Addressing the gap for racially diverse research involvement: The King's Model for minority ethnic research participant recruitment.

Objectives: Ethnic minorities (EM) are still underrepresented in research recruitment. Despite wide literature outlining the barriers, enablers and recommendations for driving inclusion and diversity in research, there is still little evidence for successful diversity in research participation, which has a direct impact on the quality of care provided to ethnically diverse individuals. A new, comprehensive approach to recruitment strategies is therefore necessary. Study design: service improvement initiative. Methods: In the light of the Covid-19 pandemic and the key public health need to address the disparity in care provided to non-white populations, we used a novel, comprehensive approach (The King's Model) comprising of local and community actions to promote inclusive research recruitment. We then compared rates of diverse recruitment in studies where the novel approach, was applied to studies which had been closed to recruitment at the time of analysis and where ethnicity data was available. Results: Our results demonstrate that following the introduction of the King's Model for diverse recruitment, commercial interventional study diverse recruitment increased from 6.4% to 16.1%, and for non-commercial studies, from 30.2% to 41.0% and 59.2% in the selected studies. Conclusions: King's Model is potentially a useful tool in enhancing non-Caucasian recruitment to clinical research. Enriched by additional recommendations based on our experiences during the Covid-19 research recruitment drive, we propose the King's Model is used to support ethnically diverse research recruitment. Further evidence is needed to replicate our findings, although this preliminary evidence provides granular details necessary to address the key unmet need of validating clinical research outcomes in non-white populations.

Analysis of the aetiology of epilepsy in 3,216 adult patients attending a tertiary referral center enabled by an electronic patient record.

PURPOSE: The aim of this study was to review the causes of the epilepsies in our institution, an adult tertiary referral center for neurology and neurosurgery in Dublin, Ireland. Data was obtained from a bespoke epilepsy electronic patient record (EPR). METHODS: Predetermined search parameters of well-established broad categories of epilepsy aetiology were used to identify patients with a diagnosis of epilepsy attending Beaumont Hospital, Dublin. There were 3216 patients that met the inclusion criteria for this study. We included living patients with epilepsy attending our institution. We then excluded patients with a diagnosis of pure non-epileptic attack disorder and patients found to have idiopathic generalised epilepsy (IGE) (n = 382) from our final cohort. We excluded IGE due to the complex polygenic basis underlying this patient group. RESULTS: An aetiology was identified in 54.3 % (n = 1747) of the total number of patients studied. Of the symptomatic epilepsies, 41.08 % (n = 1321) were acquired and 13.3 % (n = 426) were predominantly of genetic or developmental aetiology. The most common causes of the acquired epilepsies were hippocampal sclerosis (n = 380; 28.75 %), cerebral tumor (n = 279; 21.06 %), traumatic brain injury (n = 248; 18.77 %), stroke and cerebrovascular disease (n = 151; 11.43 %) and perinatal causes (n = 138; 10.45 %). The leading causes in the genetic / developmental category included cavernous haemangiomas (n = 62, 22.22 %), arteriovenous malformations (n = 59; 21.15 %) and cortical dysplasia (n = 55; 19.71 %). The aetiology of a patient's epilepsy was undetermined in 45.68 % (n = 1469) of individuals. CONCLUSION: This study emphasizes the clinical utility of the ILAE's 2017 revised classification of the epilepsies and highlights the evolving dynamic nature of attributing causality in epilepsy. This is the largest single centre analysis of the aetiology of the epilepsies described in the literature. It is also the first large scale study examining aetiology utilising a bespoke electronic patient record in epilepsy.

Anatomical integration and rich-club connectivity in euthymic bipolar disorder.

