APC sets the Wnt tone necessary for cerebral cortical progenitor development.

Adenomatous polyposis coli (APC) regulates the activity of ß-catenin, an integral component of Wnt signaling. However, the selective role of the APC-ß-catenin pathway in cerebral cortical development is unknown. Here we genetically dissected the relative contributions of APC-regulated ß-catenin signaling in cortical progenitor development, a necessary early step in cerebral cortical formation. Radial progenitor-specific inactivation of the APC-ß-catenin pathway indicates that the maintenance of appropriate ß-catenin-mediated Wnt tone is necessary for the orderly differentiation of cortical progenitors and the resultant formation of the cerebral cortex. APC deletion deregulates ß-catenin, leads to high Wnt tone, and disrupts Notch1 signaling and primary cilium maintenance necessary for radial progenitor functions. ß-Catenin deregulation directly disrupts cilium maintenance and signaling via Tulp3, essential for intraflagellar transport of ciliary signaling receptors. Surprisingly, deletion of ß-catenin or inhibition of ß-catenin activity in APC-null progenitors rescues the APC-null phenotype. These results reveal that APC-regulated ß-catenin activity in cortical progenitors sets the appropriate Wnt tone necessary for normal cerebral cortical development.

A Million Crystal Structures: The Whole Is Greater than the Sum of Its Parts.

The founding in 1965 of what is now called the Cambridge Structural Database (CSD) has reaped dividends in numerous and diverse areas of chemical research. Each of the million or so crystal structures in the database was solved for its own particular reason, but collected together, the structures can be reused to address a multitude of new problems. In this Review, which is focused mainly on the last 10 years, we chronicle the contribution of the CSD to research into molecular geometries, molecular interactions, and molecular assemblies and demonstrate its value in the design of biologically active molecules and the solid forms in which they are delivered. Its potential in other commercially relevant areas is described, including gas storage and delivery, thin films, and (opto)electronics. The CSD also aids the solution of new crystal structures. Because no scientific instrument is without shortcomings, the limitations of CSD research are assessed. We emphasize the importance of maintaining database quality: notwithstanding the arrival of big data and machine learning, it remains perilous to ignore the principle of garbage in, garbage out. Finally, we explain why the CSD must evolve with the world around it to ensure it remains fit for purpose in the years ahead.

Identification of Noncompetitive Protein-Ligand Interactions for Structural Optimization.

For efficient structure-guided drug design, it is important to have an excellent understanding of the quality of interactions between the target receptor and bound ligands. Identification and characterization of poor intermolecular contacts offers the possibility to focus design efforts directly on ligand regions with suboptimal molecular recognition. To enable a more straightforward identification of these in a structural model, we use a suitably enhanced version of our previously introduced statistical ratio of frequencies (RF) approach. This allows us to highlight protein-ligand interactions and geometries that occur much less often in the Protein Data Bank than would be expected from the exposed surface areas of the interacting atoms. We provide a comprehensive overview of such noncompetitive interactions and geometries for a set of common ligand substituents. Through retrospective case studies on congeneric series and single-point mutations for several pharmaceutical targets, we illustrate how knowledge of noncompetitive interactions could be exploited in the drug design process.

Renal function and the long-term clinical outcomes of cardiac resynchronization therapy with or without defibrillation.

