Sharpening the lens to evaluate interprofessional education and interprofessional collaboration by improving the conceptual framework: a critical discussion.

It has been difficult to demonstrate that interprofessional education (IPE) and interprofessional collaboration (IPC) have positive effects on patient care quality, cost effectiveness of patient care, and healthcare provider satisfaction. Here we propose a detailed explanation for this difficulty based on an adjusted theory about cause and effect in the field of IPE and IPC by asking: 1) What are the critical weaknesses of the causal models predominantly used which link IPE with IPC, and IPE and IPC with final outcomes? 2) What would a more precise causal model look like? 3) Can the proposed novel model help us better understand the challenges of IPE and IPC outcome evaluations? In the format of a critical theoretical discussion, based on a critical appraisal of the literature, we first reason that a monocausal, IPE-biased view on IPC and IPC outcomes does not form a sufficient foundation for proper IPE and IPC outcome evaluations; rather, interprofessional organization (IPO) has to be considered an additional necessary cause for IPC; and factors outside of IPC additional causes for final outcomes. Second, we present an adjusted model representing the "multi-stage multi-causality" of patient, healthcare provider, and system outcomes. Third, we demonstrate the model's explanatory power by employing it to deduce why misuse of the modified Kirkpatrick classification as a causal model in IPE and IPC outcome evaluations might have led to inconclusive results in the past. We conclude by applying the derived theoretical clarification to formulate recommendations for enhancing future evaluations of IPE, IPO, and IPC. Our main recommendations: 1) Focus should be placed on a comprehensive evaluation of factual IPC as the fundamental metric and 2) A step-by-step approach should be used that separates the outcome evaluation of IPE from that of IPC in the overarching quest for proving the benefits of IPE, IPO and IPC for patients, healthcare providers, and health systems. With this critical discussion we hope to enable more effective evaluations of IPE, IPO and IPC in the future.

Mixed methods instrument validation: Evaluation procedures for practitioners developed from the validation of the Swiss Instrument for Evaluating Interprofessional Collaboration.

BACKGROUND: Quantitative and qualitative procedures are necessary components of instrument development and assessment. However, validation studies conventionally emphasise quantitative assessments while neglecting qualitative procedures. Applying both methods in a mixed methods design provides additional insights into instrument quality and more rigorous validity evidence. Drawing from an extensive review of the methodological and applied validation literature on mixed methods, we showcase our use of mixed methods for validation which applied the quality criteria of congruence, convergence, and credibility on data collected with an instrument measuring interprofessional collaboration in the context of Swiss healthcare, named the Swiss Instrument for Evaluating Interprofessional Collaboration. METHODS: We employ a convergent parallel mixed methods design to analyse quantitative and qualitative questionnaire data. Data were collected from staff, supervisors, and patients of a university hospital and regional hospitals in the German and Italian speaking regions of Switzerland. We compare quantitative ratings and qualitative comments to evaluate the quality criteria of congruence, convergence, and credibility, which together form part of an instrument's construct validity evidence. RESULTS: Questionnaires from 435 staff, 133 supervisors, and 189 patients were collected. Analysis of congruence potentially provides explanations why respondents' comments are off topic. Convergence between quantitative ratings and qualitative comments can be interpreted as an indication of convergent validity. Credibility provides a summary evaluation of instrument quality. These quality criteria provide evidence that questions were understood as intended, provide construct validity, and also point to potential item quality issues. CONCLUSIONS: Mixed methods provide alternative means of collecting construct validity evidence. Our suggested procedures can be easily applied on empirical data and allow the congruence, convergence, and credibility of questionnaire items to be evaluated. The described procedures provide an efficient means of enhancing the rigor of an instrument and can be used alone or in conjunction with traditional quantitative psychometric approaches.

Entrustment versus performance scale in high-stakes OSCEs: Rater insights and psychometric properties.