BACKGROUND: Although repeatedly associated with white matter microstructural alterations, bipolar disorder (BD) has been relatively unexplored using complex network analysis. This method combines structural and diffusion magnetic resonance imaging (MRI) to model the brain as a network and evaluate its topological properties. A group of highly interconnected high-density structures, termed the 'rich-club', represents an important network for integration of brain functioning. This study aimed to assess structural and rich-club connectivity properties in BD through graph theory analyses. METHOD: We obtained structural and diffusion MRI scans from 42 euthymic patients with BD type I and 43 age- and gender-matched healthy volunteers. Weighted fractional anisotropy connections mapped between cortical and subcortical structures defined the neuroanatomical networks. Next, we examined between-group differences in features of graph properties and sub-networks. RESULTS: Patients exhibited significantly reduced clustering coefficient and global efficiency, compared with controls globally and regionally in frontal and occipital regions. Additionally, patients displayed weaker sub-network connectivity in distributed regions. Rich-club analysis revealed subtly reduced density in patients, which did not withstand multiple comparison correction. However, hub identification in most participants indicated differentially affected rich-club membership in the BD group, with two hubs absent when compared with controls, namely the superior frontal gyrus and thalamus. CONCLUSIONS: This graph theory analysis presents a thorough investigation of topological features of connectivity in euthymic BD. Abnormalities of global and local measures and network components provide further neuroanatomically specific evidence for distributed dysconnectivity as a trait feature of BD.

Applying neuroimaging to detect neuroanatomical dysconnectivity in psychosis.

This editorial discusses the application of a novel brain imaging analysis technique in the assessment of neuroanatomical dysconnectivity in psychotic illnesses. There has long been a clinical interest in psychosis as a disconnection syndrome. In recent years graph theory metrics have been applied to functional and structural imaging datasets to derive measures of brain connectivity, which represent the efficiency of brain networks. These metrics can be derived from structural neuroimaging datasets acquired using diffusion imaging whereby cortical structures are parcellated into nodes and white matter tracts represent edges connecting these nodes. Furthermore neuroanatomical measures of connectivity may be decoupled from measures of physiological connectivity as assessed using functional imaging, underpinning the need for multi-modal imaging approaches to probe brain networks. Studies to date have reported a number of structural brain connectivity abnormalities associated with schizophrenia that carry potential as illness biomarkers. Structural connectivity abnormalities have also been reported in well patients with bipolar disorder and in unaffected relatives of patients with schizophrenia. Such connectivity metrics may represent clinically relevant biomarkers in studies employing a longitudinal design of illness course in psychosis.

The otolaryngology, head and neck training appraisal questionnaire: a national general practice perspective.

BACKGROUND: Diseases of the Ear, Nose and Throat (ENT) make up a considerable proportion of the everyday workload of general practitioners (GPs). It is recognized that ENT makes up a very small part of the undergraduate curriculum, but some post-graduate training schemes are now offering placements in Otolaryngology. AIM: The aim of the study was to examine a perceived knowledge 'gap' of GPs in the area of Otolaryngology. METHOD: A postal questionnaire was sent to 1,000 GPs distributed evenly throughout the country. RESULTS: There was a 47.3 % response rate; 72 % of GPs felt that they would see at least three or more children with a relevant ENT problem each day. Almost 70 % of GPs had less than a month exposure to ENT in medical school and 84 % of GPs felt that further emphasis was required at the undergraduate level. Twenty-one per cent of GPs surveyed had spent some time in Postgraduate ENT training. Ninety-one per cent of GPs agreed that further emphasis on ENT training was required at the Postgraduate level. CONCLUSION: General Practitioners feel that increased importance should be placed on the study of Otolaryngology at both undergraduate and Postgraduate level.

Therapeutic hypothermia following out-of-hospital cardiac arrest (OHCA): an audit of compliance at a large Australian hospital.

Therapeutic hypothermia (TH) is now largely considered the standard of care for patients following out-of-hospital cardiac arrest caused by ventricular arrhythmias, although the effective implementation of TH for individual patients can be challenging. This study aimed to document the effectiveness of TH when it is used at the discretion of treating physicians and not under the auspices of a research trial or protocol. A retrospective review of intensive care unit admissions over a four-year period detected 43 patients appropriate for TH. In the emergency department, only 20% of patients had TH commenced. Forty-four percent of patients required angiography in the cardiac catheterisation laboratory. It took, on average, 595 minutes for patients to reach their goal temperature, which was not reached at all in 13% of patients. Nineteen patients (44%) had a positive neurological outcome while 24 patients (56%) either died or had a poor neurological outcome. Without the control of a hospital protocol it was apparent that the implementation of TH in patients with an out-of-hospital cardiac arrest in our institution was inadequate. We recommend that TH is undertaken within the framework of a protocol that encompasses all the relevant departments.