BACKGROUND AND AIMS: Patients with moderate-to-severe chronic kidney disease (CKD) are underrepresented in clinical trials of cardiac resynchronization therapy (CRT)-defibrillation (CRT-D) or CRT-pacing (CRT-P). We sought to determine whether outcomes after CRT-D are better than after CRT-P over a wide spectrum of CKD. METHODS AND RESULTS: Clinical events were quantified in relation to preimplant estimated glomerular filtration rate (eGFR) after CRT-D (n = 410 [39.2%]) or CRT-P (n = 636 [60.8%]) implantation. Over a follow-up period of 3.7 years (median, interquartile range: 2.1-5.7), the eGFR < 60 group (n = 598) had a higher risk of total mortality (adjusted hazard ratio [aHR]: 1.28; P = 0.017), total mortality or heart failure (HF) hospitalization (aHR: 1.32; P = 0.004), total mortality or hospitalization for major adverse cardiac events (MACEs, aHR: 1.34; P = 0.002), and cardiac mortality (aHR: 1.33; P = 0.036), compared to the eGFR ≥ 60 group (n = 448), after covariate adjustment. In analyses of CRT-D versus CRT-P, CRT-D was associated with a lower risk of total mortality (eGFR ≥ 60 HR: 0.65; P = 0.028; eGFR < 60 HR: 0.64, P = 0.002), total mortality or HF hospitalization (eGFR ≥ 60 aHR: 0.66; P = 0.021; eGFR < 60 aHR: 0.69, P = 0.007), total mortality or hospitalization for MACEs (eGFR ≥ 60 aHR: 0.70; P = 0.039; eGFR < 60 aHR: 0.69, P = 0.005), and cardiac mortality (eGFR ≥ 60 aHR: 0.60; P = 0.026; eGFR < 60 aHR: 0.55; P = 0.003). CONCLUSION: In CRT recipients, moderate CKD is associated with a higher mortality and morbidity compared to normal renal function or mild CKD. Despite less favorable absolute outcomes, patients with moderate CKD had better outcomes after CRT-D than after CRT-P.

Knowledge-Based Conformer Generation Using the Cambridge Structural Database.

Fast generation of plausible molecular conformations is central to molecular modeling. This paper presents an approach to conformer generation that makes extensive use of the information available in the Cambridge Structural Database. By using geometric distributions derived from the Cambridge Structural Database, it is possible to create biologically relevant conformations in the majority of cases analyzed. The paper compares the performance of the approach with previously published evaluations, and presents some cases where the method fails. The method appears to show significantly improved performance in reproduction of the conformations of structures observed in the Cambridge Structural Database and the Protein Data Bank as compared to other published methods of a similar speed.

Long-term clinical outcomes of cardiac resynchronization therapy with or without defibrillation: impact of the aetiology of cardiomyopathy.

Aims: There is a continuing debate as to whether cardiac resynchronization therapy-defibrillation (CRT-D) is superior to CRT-pacing (CRT-P), particularly in patients with non-ischaemic cardiomyopathy (NICM). We sought to quantify the clinical outcomes after primary prevention of CRT-D and CRT-P and identify whether these differed according to the aetiology of cardiomyopathy. Methods and results: Analyses were undertaken in the total study population of patients treated with CRT-D (n = 551) or CRT-P (n = 999) and in propensity-matched samples. Device choice was governed by the clinical guidelines in the United Kingdom. In univariable analyses of the total study population, for a maximum follow-up of 16 years (median 4.7 years, interquartile range 2.4-7.1), CRT-D was associated with a lower total mortality [hazard ratio (HR) 0.72] and the composite endpoints of total mortality or heart failure (HF) hospitalization (HR 0.72) and total mortality or hospitalization for major adverse cardiac events (MACE; HR 0.71) (all P < 0.001). After propensity matching (n = 796), CRT-D was associated with a lower total mortality (HR 0.72) and the composite endpoints (all P < 0.01). When further stratified according to aetiology, CRT-D was associated with a lower total mortality (HR 0.62), total mortality or HF hospitalization (HR 0.63), and total mortality or hospitalization for MACE (HR 0.59) (all P < 0.001) in patients with ischaemic cardiomyopathy (ICM). There were no differences in outcomes between CRT-D and CRT-P in patients with NICM. Conclusion: In this study of real-world clinical practice, CRT-D was superior to CRT-P with respect to total mortality and composite endpoints, independent of known confounders. The benefit of CRT-D was evident in ICM but not in NICM.

Systematics of Cladophora spp. (Chlorophyta) from North Carolina, USA, based upon morphology and DNA sequence data with a description of Cladophora subtilissima sp. nov.

