Association between anesthesia technique and death after hip fracture repair for patients with COVID-19.

PURPOSE: Patients with COVID-19 undergoing hip fracture surgeries have a 30-day mortality of up to 34%. We aimed to evaluate the association between anesthesia technique and 30-day mortality after hip fracture surgery in patients with COVID-19. METHODS: After ethics approval, we performed a retrospective cohort analysis of the American College of Surgeons National Surgical Quality Improvement Program data set from January to December 2021. Inclusion criteria were age ≥ 19 yr, laboratory-confirmed SARS-CoV-2 infection within 14 days preoperatively, and hip fracture surgery under general anesthesia (GA) or spinal anesthesia (SA). Exclusion criteria were American Society of Anesthesiologists Physical Status V, ventilator dependence, international normalized ratio ≥ 1.5, partial thromboplastin time > 35 sec, and platelet count < 80 × 109 L-1. The primary outcome was all-cause 30-day mortality. The adjusted association between anesthetic technique and 30-day mortality was analyzed using multivariable logistic regression. RESULTS: Of 23,045 patients undergoing hip fracture surgery, 331 patients met the study criteria. The median [interquartile range] age was 82 [74-88] yr, and 32.3% were male. The 30-day mortality rate was 10.0% (33/331) for the cohort (10.7%, 29/272 for GA vs 6.8%, 4/59 for SA; P = 0.51; standardized mean difference, 0.138). The use of SA, compared with GA, was not associated with decreased mortality (adjusted odds ratio, 0.61; 95% confidence interval, 0.21 to 1.8; E-value, 2.49). CONCLUSION: Anesthesia technique was not associated with mortality in patients with COVID-19 undergoing hip fracture surgery. The findings were limited by a small sample size. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT05133648); registered 24 November 2021.

RéSUMé: OBJECTIF: Les personnes atteintes de COVID-19 bénéficiant d'une chirurgie de fracture de la hanche ont une mortalité à 30 jours allant jusqu'à 34 %. Notre objectif était d'évaluer l'association entre la technique d'anesthésie et la mortalité à 30 jours après une chirurgie de fracture de la hanche chez les personnes atteintes de COVID-19. MéTHODE: Après l'approbation du comité d'éthique, nous avons réalisé une analyse de cohorte rétrospective de l'ensemble de données du Programme national d'amélioration de la qualité chirurgicale de l'American College of Surgeons de janvier à décembre 2021. Les critères d'inclusion étaient un âge ≥ 19 ans, une infection par le SRAS-CoV-2 confirmée en laboratoire dans les 14 jours préopératoires et une chirurgie de fracture de la hanche sous anesthésie générale (AG) ou rachianesthésie (RA). Les critères d'exclusion étaient un statut physique V selon l'American Society of Anesthesiologists, la dépendance à une assistance ventilatoire, un ratio international normalisé ≥ 1,5, un temps de thromboplastine partielle > 35 sec, et une numération plaquettaire < 80 × 109 L−1. Le critère d'évaluation principal était la mortalité à 30 jours toutes causes confondues. L'association ajustée entre la technique anesthésique et la mortalité à 30 jours a été analysée à l'aide d'une régression logistique multivariée. RéSULTATS: Sur 23 045 patient·es opéré·es pour une fracture de la hanche, 331 répondaient aux critères de l'étude. L'âge médian (écart interquartile) était de 82 [74­88] ans et 32,3 % étaient des hommes. Le taux de mortalité à 30 jours était de 10,0 % (33/331) pour la cohorte (10,7 %, 29/272 pour l'AG vs 6,8 %, 4/59 pour la RA; P = 0,51; différence moyenne standardisée, 0,138). L'utilisation de la RA, par rapport à l'AG, n'a pas été associée à une diminution de la mortalité (rapport de cotes ajusté, 0,61; intervalle de confiance à 95 %, 0,21 à 1,8; valeur E, 2,49). CONCLUSION: La technique d'anesthésie n'a pas été associée à la mortalité chez les personnes atteintes de COVID-19 bénéficiant d'une chirurgie de fracture de la hanche. Les résultats ont été limités par la petite taille de l'échantillon. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT05133648); enregistrée le 24 novembre 2021.