BACKGROUND: Although entrustment scales are increasingly applied in workplace-based assessments, their role in OSCEs remains unclear. We investigated raters' perceptions using an entrustment scale and psychometric analyses. METHOD: A mixed-methods design was used. OSCE raters' (n = 162) perceptions were explored via questionnaire and four focus groups (n = 14). Psychometric OSCE properties were analyzed statistically. RESULTS: Raters (n = 53, response rate = 41%) considered the entrustment scale comprehensible (89%) and applicable (60%). A total of 43% preferred the entrustment scale, 21% preferred the global performance scale, and 36% were undecided. Raters' written comments indicated that while they appreciated the authenticity of entrustment levels, they considered them subjective. The focus groups highlighted three main themes: (1) recollections of the clinical workplace as a cognitive reference triggered by entrustment scales; (2) factors influencing entrustment decisions; and (3) cognitive load is reduced at the perceived cost of objectivity. Psychometric analyses (n = 480 students) revealed improvements in some OSCE metrics when entrustment and global performance scales were combined. CONCLUSION: Entrustment scales are beneficial for high-stakes OSCEs and have greater clinical relevance from the raters' perspective. Our findings support the use of entrustment and global performance scales in combination.

Presynaptic NMDA Receptors Influence Ca2+ Dynamics by Interacting with Voltage-Dependent Calcium Channels during the Induction of Long-Term Depression.

Spike-timing-dependent long-term depression (t-LTD) of glutamatergic layer (L)4-L2/3 synapses in developing neocortex requires activation of astrocytes by endocannabinoids (eCBs), which release glutamate onto presynaptic NMDA receptors (preNMDARs). The exact function of preNMDARs in this context is still elusive and strongly debated. To elucidate their function, we show that bath application of the eCB 2-arachidonylglycerol (2-AG) induces a preNMDAR-dependent form of chemically induced LTD (eCB-LTD) in L2/3 pyramidal neurons in the juvenile somatosensory cortex of rats. Presynaptic Ca2+ imaging from L4 spiny stellate axons revealed that action potential (AP) evoked Ca2+ transients show a preNMDAR-dependent broadening during eCB-LTD induction. However, blockade of voltage-dependent Ca2+ channels (VDCCs) did not uncover direct preNMDAR-mediated Ca2+ transients in the axon. This suggests that astrocyte-mediated glutamate release onto preNMDARs does not result in a direct Ca2+ influx, but that it instead leads to an indirect interaction with presynaptic VDCCs, boosting axonal Ca2+ influx. These results reveal one of the main remaining missing pieces in the signaling cascade of t-LTD at developing cortical synapses.

Ten caveats of learning analytics in health professions education: A consumer's perspective.

A group of 22 medical educators from different European countries, gathered in a meeting in Utrecht in July 2019, discussed the topic of learning analytics (LA) in an open conversation and addressed its definition, its purposes and potential risks for learners and teachers. LA was seen as a significant advance with important potential to improve education, but the group felt that potential drawbacks of using LA may yet be under-exposed in the literature. After transcription and interpretation of the discussion's conclusions, a document was drafted and fed back to the group in two rounds to arrive at a series of 10 caveats educators should be aware of when developing and using LA, including too much standardized learning, with undue consequences of over-efficiency and pressure on learners and teachers, and a decrease of the variety of 'valid' learning resources. Learning analytics may misalign with eventual clinical performance and can run the risk of privacy breaches and inescapability of documented failures. These consequences may not happen, but the authors, on behalf of the full group of educators, felt it worth to signal these caveats from a consumers' perspective.

Swiss general internal medicine board examination: quantitative effects of publicly available and unavailable questions on question difficulty and test performance.