Identification of Cladophora species is challenging due to conservation of gross morphology, few discrete autapomorphies, and environmental influences on morphology. Twelve species of marine Cladophora were reported from North Carolina waters. Cladophora specimens were collected from inshore and offshore marine waters for DNA sequence and morphological analyses. The nuclear-encoded rRNA internal transcribed spacer regions (ITS) were sequenced for 105 specimens and used in molecular assisted identification. The ITS1 and ITS2 region was highly variable, and sequences were sorted into ITS Sets of Alignable Sequences (SASs). Sequencing of short hyper-variable ITS1 sections from Cladophora type specimens was used to positively identify species represented by SASs when the types were made available. Secondary structures for the ITS1 locus were also predicted for each specimen and compared to predicted structures from Cladophora sequences available in GenBank. Nine ITS SASs were identified and representative specimens chosen for phylogenetic analyses of 18S and 28S rRNA gene sequences to reveal relationships with other Cladophora species. Phylogenetic analyses indicated that marine Cladophorales were polyphyletic and separated into two clades, the Cladophora clade and the "Siphonocladales" clade. Morphological analyses were performed to assess the consistency of character states within species, and complement the DNA sequence analyses. These analyses revealed intra- and interspecific character state variation, and that combined molecular and morphological analyses were required for the identification of species. One new report, Cladophora dotyana, and one new species Cladophora subtilissima sp. nov., were revealed, and increased the biodiversity of North Carolina marine Cladophora to 14 species.

Mechanical effects of left ventricular midwall fibrosis in non-ischemic cardiomyopathy.

BACKGROUND: Left ventricular (LV) mid-wall fibrosis (MWF), which occurs in about a quarter of patients with non-ischemic cardiomyopathy (NICM), is associated with high risk of pump failure. The mid LV wall is the site of circumferential myocardial fibers. We sought to determine the effect of MWF on LV myocardial mechanics. METHODS: Patients with NICM (n = 116; age: 62.8 ± 13.2 years; 67% male) underwent late gadolinium enhancement cardiovascular magnetic resonance (CMR) and were categorized according to the presence (+) or absence (-) of MWF. Feature tracking (FT) CMR was used to assess myocardial deformation. RESULTS: Despite a similar LVEF (24.3 vs. 27.5%, p = 0.20), patients with MWF (32 [24%]) had lower global circumferential strain (Ɛcc: -6.6% vs. -9.4 %, P = 0.004), but similar longitudinal (Ɛll: -7.6 % vs. -9.4 %, p = 0.053) and radial (Ɛrr: 14.6% vs. 17.8% p = 0.18) strain. Compared with - MWF, + MWF was associated with reduced LV systolic, circumferential strain rate (-0.38 ± 0.1 vs. -0.56 ± 0.3 s(-1), p = 0.005) and peak LV twist (4.65 vs. 6.31°, p = 0.004), as well as rigid LV body rotation (64 % vs. 28 %, P <0.001). In addition, +MWF was associated with reduced LV diastolic strain rates (DSRcc: 0.34 vs. 0.46 s(-1); DSRll: 0.38 vs. 0.50s(-1); DSRrr: -0.55 vs. -0.75 s(-1); all p <0.05). CONCLUSIONS: MWF is associated with reduced LV global circumferential strain, strain rate and torsion. In addition, MWF is associated with rigid LV body rotation and reduced diastolic strain rates. These systolic and diastolic disturbances may be related to the increased risk of pump failure observed in patients with NICM and MWF.

The clinical outcome of cardiac resynchronization therapy in post-surgical valvular cardiomyopathy.