Moonlighting matrix metalloproteinase substrates: Enhancement of proinflammatory functions of extracellular tyrosyl-tRNA synthetase upon cleavage.

Tyrosyl-tRNA synthetase ligates tyrosine to its cognate tRNA in the cytoplasm, but it can also be secreted through a noncanonical pathway. We found that extracellular tyrosyl-tRNA synthetase (YRS) exhibited proinflammatory activities. In addition to acting as a monocyte/macrophage chemoattractant, YRS initiated signaling through Toll-like receptor 2 (TLR2) resulting in NF-κB activation and release of tumor necrosis factor α (TNFα) and multiple chemokines, including MIP-1α/ß, CXCL8 (IL8), and CXCL1 (KC) from THP1 monocyte and peripheral blood mononuclear cell-derived macrophages. Furthermore, YRS up-regulated matrix metalloproteinase (MMP) activity in a TNFα-dependent manner in M0 macrophages. Because MMPs process a variety of intracellular proteins that also exhibit extracellular moonlighting functions, we profiled 10 MMPs for YRS cleavage and identified 55 cleavage sites by amino-terminal oriented mass spectrometry of substrates (ATOMS) positional proteomics and Edman degradation. Stable proteoforms resulted from cleavages near the start of the YRS C-terminal EMAPII domain. All of the MMPs tested cleaved at ADS386↓387LYV and VSG405↓406LVQ, generating 43- and 45-kDa fragments. The highest catalytic efficiency for YRS was demonstrated by MMP7, which is highly expressed by monocytes and macrophages, and by neutrophil-specific MMP8. MMP-cleaved YRS enhanced TLR2 signaling, increased TNFα secretion from macrophages, and amplified monocyte/macrophage chemotaxis compared with unprocessed YRS. The cleavage of YRS by MMP8, but not MMP7, was inhibited by tyrosine, a substrate of the YRS aminoacylation reaction. Overall, the proinflammatory activity of YRS is enhanced by MMP cleavage, which we suggest forms a feed-forward mechanism to promote inflammation.

Uncovering a Role for the Dorsal Hippocampal Commissure in Recognition Memory.

The dorsal hippocampal commissure (DHC) is a white matter tract that provides interhemispheric connections between temporal lobe brain regions. Despite the importance of these regions for learning and memory, there is scant evidence of a role for the DHC in successful memory performance. We used diffusion-weighted magnetic resonance imaging (DW-MRI) and white matter tractography to reconstruct the DHC in both humans (in vivo) and nonhuman primates (ex vivo). Across species, our findings demonstrate a close consistency between the known anatomy and tract reconstructions of the DHC. Anterograde tract-tracer techniques also highlighted the parahippocampal origins of DHC fibers in nonhuman primates. Finally, we derived diffusion tensor MRI metrics from the DHC in a large sample of human subjects to investigate whether interindividual variation in DHC microstructure is predictive of memory performance. The mean diffusivity of the DHC correlated with performance in a standardized recognition memory task, an effect that was not reproduced in a comparison commissure tract-the anterior commissure. These findings highlight a potential role for the DHC in recognition memory, and our tract reconstruction approach has the potential to generate further novel insights into the role of this previously understudied white matter tract in both health and disease.

Matrix metalloproteinases inactivate the proinflammatory functions of secreted moonlighting tryptophanyl-tRNA synthetase.

Tryptophanyl-tRNA synthetase (WRS) is a cytosolic aminoacyl-tRNA synthetase essential for protein synthesis. WRS is also one of a growing number of intracellular proteins that are attributed distinct noncanonical "moonlighting" functions in the extracellular milieu. Moonlighting aminoacyl-tRNA synthetases regulate processes such as inflammation, but how these multifunctional enzymes are themselves regulated remains unclear. Here, we demonstrate that WRS is secreted from human macrophages, fibroblasts, and endothelial cells in response to the proinflammatory cytokine interferon γ (IFNγ). WRS signaled primarily through Toll-like receptor 2 (TLR2) in macrophages, leading to phosphorylation of the p65 subunit of NF-κB with associated loss of NF-κB inhibitor α (IκB-α) protein. This signaling initiated secretion of tumor necrosis factor α (TNFα) and CXCL8 (IL8) from macrophages. We also demonstrated that WRS is a potent monocyte chemoattractant. Of note, WRS increased matrix metalloproteinase (MMP) activity in the conditioned medium of macrophages in a TNFα-dependent manner. Using purified recombinant proteins and LC-MS/MS to identify proteolytic cleavage sites, we demonstrated that multiple MMPs, but primarily macrophage MMP7 and neutrophil MMP8, cleave secreted WRS at several sites. Loss of the WHEP domain following cleavage at Met48 generated a WRS proteoform that also results from alternative splicing, designated Δ1-47 WRS. The MMP-cleaved WRS lacked TLR signaling and proinflammatory activities. Thus, our results suggest that moonlighting WRS promotes IFNγ proinflammatory activities, and these responses can be dampened by MMPs.

