and consequently cannot differentiate between poor matches and actual structural variation within a single molecule. These platforms also require purified input DNA, which is typically sheared during handling steps, cannot produce maps longer than a few hundred kilobases, and cannot readily recover the mapped DNA molecules to perform conventional genomic analysis. Finally, although confinement in nanochannels can provide high stretching under extreme buffer conditions (23), it is desirable to achieve full stretching independently of buffer composition.Here we describe a laboratory-on-a-chip design that overcomes these technical limitations and a procedure that offers an integrated view of human genome structure. By integrating a nanofluidic system with elongation flow into a laboratory-on-a-chip, (i) haplotype-phased chromosome substructures can be visualized on single megabase-scale molecules, (ii) structural variation ranging in size from a few kilobases to megabases can then be detected, (iii) our experimental maps can be compared with theoretical maps based on different genome assemblies, and variations can be detected, and (iv) interrogation of the same molecule can be zoomed out to the cytogenetic level and zoomed in to the sequence level.