AIMS: Trials have shown that cardiac resynchronization therapy (CRT) is effective in patients with 'non-ischaemic cardiomyopathy'. Patients with post-surgical valvular cardiomyopathy (PSVCM) have been excluded from such trials. We sought to compare the clinical outcome of CRT in patients with PSVCM, idiopathic dilated cardiomyopathy (IDCM), or ischaemic cardiomyopathy (ICM). METHODS AND RESULTS: Clinical events and response to CRT were quantified in 556 patients (PSVCM = 38; IDCM = 165; ICM = 353) over 4.52 years [median, inter-quartile range (IQR): 4.42]. Response to CRT was defined as survival for ≥1 year free of hospitalizations plus improvement by ≥1 NYHA class or ≥25% in 6-min walking distance. Cardiac resynchronization therapy was initiated at 5.86 years (median, IQR: 9.86) after aortic valve replacement (73.7%) or mitral valve replacement/repair (44.7%). Compared with PSVCM, IDCM was associated with a lower total mortality [hazards ratio, HR: 0.54 (95% confidence interval, CI 0.34-0.84)], cardiac mortality [HR: 0.43 (95% CI 0.26-0.70)], and total mortality or major adverse cardiovascular events [HR: 0.57 (95% CI 0.37-0.87)], independent of known confounders. Compared with PSVCM, ICM was associated with a similar risk of death from pump failure [HR: 0.83 (95% CI 0.50-1.37)] and IDCM was associated with a lower risk [HR: 0.46 (95% CI 0.26-0.82)]. Response to CRT was similar across the groups. CONCLUSIONS: Compared with IDCM, PSVCM was associated with a worse outcome after CRT. Outcomes from PSVCM were similar to ICM. These findings indicate that PSVCM behaves very differently to IDCM after CRT.

Haemodynamic effects of cardiac resynchronization therapy using single-vein, three-pole, multipoint left ventricular pacing in patients with ischaemic cardiomyopathy and a left ventricular free wall scar: the MAESTRO study.

AIMS: The clinical response to cardiac resynchronization therapy (CRT) is variable. Multipoint left ventricular (LV) pacing could achieve more effective haemodynamic response than single-point LV pacing. Deployment of an LV lead over myocardial scar is associated with a poor haemodynamic response to and clinical outcome of CRT. We sought to determine whether the acute haemodynamic response to CRT using three-pole LV multipoint pacing (CRT3P-MPP) is superior to that to conventional CRT using single-site LV pacing (CRTSP) in patients with ischaemic cardiomyopathy and an LV free wall scar. METHODS AND RESULTS: Sixteen patients with ischaemic cardiomyopathy [aged 72.6 ± 7.7 years (mean ± SD), 81.3% male, QRS: 146.0 ± 14.2 ms, LBBB in 14 (87.5%)] in whom the LV lead was intentionally deployed straddling an LV free wall scar (assessed using cardiac magnetic resonance), underwent assessment of LV + dP/dtmax during CRT3P-MPP and CRTSP. Interindividually, the ΔLV + dP/dtmax in relation to AAI pacing with CRT3P-MPP (6.2 ± 13.3%) was higher than with basal and mid CRTSP (both P < 0.001), but similar to apical CRTSP. Intraindividually, significant differences in the ΔLV + dP/dtmax to optimal and worst pacing configurations were observed in 10 (62.5%) patients. Of the 8 patients who responded to at least one configuration, CRT3P-MPP was optimal in 5 (62.5%) and apical CRTSP was optimal in 3 (37.5%) (P = 0.0047). CONCLUSIONS: In terms of acute haemodynamic response, CRT3P-MPP was comparable an apical CRTSP and superior to basal and distal CRTSP. In the absence of within-device haemodynamic optimization, CRT3P-MPP may offer a haemodynamic advantage over a fixed CRTSP configuration.

Relationship of Right Ventricular Size and Function with Respiratory Status in Duchenne Muscular Dystrophy.