Differentiating borderline personality disorder (BPD) from bipolar disorder: diagnostic efficiency of DSM BPD criteria.

OBJECTIVE: We sought to determine the differential diagnostic efficiency of all DSM-IV borderline personality disorder (BPD) criteria by studying a sample of those with BPD and a contrast group with a bipolar disorder (BP). METHOD: Participants were clinically assessed and assigned diagnoses based on DSM criteria - with prevalence rates and diagnostic efficiency values calculated. RESULTS: Fifty-three participants were assigned a BPD diagnosis, 83 a BP diagnosis, with comorbid participants excluded. The mean number of DSM BPD criteria assigned was 6.6 (SD = 1.0) in the BPD group and 1.9 (SD = 1.3) in the BP group. The most prevalent criterion in the BPD group was 'affective instability' (AI) (92.5%), with 'inappropriate anger' least endorsed (49%). The highest specificity criterion was 'abandonment fears', which displayed the greatest positive predictive value (PPV) = 0.9, and with AI offering the lowest specificity. 'Unstable relationships' had the highest overall negative predictive value (NPV) = 0.91. The highest percentage accuracy of classification was provided by 'identity disturbance' and 'abandonment fears' criteria, both 85%. CONCLUSION: The transdiagnostic nature of 'affective instability' means it is less useful for diagnostic decisions, whereas 'abandonment fears' and 'identity disturbance' offer superior diagnostic efficiency in distinguishing BPD from BP.

Differentiating clinical and non-clinical depression: a heuristic study offering a template for extension studies.

OBJECTIVE: To differentiate clinical and non-clinical depression via a set of symptoms. METHODS: A sample of 140 patients attending a clinical service for those with mood disorders together with 40 subjects denying ever experiencing a clinical episode of depression were compared, with participants completing a questionnaire capturing many symptoms of depression as well as illness correlates. RESULTS: A latent class analysis of symptom data identified two classes and with class assignment corresponding strongly with initial clinical vs. non-clinical assignment. Univariate analyses identified the extent to which individual symptoms contributed to differentiation. Study data suggested DSM criteria that would benefit from re-writing or of reassignment. Two models for classifying clinical depression were generated. The first involved individuals feeling hopeless and also being suicidal or at risk of self-harm. The second involved a symptom set corresponding to DSM-5 criteria but with only five making significant independent contributions to diagnostic differentiation. CONCLUSION: The study is heuristic in offering a strategy for more precisely differentiating clinical and non-clinical depression in more representative samples, so allowing resolution of key features, and determining whether a monothetic or polythetic diagnostic symptom criterion model is optimal.

Refined diagnostic criteria for the bipolar disorders: phase two of the AREDOC project.

OBJECTIVE: As limitations exist across DSM criteria sets for defining and differentiating the bipolar disorders generally and their component bipolar I (BP-1) and bipolar II (BP-II) sub-types, we sought to generate empirically based criteria. METHOD: We formed an international Task Force (TF) comprising members with bipolar disorder expertise, and who recruited 74 patients with a TF-diagnosed bipolar I and 104 with a bipolar II condition (with patients responding to definitional queries and symptom questionnaires), while 33 unipolar depressed patients recruited by the first author also completed the symptom questionnaire. A factor analysis sought to determine granular hypo/manic constructs. RESULTS: The bipolar disorder subjects strongly affirmed a new general definition of a bipolar disorder (capturing both manic and hypomanic episodes). While DSM-5 requires impaired functioning, we established that a high percentage of individuals with a BP-I or a BP-II disorder reported improved functioning and therefore modified this criterion. Analyses identified syptoms with differential high rates in individuals with bipolar disorder and its sub-types (and thus not simply capturing happiness), while a factor analysis generated seven symptom constructs both linked with and differing from DSM-5 bipolar symptom criteria. CONCLUSION: This second-stage report details a new set of criteria for differentiating the bipolar disorders from unipolar depressive conditions, while arguing for BP-I and BP-II disorders being differentiated principally by the respective presence or absence of psychotic features. Future studies will evaluate whether further modifications are required and examine for differential treatment benefits for those with a BP-I versus a BP-II condition.