Intensive care unit experience of haemopoietic stem cell transplant patients.

BACKGROUND: Previous research at our institution (1988-1998) established an intensive care unit (ICU) and hospital mortality between 70% and 80% in haemopoietic stem cell transplant (HSCT) patients requiring ICU admission. AIMS: This study explored mortality in a more contemporary cohort while comparing outcomes to published literature and our previous experience. METHODS: Retrospective chart review of HSCT patients admitted to ICU between December 1998 and June 2008. RESULTS: Of 146 admissions, 53% were male, with a mean age of 44 years, an Acute Physiologic and Chronic Health Evaluation II score of 28 and Sepsis Organ Failure Assessment score of 11. Fifty-six per cent had graft versus host disease (GVHD), with respiratory failure (67%) being the most common admission diagnosis. All but one received mechanical ventilation. The ICU and hospital mortality were 42% (72% 1988-1998 cohort) and 64% (82% 1998-1998 cohort) respectively. The 6- and 12-month survivals were 29% and 24% respectively for the 1998-2008 cohort. Dying in ICU was independently predicted by fungal infection (P= 0.02) and early onset of organ failure (P < 0.001), while GVHD (P= 0.04) predicted survival. Mortality at 12 months was independently predicted by the acute physiology score (P= 0.002), increasing number of organ failures (P= 0.001), and cytomegalovirus positive serology (P= 0.005), while blood stream infection (P= 0.003), an antibiotic change on admission to the ICU (P= 0.007) and a diagnosis of non-Hodgkin lymphoma (P= 0.02) predicted survival. CONCLUSION: Our study found that acute admission of HSCT patients to the ICU is associated with improved survival compared to our previous experience, with organ failure progression a strong predictor of ICU outcome, and specific disease characteristics contributing to long-term survival.

Optical linewidth of a passively mode-locked semiconductor laser.

We measured the optical linewidths of a passively mode-locked quantum dot laser and show that, in agreement with theoretical predictions, the modal linewidth exhibits a parabolic dependence with the mode optical frequency. The minimum linewidth follows a Schawlow-Townes behavior with a rebroadening at high power. In addition, the slope of the parabola is proportional to the RF linewidth of the laser and can therefore provide a direct measurement of the timing jitter. Such a measurement could be easily applied to mode-locked semiconductor lasers with a fast repetition rate where the RF linewidth cannot be directly measured.

Acquired hypernatraemia is an independent predictor of mortality in critically ill patients.

This study reports the incidence and associated mortality of acquired hypernatraemia (Na > 150 mmol x l(-1)) in a general medical/surgical intensive care unit. Patients admitted over a 5-year period with normal sodium values were eligible for inclusion; exclusions were made for burn/neurosurgical diagnoses and for hypertonic saline therapy. From 3475 admissions (3317 patients), 266 (7.7%) episodes of hypernatraemia were observed. Hospital mortality was 33.5% in the hypernatraemic group and 7.7% in the normonatraemic group (p < 0.001). Acquired hypernatraemia was an independent risk factor for in-hospital mortality (OR 1.97, 95% CI 1.37-2.82, p < 0.001). Intermediate sodium levels (145-150 mmol x l(-1)) were associated with increased mortality (OR 1.42, 95% CI 1.02-1.98). Uncorrected sodium at discharge (p = 0.001) and peak sodium (p = 0.001) were better predictors of mortality than time to onset (p = 0.71) and duration of hypernatraemia (p = 1.0). Hypernatraemia avoidance is justified, but determinants of hypernatraemia and benefits of targeted treatment strategies require further elucidation.

Point of care measurement of plasma creatinine in critically ill patients with acute kidney injury.