The relationship between pulmonary function and right ventricle (RV) in Duchenne muscular dystrophy (DMD) has not been evaluated. Using cardiac magnetic resonance (CMR), we describe the relationship of RV size and function with spirometry in a DMD cohort. Fifty-seven boys undergoing CMR and pulmonary function testing within 1 month at a single center (2013-2015) were enrolled. Comparisons of RV ejection fraction (RVEF) and end-diastolic volume index (RVEDVI) were made across categories of percent forced vital capacity (FVC%), and relationships were assessed. Mean age was 15.5 ± 3.5 years. Spirometry and CMR were performed within 3.9 ± 4.1 days. Median FVC% was 92.0 % (67.5-116.5 %). Twenty-three (40 %) patients had abnormal FVC% (<80 %) of which 13 (57 %) had mild (FVC% 60-79 %), 6 (26 %) had moderate (FVC% 40-59 %), and 4 (17 %) had severe (FVC <40 %) reductions. Mean RVEF was 58.3 ± 3.7 %. Patients with abnormal FVC% were older and had lower RVEF and RVEDVI. Both RVEF and RVEDVI were significantly associated with FVC% (r = 0.31, p = 0.02 and r = 0.39, p = 0.003, respectively). In a large DMD cohort, RVEF and RVEDVI were related to FVC%. Worsening respiratory status may guide monitoring of cardiac function in these patients.

Outbreak of Norovirus GII.P17-GII.17 in the Canadian Province of Nova Scotia.

Background. Norovirus is the leading cause of viral gastroenteritis, with GII.4 being the most common circulating genotype. Recently, outbreaks in China revealed that norovirus GII.17 GII.P17 had become predominant. Objective. This study aimed to characterize the distribution of norovirus genotypes circulating in Nova Scotia. Methods. Stool specimens were collected from gastrointestinal outbreaks in Nova Scotia between Jan 2014 and June 2015 and subjected to real-time RT-PCR. Norovirus-positive specimens were referred to the National Microbiology Laboratory for sequence-based genotyping. Results. The first norovirus GII.P17-GII.17 outbreak in Canada was identified, but no widespread activity was observed in Nova Scotia. Discussion. It is unknown whether GII.P17-GII.17 is more widespread in Canada since contributions to Canadian surveillance are too sparse to effectively monitor the epidemiology of emerging norovirus genotypes. Conclusions. Presence of norovirus GII.17:P17 in Canada highlights the need for more systematic surveillance to ensure that molecular targets used for laboratory detection are effective and help understand norovirus evolution, epidemiology, and pathogenesis.

Comparison of magnetic resonance feature tracking for systolic and diastolic strain and strain rate calculation with spatial modulation of magnetization imaging analysis.

PURPOSE: To compare cardiovascular magnetic resonance-feature tracking (CMR-FT) with spatial modulation of magnetization (SPAMM) tagged imaging for the calculation of short and long axis Lagrangian strain measures in systole and diastole. MATERIALS AND METHODS: Healthy controls (n = 35) and patients with dilated cardiomyopathy (n = 10) were identified prospectively and underwent steady-state free precession (SSFP) cine imaging and SPAMM imaging using a gradient-echo sequence. A timed offline analysis of images acquired at identical horizontal long and short axis slice positions was performed using CMR-FT and dynamic tissue-tagging (CIMTag2D). Agreement between strain and strain rate (SR) values calculated using these two different methods was assessed using the Bland-Altman technique. RESULTS: Across all participants, there was good agreement between CMR-FT and CIMTag for calculation of peak systolic global circumferential strain (-22.7 ± 6.2% vs. -22.5 ± 6.9%, bias 0.2 ± 4.0%) and SR (-1.35 ± 0.42 1/s vs. -1.22 ± 0.42 1/s, bias 0.13 ± 0.33 1/s) and early diastolic global circumferential SR (1.21 ± 0.44 1/s vs. 1.07 ± 0.30 1/s, bias -0.14 ± 0.34 1/s) at the subendocardium. There was satisfactory agreement for derivation of peak systolic global longitudinal strain (-18.1 ± 5.0% vs. -16.7 ± 4.8%, bias 1.3 ± 3.8%) and SR (-1.04 ± 0.29 1/s vs. -0.95 ± 0.32 1/s, bias 0.09 ± 0.26 1/s). The weakest agreement was for early diastolic global longitudinal SR (1.10 ± 0.40 1/s vs. 0.67 ± 0.32 1/s, bias -0.42 ± 0.40 1/s), although the correlation remained significant (r = 0.42, P < 0.01). CMR-FT generated these data over four times quicker than CIMTag. CONCLUSION: There is sufficient agreement between systolic and diastolic strain measures calculated using CMR-FT and myocardial tagging for CMR-FT to be considered as a potentially feasible and rapid alternative.