Best practices for after-action review: turning lessons observed into lessons learned for preparedness policy.

All-hazards preparedness and response planning requires ongoing individual, organisational and multi-jurisdictional learning. Disaster after-action reviews are an established emergency management practice to acquire knowledge through a process of analysing what happened and why, to improve the emergency response before the next crisis. After-action reviews help individuals and organisations learn, and are an essential step in the preparedness cycle. Human and animal health authorities have begun to employ after-action reviews for disaster preparedness and response among public health and Veterinary Services. The World Organisation for Animal Health (OIE) encourages Members to establish after-action reviews and share best practice. The adoption of afteraction review is an essential step for all provincial, national and multinational emergency management authorities to mitigate the impact of disasters on human and animal health. Emerging and re-emerging infectious diseases with pandemic potential pose unique preparedness challenges, requiring high-level policy attention to close long-standing gaps. A review of after-action reports from the 2001 anthrax bioterror attacks and of naturally occurring infectious disease crises, from the 2003 outbreak of severe acute respiratory syndrome (SARS) to the 2014 Ebola epidemic, reveal a similar pattern of repeated weakness and failures. These phenomena are described as 'lessons observed but not lessons learned'. Most infectious disease outbreaks with pandemic potential are zoonotic and require a One Health approach to prevent, prepare for and respond to global health security crises. After-action reviews in a One Health security context are essential to improve the pandemic preparedness of public health and Veterinary Services. After-action reviews can also provide the evidence-based 'feedback loop' needed to galvanise public policy and political will to translate lessons observed into sustained and applied lessons learned.

La planification de la préparation et de la réponse à tous les risques est un processus qui exige un apprentissage permanent tant à l'échelle des individus que des organisations et des différentes autorités compétentes. Les retours d'expérience (ou « revues après action¼) suite à une catastrophe constituent un exercice éprouvé de gestion des urgences visant à acquérir de nouvelles connaissances en procédant à l'analyse de ce qui est arrivé et des raisons pour lesquelles c'est arrivé, dans le but d'améliorer les capacités d'intervention d'urgence avant que ne survienne la prochaine crise. Les individus et les organisations trouvent dans ces retours un cadre pour tirer des enseignements de leur expérience, ce qui constitue une étape essentielle du cycle de préparation. Les autorités en charge de la santé humaine et de la santé animale ont commencé à utiliser les retours d'expérience pour planifier la préparation et la réponse au sein des Services de santé publique et des Services vétérinaires. L'Organisation mondiale de la santé animale (OIE) encourage ses Membres à mettre en place des retours d'expérience et à partager les meilleures pratiques en la matière. L'analyse des retours d'expérience est une étape cruciale pour que les autorités en charge de la gestion des urgences à l'échelle provinciale, nationale et internationale puissent atténuer l'impact des catastrophes sur la santé humaine et animale. Les maladies émergentes et ré-émergentes ayant un potentiel pandémique posent des défis exceptionnels en termes de préparation et exigent des prises de décision de haut niveau afin de pallier des lacunes souvent anciennes. L'examen des retours d'expérience datant des attentats terroristes à l'anthrax de 2001 et des crises sanitaires dues à des maladies infectieuses d'origine naturelle (depuis l'épidémie du syndrome respiratoire aigu sévère [SRAS] en 2003 jusqu'à l'épidémie d'Ebola en 2014) révèle des caractéristiques toujours similaires, avec à chaque fois les mêmes faiblesses et les mêmes écueils. Ce phénomène correspond à ce que l'on peut appeler des « leçons observées mais non apprises ¼. Compte tenu de la nature zoonotique de la plupart des foyers de maladies infectieuses ayant un potentiel pandémique, c'est l'approche Une seule santé qui doit prévaloir en matière de prévention, de préparation et de réponse aux crises de sécurité sanitaire d'envergure mondiale. Les retours d'expérience dans un contexte de sécurité Une seule santé sont essentiels pour améliorer la préparation des Services de santé publique et des Services vétérinaires aux pandémies. En outre, les « boucles de réaction¼ fondées sur des éléments factuels résultant des retours d'expérience apportent un éclairage indispensable pour inciter les pouvoirs publics à élaborer des mesures appropriées et pour créer la volonté politique de traduire les leçons observées en leçons durablement apprises et appliquées.