BACKGROUND: Formerly, a substantial number of the 120 multiple-choice questions of the Swiss Society of General Internal Medicine (SSGIM) board examination were derived from publicly available MKSAP questions (Medical Knowledge Self-Assessment Program®). The possibility to memorise publicly available questions may unduly influence the candidates' examination performance. Therefore, the examination board raised concerns that the examination did not meet the objective of evaluating the application of knowledge. The society decided to develop new, "Helvetic" questions to improve the examination. The aim of the present study was to quantitatively assess the degree of difficulty of the Helvetic questions (HQ) compared with publicly available and unavailable MKSAP questions and to investigate whether the degree of difficulty of MKSAP questions changed over time as their status changed from publicly available to unavailable. METHODS: The November 2019 examination consisted of 40 Helvetic questions, 40 publicly available questions from MKSAP edition 17 (MKSAP-17) and 40 questions from MKSAP-15/16, which were no longer publicly available at the time of the examination. An one factorial univariate analysis of variance (ANOVA) examined question difficulty (lower values mean higher difficulty) between these three question sets. A repeated ANOVA compared the difficulty of MKSAP-15/16 questions in the November 2019 examination with the difficulty of the exact same questions from former examinations, when these questions belonged to the publicly available MKSAP edition. The publicly available MKSAP-17 and the publicly unavailable Helvetic questions served as control. RESULTS: The analysis of the November 2019 exam showed a significant difference in average item difficulty between Helvetic and MKSAP-17 questions (71% vs 86%, p <0.001) and between MKSAP-15/16 and MKSAP-17 questions (70% vs 86%, p <0.001). There was no significant difference in item difficulty between Helvetic and MKSAP-15/16 questions (71% vs 70%, p = 0.993). The repeated measures ANOVA on question use and the three question categories showed a significant interaction (p <0.001, partial eta-squared = 0.422). The change in the availability of MKSAP-15/16 questions had a strong effect on difficulty. Questions became on average 21.9% more difficult when they were no longer publicly available. In contrast, the difficulty of the MKSAP-17 and Helvetic questions did not change significantly across administrations. DISCUSSION: This study provides the quantitative evidence that the public availability of questions has a decisive influence on question difficulty and thus on SSGIM board examination performance. Reducing the number of publicly available questions in the examination by introducing confidential, high-quality Helvetic questions contributes to the validity of the board examination by addressing higher order cognitive skills and making rote-learning strategies less effective.

Heuristically optimal path scanning for high-speed multiphoton circuit imaging.

Population dynamics of patterned neuronal firing are fundamental to information processing in the brain. Multiphoton microscopy in combination with calcium indicator dyes allows circuit dynamics to be imaged with single-neuron resolution. However, the temporal resolution of fluorescent measures is constrained by the imaging frequency imposed by standard raster scanning techniques. As a result, traditional raster scans limit the ability to detect the relative timing of action potentials in the imaged neuronal population. To maximize the speed of fluorescence measures from large populations of neurons using a standard multiphoton laser scanning microscope (MPLSM) setup, we have developed heuristically optimal path scanning (HOPS). HOPS optimizes the laser travel path length, and thus the temporal resolution of neuronal fluorescent measures, using standard galvanometer scan mirrors. Minimizing the scan path alone is insufficient for prolonged high-speed imaging of neuronal populations. Path stability and the signal-to-noise ratio become increasingly important factors as scan rates increase. HOPS addresses this by characterizing the scan mirror galvanometers to achieve prolonged path stability. In addition, the neuronal dwell time is optimized to sharpen the detection of action potentials while maximizing scan rate. The combination of shortest path calculation and minimization of mirror positioning time allows us to optically monitor a population of neurons in a field of view at high rates with single-spike resolution, ∼ 125 Hz for 50 neurons and ∼ 8.5 Hz for 1,000 neurons. Our approach introduces an accessible method for rapid imaging of large neuronal populations using traditional MPLSMs, facilitating new insights into neuronal circuit dynamics.

GABAB receptor-dependent modulation of network activity in the rat prefrontal cortex in vitro.