Knowledge-based libraries for predicting the geometric preferences of druglike molecules.

We describe the automated generation of libraries for predicting the geometric preferences of druglike molecules. The libraries contain distributions of molecular dimensions based on crystal structures in the Cambridge Structural Database (CSD). Searching of the libraries is performed in cascade fashion to identify the most relevant distributions in cases where precise structural features are poorly represented by existing crystal structures. The libraries are fully comprehensive for bond lengths, valence angles, and rotamers and produce templates for the large majority of unfused and fused rings. Geometry distributions for rotamers and rings take into account any atom chirality that may be present. Library validation has been performed on a set of druglike molecules whose structures were published after the latest CSD entry contributing to the libraries. Hence, the validation gives a true indication of prediction accuracy.

Oculomics: A Crusade Against the Four Horsemen of Chronic Disease.

Chronic, non-communicable diseases present a major barrier to living a long and healthy life. In many cases, early diagnosis can facilitate prevention, monitoring, and treatment efforts, improving patient outcomes. There is therefore a critical need to make screening techniques as accessible, unintimidating, and cost-effective as possible. The association between ocular biomarkers and systemic health and disease (oculomics) presents an attractive opportunity for detection of systemic diseases, as ophthalmic techniques are often relatively low-cost, fast, and non-invasive. In this review, we highlight the key associations between structural biomarkers in the eye and the four globally leading causes of morbidity and mortality: cardiovascular disease, cancer, neurodegenerative disease, and metabolic disease. We observe that neurodegenerative disease is a particularly promising target for oculomics, with biomarkers detected in multiple ocular structures. Cardiovascular disease biomarkers are present in the choroid, retinal vasculature, and retinal nerve fiber layer, and metabolic disease biomarkers are present in the eyelid, tear fluid, lens, and retinal vasculature. In contrast, only the tear fluid emerged as a promising ocular target for the detection of cancer. The retina is a rich source of oculomics data, the analysis of which has been enhanced by artificial intelligence-based tools. Although not all biomarkers are disease-specific, limiting their current diagnostic utility, future oculomics research will likely benefit from combining data from various structures to improve specificity, as well as active design, development, and optimization of instruments that target specific disease signatures, thus facilitating differential diagnoses.

Long-term diseases can stop people living long and healthy lives. In many cases, early diagnosis can help to prevent, monitor, and treat disease, which can improve patients' health. In order to diagnose disease, we need tools that are easy for patients to access, painless, and low-cost. The eye may provide the solution. In this review, we discuss the link between changes in the eye and four types of long-term disease that, together, kill most of the population: (1) Cardiovascular disease (affecting the heart and/or blood). (2) Cancer (abnormal growth of cells). (3) Neurodegenerative disease (affecting the brain and/or nervous system). (4) Metabolic disease (problems storing, accessing, and using the body's fuel). We show that neurodegenerative disease leaves tell-tale signs in lots of different parts of the eye. Signs of cardiovascular and metabolic disease biomarkers are mostly found in the back of the eye, and signs of cancer can be found in the tear fluid. Although signs of disease can be seen in the eye, not all of them will tell us what the disease is. We believe that future research will help us to understand more about long-term disease and how to detect it if we combine information from different structures within the eye and develop new tools to target these specific structures.

A novel inhibitor of the alternative pathway of complement reverses inflammation and bone destruction in experimental arthritis.