La planificación de las labores de preparación y respuesta ante toda clase de peligros exige un permanente aprendizaje tanto personal como institucional y desde múltiples competencias. El examen de las intervenciones tras un desastre constituye un arraigado proceder de gestión de emergencias que sirve para aprender de la experiencia analizando el cómo y el porqué de lo sucedido y, a partir de ahí, mejorar los procesos de respuesta de emergencia antes de que advenga la siguiente crisis. Estos exámenes posteriores a las intervenciones, que ayudan a las personas y organizaciones a aprender, son una etapa fundamental del ciclo de preparación. Las autoridades sanitarias y zoosanitarias han empezado a utilizarlos en los servicios de salud pública y los Servicios Veterinarios con fines de preparación y respuesta para casos de desastre. La Organización Mundial de Sanidad Animal (OIE) alienta a sus Miembros a que establezcan este tipo de exámenes y pongan en común prácticas óptimas al respecto. La implantación del examen posterior a las intervenciones es un paso esencial para que todas las autoridades provinciales, nacionales e internacionales de gestión de emergencias estén en condiciones de mitigar los efectos sanitarios y zoosanitarios de un desastre. Las enfermedades infecciosas emergentes y reemergentes con potencial pandémico plantean singulares problemas de preparación, que requieren una atención y una labor normativa de alto nivel para solventar carencias históricas. El examen de los informes posteriores a las actuaciones de respuesta a los ataques bioterroristas perpetrados en 2001 con bacterias de carbunco (ántrax) y a crisis infecciosas de origen natural, desde el brote registrado en 2003 de síndrome respiratorio agudo severo (SRAS) hasta la epidemia causada por el virus del Ébola en 2014, revela un parecido patrón de fallos y carencias que se van repitiendo, fenómeno que se describe como «hechos observados sin enseñanzas extraídas¼. La mayoría de los brotes de enfermedades infecciosas con potencial pandémico son zoonóticos y exigen la aplicación de la lógica de Una sola salud para prevenir crisis sanitarias de dimensión mundial, prepararse para ellas y darles respuesta. Los exámenes posteriores a una intervención inscritos en el contexto de seguridad sanitaria de Una sola salud son esenciales para mejorar la preparación de los servicios de salud pública y los Servicios Veterinarios para episodios de pandemia. Estos procesos de examen también pueden alimentar con datos científicos el «ciclo de retroalimentación¼ que se requiere para galvanizar las políticas públicas y la voluntad política de traducir los hechos observados en enseñanzas extraídas que sean duraderas y se apliquen en la práctica.

Predicting vertical ground reaction force during running using novel piezoresponsive sensors and accelerometry.

Running is a common exercise with numerous health benefits. Vertical ground reaction force (vGRF) influences running injury risk and running performance. Measurement of vGRF during running is now primarily constrained to a laboratory setting. The purpose of this study was to evaluate a new approach to measuring vGRF during running. This approach can be used outside of the laboratory and involves running shoes instrumented with novel piezoresponsive sensors and a standard accelerometer. Thirty-one individuals ran at three different speeds on a force-instrumented treadmill while wearing the instrumented running shoes. vGRF was predicted using data collected from the instrumented shoes, and predicted vGRF were compared to vGRF measured via the treadmill. Per cent error of the resulting predictions varied depending upon the predicted vGRF characteristic. Per cent error was relatively low for predicted vGRF impulse (2-7%), active peak vGRF (3-7%), and ground contact time (3-6%), but relatively high for predicted vGRF load rates (22-29%). These errors should decrease with future iterations of the instrumented shoes and collection of additional data from a more diverse sample. The novel technology described herein might become a feasible way to collect large amounts of vGRF data outside of the traditional biomechanics laboratory.