GABA (gamma-aminobutyric acid) can mediate inhibition via pre- and post/extrasynaptic GABA receptors. In this paper we demonstrate potentially post/extrasynaptic GABA(B) receptor-dependent tonic inhibition in L2/3 pyramidal cells of rat medial prefrontal cortex (mPFC) in vitro. First, we show via voltage-clamp experiments the presence of a tonic GABA(B) receptor-dependent outward current in these neurons. This GABA(B)ergic current could be induced by ambient GABA when present at sufficient concentrations. To increase ambient GABA levels in the usually silent slice preparation, we amplified network activity and hence synaptic GABA release with a modified artificial cerebrospinal fluid. The amplitude of tonic GABA(B) current was similar at different temperatures. In addition to the tonic GABA(B) current, we found presynaptic GABA(B) effects, GABA(B)-mediated inhibitory postsynaptic currents and tonic GABA(A) currents. Second, we performed current-clamp experiments to evaluate the functional impact of GABA(B) receptor-mediated inhibition in the mPFC. Activating or inactivating GABA(B) receptors led to rightward (reduction of excitability) or leftward (increase of excitability) shifts, respectively, of the input-output function of mPFC L2/3 pyramidal cells without effects on the slope. Finally, we showed in electrophysiological recordings and epifluorescence Ca(2+)-imaging that GABA(B) receptor-mediated tonic inhibition is capable of regulating network activity. Blocking GABA(B) receptors increased the frequency of excitatory postsynaptic currents impinging on a neuron and prolonged network upstates. These results show that ambient GABA via GABA(B) receptors is powerful enough to modulate neuronal excitability and the activity of neural networks.

Local changes in neocortical circuit dynamics coincide with the spread of seizures to thalamus in a model of epilepsy.

During the generalization of epileptic seizures, pathological activity in one brain area recruits distant brain structures into joint synchronous discharges. However, it remains unknown whether specific changes in local circuit activity are related to the aberrant recruitment of anatomically distant structures into epileptiform discharges. Further, it is not known whether aberrant areas recruit or entrain healthy ones into pathological activity. Here we study the dynamics of local circuit activity during the spread of epileptiform discharges in the zero-magnesium in vitro model of epilepsy. We employ high-speed multi-photon imaging in combination with dual whole-cell recordings in acute thalamocortical (TC) slices of the juvenile mouse to characterize the generalization of epileptic activity between neocortex and thalamus. We find that, although both structures are exposed to zero-magnesium, the initial onset of focal epileptiform discharge occurs in cortex. This suggests that local recurrent connectivity that is particularly prevalent in cortex is important for the initiation of seizure activity. Subsequent recruitment of thalamus into joint, generalized discharges is coincident with an increase in the coherence of local cortical circuit activity that itself does not depend on thalamus. Finally, the intensity of population discharges is positively correlated between both brain areas. This suggests that during and after seizure generalization not only the timing but also the amplitude of epileptiform discharges in thalamus is entrained by cortex. Together these results suggest a central role of neocortical activity for the onset and the structure of pathological recruitment of thalamus into joint synchronous epileptiform discharges.

Predictive factors for successful salvage high-dose therapy in patients with multiple myeloma relapsing after autologous blood stem cell transplantation.

For patients with relapsed or refractory multiple myeloma (MM) treated with a prior high-dose therapy (HDT) followed by autologous peripheral blood stem cell transplantation (PBSCT), the reapplication of HDT is a widely used salvage strategy. In this retrospective study, we report on 55 patients who were treated with salvage HDT at our institution. The conditioning regimen consisted of melphalan 200 mg/m(2) (27%), melphalan 140 mg/m(2) and busulfan 12 mg/kg body weight (40%), or melphalan 200 mg/m(2) and bortezomib 1.3 mg/m(2) (33%). Treatment-related mortality was 5% and response rates were as follows: 9% complete remission, 9% very good partial remission, 56% partial remission, 11% minimal response + stable disease, and 4% progressive disease (5% not assessable). Toxicity was moderate and the median event-free (EFS) and overall survival (OS) were 14 months and 52 months, respectively. The different conditioning regimens did not result in differences in terms of remission rates, EFS and OS, or toxicity. In multivariate analysis a duration of remission of more than 12 months after the first transplant was the only predictive factor for both EFS (p < 0.0001) and OS (p = 0.0001). In conclusion, salvage HDT followed by autologous PBSCT is an effective treatment option for patients with relapsed or refractory MM, while patients with an early relapse after their first transplant do not benefit from this treatment modality.

Somatodendritic integration under increased network activity in layer 5 pyramidal cells of the somatosensory cortex.