Complement is an important component of the innate and adaptive immune response, yet complement split products generated through activation of each of the three complement pathways (classical, alternative, and lectin) can cause inflammation and tissue destruction. Previous studies have shown that complement activation through the alternative, but not classical, pathway is required to initiate antibody-induced arthritis in mice, but it is unclear if the alternative pathway (AP) plays a role in established disease. Previously, we have shown that human complement receptor of the immunoglobulin superfamily (CRIg) is a selective inhibitor of the AP of complement. Here, we present the crystal structure of murine CRIg and, using mutants, provide evidence that the structural requirements for inhibition of the AP are conserved in human and mouse. A soluble form of CRIg reversed inflammation and bone loss in two experimental models of arthritis by inhibiting the AP of complement in the joint. Our data indicate that the AP of complement is not only required for disease induction, but also disease progression. The extracellular domain of CRIg thus provides a novel tool to study the effects of inhibiting the AP of complement in established disease and constitutes a promising therapeutic with selectivity for a single complement pathway.

Cardio-vocal syndrome - How 'benign' condition can turn 'malignant'?

Cardio-vocal syndrome (also called as Ortner's syndrome) is hoarseness of voice due to compression of left recurrent laryngeal nerve secondary to enlarged cardiac chambers and structures. We present two cases of Ortner's syndrome secondary to atrial fibrillation causing enlargement of left atrium compressing the left recurrent laryngeal nerve, and their clinical outcomes.

Contemporary pedagogy? The use of theory in practice: An evidence-informed perspective.

Utilizing cognitive psychology as a foundation, this paper offers a deeper consideration of contemporary theoretical influences on coaching pedagogy. Countering recent dichotomies suggested between pedagogic approaches, we reintroduce key findings from the cognitive tradition and their implications for practice which coaches may find useful. Using cognitive load, novice and expert differences, desirable difficulty, and fidelity, we suggest that the lines drawn between different "pedagogies" may not be as sharp as suggested. Instead, we suggest that coaches avoid defining themselves as being aligned to a specific pedagogical or paradigmatic stance. We conclude by advocating for research informed practice, absent of strict theoretical boundaries and instead, considering contemporary pedagogy as drawing on the needs of the context, the experience of the coach and the best available evidence.

Out-of-hours decision-making in deteriorating patients by foundation year doctors: Relationship to moral distress.

BACKGROUND: Moral distress (MD) refers to psychological unease when healthcare professionals identify morally correct actions to take but are constrained in their ability to take those actions. METHODS: This study evaluated the relationship between out-of-hours decisions and MD among 40 Foundation Year 2 (FY2) doctors. They were asked to choose the 'expected' and the 'right' management options for five out-of-hours scenarios and complete an adapted Measure of Moral Distress for Health Professionals (MMD-HP) questionnaire. RESULTS: 28/40 (70%) reported discordance between 'expected' and 'right' options more frequently than concordance. The mean total MMD-HP score was low: 64.9 (SD = 26.9), range 13-143, maximum 288. The association between decision-making discordance and MMD-HP score was weak. CONCLUSION: Out-of-hours decisions by FY2 doctors were characterised by doing what is 'expected' rather than what is perceived to be 'right'. Providing guidance regarding decision-making in deteriorating patients is needed for patient safety and staff well-being.

Older adults and non-response to rabies post-exposure prophylaxis: Challenges and approaches.

Rabies vaccines are highly effective and immunogenic in most populations, including when used as rabies post-exposure prophylaxis (RPEP); however, there is mounting evidence that the immune response to rabies vaccines, though predicted to be adequate, may be lower in older adults. Despite this, there are no specific recommendations in Canadian guidance to monitor the serological response of older adults following RPEP. Furthermore, while Canadian guidance recommends the intramuscular route for RPEP vaccination, there is good evidence supporting the immunogenicity, effectiveness and safety of RPEP vaccination using the intradermal route. We present a case of an 87-year-old male with rabies exposure who failed to respond to two series of RPEP with intramuscular rabies vaccination but responded to a third series using intradermal vaccine administration and provide reasoning for subsequent management. This case is brought forward to prompt discussion and research as to the utility of completing serology in older adults receiving RPEP as well as vaccination strategies, including route of administration, in those who do not respond to an initial course of RPEP vaccination.