How to choose an antidepressant medication.

OBJECTIVE: We consider how to choose an antidepressant (AD) medication for the treatment of clinical depression. METHOD: A narrative review was undertaken addressing antidepressant 'choice' considering a range of parameters either weighted by patients and clinicians or suggested in the scientific literature. Findings were synthesised and incorporated with clinical experience into a model to assist AD choice. RESULTS: Efficacy studies comparing ADs offer indicative guidance, while precision psychiatry prediction based on genetics, developmental trauma, neuroimaging, behavioural and cognitive biomarkers, currently has limited clinical utility. Our model offers guidance for AD choice by assessing first for the presence of a depressive subtype or symptom cluster and matching choice of AD class accordingly. Failing this, an AD can be chosen based on depression severity. Within-class choice can be determined by reference to personality style, patient preference, medical or psychiatric comorbidities and side-effect profile. CONCLUSION: Clarification of AD choice would occur if medications are trialled in specific depressive subtypes rather than using the generic diagnosis of major depressive disorder (MDD). Such 'top-down' methods could be enhanced by 'bottom-up' studies to classify individuals according to symptom clusters and biomarkers with AD efficacy tested in these categories. Both methods could be utilised for personalised AD choice.

New intracellular activities of matrix metalloproteinases shine in the moonlight.

Adaption of a single protein to perform multiple independent functions facilitates functional plasticity of the proteome allowing a limited number of protein-coding genes to perform a multitude of cellular processes. Multifunctionality is achievable by post-translational modifications and by modulating subcellular localization. Matrix metalloproteinases (MMPs), classically viewed as degraders of the extracellular matrix (ECM) responsible for matrix protein turnover, are more recently recognized as regulators of a range of extracellular bioactive molecules including chemokines, cytokines, and their binders. However, growing evidence has convincingly identified select MMPs in intracellular compartments with unexpected physiological and pathological roles. Intracellular MMPs have both proteolytic and non-proteolytic functions, including signal transduction and transcription factor activity thereby challenging their traditional designation as extracellular proteases. This review highlights current knowledge of subcellular location and activity of these "moonlighting" MMPs. Intracellular roles herald a new era of MMP research, rejuvenating interest in targeting these proteases in therapeutic strategies. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.

Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI.

The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'.

Volumetric dynamic oxygen-enhanced MRI (OE-MRI): comparison with CT Brody score and lung function in cystic fibrosis patients.

OBJECTIVES: To demonstrate, in patients with cystic fibrosis (CF), the correlation between three-dimensional dynamic oxygen-enhanced magnetic resonance imaging (OE-MRI) measurements and computed tomography Brody score (CF-CT) and lung function testing (LFT). METHODS: Twenty-one patients (median age, 25 years; female, n = 8) with a range of CF lung disease and five healthy volunteers (median age, 31 years; female, n = 2) underwent OE-MRI performed on a 1.5-T MRI scanner. Coronal volumes were acquired while patients alternately breathed room air and 100% oxygen. Pre-oxygen T1 was measured. Dynamic series of T1-weighted volumes were then obtained while breathing oxygen. T1-parameter maps were generated and the following OE-MRI parameters were measured: oxygen uptake (ΔPO2max), wash-in time and wash-out time. High-resolution CT and LFT were performed. The relationship between CF-CT, LFT and OE-MRI parameters were evaluated using Pearson correlation for the whole lung and regionally. RESULTS: Mean CF-CT was 24.1±17.1. Mean ΔPO2max and mean wash-in as well as skewness of wash-out showed significant correlation with CF-CT (ΔPO2max: r = -0.741, p < 0.001; mean wash-in: r = 0.501, p = 0.017; skewness of wash-out: r = 0.597, p = 0.001). There was significant correlation for the whole lung and regionally between LFT parameters and OE-MR (ΔPO2max: r = 0.718, p < 0.001; wash-in: r = -0.576, p = 0.003; wash-out skewness: r = -0.552, p = 0.004). CONCLUSIONS: Functional lung imaging using OE-MRI has the capability to assess the severity of CF lung disease and shows a significant correlation with LFT and CF-CT. KEY POINTS: • Oxygen-enhanced MRI might play a future role in evaluation and follow-up of cystic fibrosis. • Heterogeneity of parameter maps reflects localised functional impairment in cystic fibrosis. • Avoidance of cumulative radiation burden in CF is feasible using OE-MRI.