Integrative properties of single neurons have been extensively studied in acute brain slices. However, these preparations are characterized by extremely low levels of synaptic and action potential activity. In comparison to in vivo, reduced intracortical input and lack of subcortical modulation increase the effective difference between mean membrane potential and spiking threshold, preventing self-sustained network activity in vitro. To elicit an increased and stable network activity (INA) in vitro comparable to that found in awake animals, we mimicked subcortical cholinergic and serotoninergic inputs using carbachol or barium alone or in combination with serotonin in layer 5 pyramidal cells in slices of mouse somatosensory cortex. INA is primarily induced by a modulation of intrinsic conductances resulting in a depolarization of the membrane potential. We studied the impact of INA on synaptic and somatodendritic integration using extracellular stimulation and dendritic calcium imaging. Synaptic inhibition is strengthened due to an increased driving force for chloride. The critical frequency at which somatic action potentials induce a dendritic calcium action potential is lowered. Simultaneous inhibitory synaptic input is powerful enough to suppress dendritic calcium action potential generation. Pharmacologically induced INA enables the study of neuronal integration in well-accessible cortical slices within an active network.

Combined voltage and calcium epifluorescence imaging in vitro and in vivo reveals subthreshold and suprathreshold dynamics of mouse barrel cortex.

Cortical dynamics can be imaged at high spatiotemporal resolution with voltage-sensitive dyes (VSDs) and calcium-sensitive dyes (CaSDs). We combined these two imaging techniques using epifluorescence optics together with whole cell recordings to measure the spatiotemporal dynamics of activity in the mouse somatosensory barrel cortex in vitro and in the supragranular layers in vivo. The two optical signals reported distinct aspects of cortical function. VSD fluorescence varied linearly with membrane potential and was dominated by subthreshold postsynaptic potentials, whereas the CaSD signal predominantly reflected local action potential firing. Combining VSDs and CaSDs allowed us to monitor the synaptic drive and the spiking activity of a given area at the same time in the same preparation. The spatial extent of the two dye signals was different, with VSD signals spreading further than CaSD signals, reflecting broad subthreshold and narrow suprathreshold receptive fields. Importantly, the signals from the dyes were differentially affected by pharmacological manipulations, stimulation strength, and depth of isoflurane anesthesia. Combined VSD and CaSD measurements can therefore be used to specify the temporal and spatial relationships between subthreshold and suprathreshold activity of the neocortex.

The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways.

Bone morphogenetic proteins (BMPs) are multifunctional proteins regulating cell growth, differentiation, and apoptosis. BMP-2 signals via two types of receptors (BRI and BRII) that are expressed at the cell surface as homomeric as well as heteromeric complexes. Prior to ligand binding, a low but measurable level of BMP-receptors is found in preformed hetero-oligomeric complexes. The major fraction of the receptors is recruited into hetero-oligomeric complexes only after ligand addition. For this, BMP-2 binds first to the high affinity receptor BRI and then recruits BRII into the signaling complex. However, ligand binding to the preformed complex composed of BRII and BRI is still required for signaling, suggesting that it may mediate activating conformational changes. Using several approaches we have addressed the following questions: (i) Are preformed complexes incompetent of signaling in the absence of BMP-2? (ii) Which domains of the BRII receptors are essential for this complex formation? (iii) Are there differences in signals sent from BMP-induced versus preformed receptor complexes? By measuring the activation of Smads, of p38 MAPK and of alkaline phosphatase, we show that the ability of kinase-deficient BRII receptor mutants to inhibit BMP signaling depends on their ability to form heteromeric complexes with BRI. Importantly, a BRII mutant that is incapable in forming preassembled receptor complexes but recruits into a BMP-induced receptor complex does not interfere with the Smad pathway but does inhibit the induction of alkaline phosphatase as well as p38 phosphorylation. These results indicate that signals induced by binding of BMP-2 to preformed receptor complexes activate the Smad pathway, whereas BMP-2-induced recruitment of receptors activates a different, Smad-independent pathway resulting in the induction of alkaline phosphatase activity via p38 MAPK.