Correction to: Volumetric dynamic oxygen-enhanced MRI (OE-MRI): comparison with CT Brody score and lung function in cystic fibrosis patients.

The original version of this article, published on 13 April 2018, unfortunately contained a mistake.

Comparison of guidelines for the treatment of unipolar depression: a focus on pharmacotherapy and neurostimulation.

OBJECTIVE: To determine the level of agreement across a set of evidence-based guidelines for management of the unipolar depressive disorders and with a focus on physical treatments. METHOD: A literature search was undertaken using the terms 'depression', 'depressive' and 'guidelines', using PubMed, Cochrane Database of Systematic Reviews and the National Guideline Clearinghouse. Twelve national psychiatric or professional guideline-producing organizations were identified from the period 2007-2017, with guidelines qualitatively reviewed by two assessors. RESULTS: For major depressive disorder (MDD), there was general consensus to use an antidepressant (AD) in cases of greater severity, although disagreement on AD use in mild to moderate depression. There was some agreement on choice of AD class in first-line treatment recommendations, though great variability in second- and third-line management particularly in recommended augmentation and combined AD strategies. Electroconvulsive therapy was considered in all but one guideline, with other neurostimulation treatments being less consistently covered and with variable recommendations. Finally, there was low consistency in the management of dysthymia, persistent depressive disorder and treatment resistant depression. CONCLUSION: Our review identifies varying levels of consistency in guideline recommendations. Strategies to improve reliability in guideline formulation should also improve their validity.

Clinical vs. DSM diagnosis of bipolar disorder, borderline personality disorder and their co-occurrence.

OBJECTIVE: To investigate the extent and reasons contributing to discrepancies between those receiving a DSM as against a clinical diagnosis of a bipolar disorder (BP) and/or a borderline personality disorder (BPD). METHOD: We interviewed participants previously receiving a BP or BPD diagnosis, studying those who met DSM or clinical criteria for one or both conditions. We compared the numbers of participants allocated to the three diagnostic categories according to rater strategy to calculate concordance rates and determine reasons for discordance. RESULTS: Rates of assignment to BP, BPD and comorbid BP/BPD varied according to the diagnostic strategy. Concordance rates were reduced as BP disorder duration criteria were relaxed, with discordance mainly arising from clinical allocation of a BP disorder for those DSM assigned as unipolar depression. Rates of BPD allocation varied marginally, with discordance mostly arising from so clinically diagnosed receiving a comorbid BP/BPD DSM diagnosis. Finally, DSM overestimated comorbidity compared with clinician diagnoses. Of central importance, not imposing the DSM duration criteria for BP did not increase the prevalence of misdiagnosing BPD, a finding at variance with the literature. CONCLUSION: Rates and reasons for discordance between clinical and DSM diagnosis are detailed, which should assist clinical decision-making.

Is there consensus across international evidence-based guidelines for the management of bipolar disorder?

OBJECTIVE: To examine the level of agreement across professionally auspiced evidence-based guidelines for managing the bipolar disorders. METHODS: A literature search in PubMed, the National Guideline Clearinghouse, the Cochrane Database of Systematic Reviews and PsycInfo was undertaken using the search terms 'bipolar disorder' and 'guidelines', generating 11 evidence-based guidelines published by professional organisations over the 2002-2015 period. Each guideline was reviewed by two independent reviewers and key themes extracted via qualitative analyses. RESULTS: There was agreement on issues such as the first-line treatment of mania where mood-stabilising and/or an antipsychotic medication together with tapering or ceasing antidepressant medications was most commonly recommended. Differences included the extent to which (i) the different bipolar disorders were defined or not, (ii) there were separate recommendations for bipolar I and bipolar II disorders vs. non-differentiating general bipolar management strategies, (iii) 'general' vs. severity-based recommendations were made, and (iv) narrow vs. broad sets of candidate medications were nominated, while there was variable consideration of treatments such as electroconvulsive therapy (ECT). CONCLUSIONS: While there was some consistency across guidelines on key recommendations, there was also substantial inconsistencies, limiting the generation of any 'meta-consensus' model for managing the bipolar disorders.

Targeting and transforming major depression.

OBJECTIVE: To detail limitations to the construct of 'major depression', argue for repositioning it as a proxy for 'clinical depression' and then operationalize it and its principal constituent depressive subtypes, while preserving the DSM criteria-based format. METHOD: We summarize limitations to major depression being viewed as a diagnostic entity. Data from 391 clinically depressed patients were analysed to identify high-prevalence non-specific depressive symptoms to define 'clinical depression' as well as the features showing specificity to a melancholic depressive subtype. RESULTS: We identified a set of high-prevalence and generalized symptoms for defining clinical depression and with many being current criteria for major depression. We also developed a refined set of melancholic features and with their underlying distributions generating two classes that correlated strongly with clinical diagnoses of a melancholic or non-melancholic depression, thus validating its capacity to so differentiate. We append criteria sets for diagnosing clinical depression and its principal diagnostic subtypes (psychotic, melancholic and non-melancholic). CONCLUSION: This heuristic study reframes and modifies major depression's criteria set to define a domain of clinical depression with additional criteria and then allowing the delineation of three diagnostic subtypes. If this paradigm shift is accepted and further refined, greater precision in diagnosis, treatment and research would be anticipated.

Distinct neurobiological signatures of brain connectivity in depression subtypes during natural viewing of emotionally salient films.

BACKGROUND: Establishing an evidence-based diagnostic system informed by the biological (dys)function of the nervous system is a major priority in psychiatry. This objective, however, is often challenged by difficulties in identifying homogeneous clinical populations. Melancholia, a biological and endogenous subtype for major depressive disorder, presents a canonical test case in the search of biological nosology. METHOD: We employed a unique combination of naturalistic functional magnetic resonance imaging (fMRI) paradigms - resting state and free viewing of emotionally salient films - to search for neurobiological signatures of depression subtypes. fMRI data were acquired from 57 participants; 17 patients with melancholia, 17 patients with (non-melancholic) major depression and 23 matched healthy controls. RESULTS: Patients with melancholia showed a prominent loss of functional connectivity in hub regions [including ventral medial prefrontal cortex, anterior cingulate cortex (ACC) and superior temporal gyrus] during natural viewing, and in the posterior cingulate cortex while at rest. Of note, the default mode network showed diminished reactivity to external stimuli in melancholia, which correlated with the severity of anhedonia. Intriguingly, the subgenual ACC, a potential target for treating depression with deep brain stimulation (DBS), showed divergent changes between the two depression subtypes, with increased connectivity in the non-melancholic and decreased connectivity in the melancholic subsets. CONCLUSION: These findings reveal neurobiological changes specific to depression subtypes during ecologically valid behavioural conditions, underscoring the critical need to respect differing neurobiological processes underpinning depressive subtypes.

Are the bipolar disorders best modelled categorically or dimensionally?

OBJECTIVE: Considerable debate exists as to whether the bipolar disorders are best classified according to a categorical or dimensional model. This study explored whether there is evidence for a single or multiple subpopulations and the degree to which differing diagnostic criteria correspond to bipolar subpopulations. METHOD: A mixture analysis was performed on 1081 clinically diagnosed (and a reduced sample of 497 DSM-IV diagnosed) bipolar I and II disorder patients, using scores on hypomanic severity (as measured by the Mood Swings Questionnaire). Mixture analyses were conducted using two differing diagnostic criteria and two DSM markers to ascertain the most differentiating and their associated clinical features. RESULTS: The two subpopulation solution was most supported although the entropy statistic indicated limited separation and there was no distinctive point of rarity. Quantification by the odds ratio statistic indicated that the clinical diagnosis (respecting DSM-IV criteria, but ignoring 'high' duration) was somewhat superior to DSM-IV diagnosis in allocating patients to the putative mixture analysis groups. The most differentiating correlate was the presence or absence of psychotic features. CONCLUSION: Findings favour the categorical distinction of bipolar I and II disorders and argue for the centrality of the presence or absence of psychotic features to subgroup differentiation.