We report the utility of an enzymatic point of care system for estimation of plasma creatinine concentration in critically ill patients with acute kidney injury. Multiple measurements were obtained from a heterogenous population admitted to a multi-disciplinary intensive care unit. The acute kidney injury network guidelines were used to identify and stratify patients based on the creatinine concentration. Central laboratory values were used as comparators to assess the precision and bias of the system. Overall, point of care measurements correlated well with central pathology results (R(2) = 0.991, p < 0.001), although there tended to be a small negative bias in patients with acute kidney injury (3 micromol x l(-1)). The accuracy of point of care measurement is within clinically acceptable limits and given the much shorter turn around time can be used to identify and monitor patients with acute kidney injury in the critical care environment.

Uninfected random walkers in one dimension.

We consider a system of unbiased diffusing walkers (A(Phi)<-->(Phi)A) in one dimension with random initial conditions. We investigate numerically the relation between the fraction of walkers U(t) which have never encountered another walker up to time t, calling such walkers "uninfected" and the fraction of sites P(t) which have never been visited by a diffusing particle. We extend our study to include the A+B--> Phi diffusion-limited reaction in one dimension, with equal initial densities of A and B particles distributed homogeneously at t=0. We find U(t) approximately [P(t)]gamma, with gamma approximately 1.39, in both models, though there is evidence that a smaller value of gamma is required for t-->infinity.

Fraction of uninfected walkers in the one-dimensional Potts model.

The dynamics of the one-dimensional q-state Potts model, in the zero-temperature limit, can be formulated through the motion of random walkers which either annihilate (A+A-->Phi) or coalesce (A+A-->A) with a q-dependent probability. We consider all of the walkers in this model to be mutually infectious. Whenever two walkers meet, they experience mutual contamination. Walkers which avoid an encounter with another random walker up to time t remain uninfected. The fraction of uninfected walkers is known to obey a power-law decay U(t) approximately t(-phi(q)), with a nontrivial exponent phi(q) [C. Monthus, Phys. Rev. E 54, 4844 (1996); S. N. Majumdar and S. J. Cornell, ibid. 57, 3757 (1998)]. We probe the numerical values of phi(q) to a higher degree of accuracy than previous simulations and relate the exponent phi(q) to the persistence exponent theta(q) [B. Derrida, V. Hakim, and V. Pasquier, Phys. Rev. Lett. 75, 751 (1995)], through the relation phi(q)=gamma(q)theta(q) where gamma is an exponent introduced in [S. J. O'Donoghue and A. J. Bray, preceding paper, Phys. Rev. E 65, 051113 (2002)]. Our study is extended to include the coupled diffusion-limited reaction A+A-->B, B+B-->A in one dimension with equal initial densities of A and B particles. We find that the density of walkers decays in this model as rho(t) approximately t(-1/2). The fraction of sites unvisited by either an A or a B particle is found to obey a power law, P(t) approximately t(-theta) with theta approximately 1.33. We discuss these exponents within the context of the q-state Potts model and present numerical evidence that the fraction of walkers which remain uninfected decays as U(t) approximately t(-phi), where phi approximately 1.13 when infection occurs between like particles only, and phi approximately 1.93 when we also include cross-species contamination. We find that the relation between phi and theta in this model can also be characterized by an exponent gamma, where similarly, phi=gamma(theta).

Persistence in the one-dimensional A+B--> Ø reaction-diffusion model.

The persistence properties of a set of random walkers obeying the A+B--> Ø reaction, with equal initial density of particles and homogeneous initial conditions, is studied using two definitions of persistence. The probability P(t) that an annihilation process has not occurred at a given site has the asymptotic form P(t) approximately const+t(-straight theta), where straight theta is the persistence exponent (type I persistence). We argue that, for a density of particles rho>>1, this nontrivial exponent is identical to that governing the persistence properties of the one-dimensional diffusion equation, partial differential(t)straight phi= partial differential(xx)straight phi, where straight theta approximately 0.1207 [S. N. Majumdar, C. Sire, A. J. Bray, and S. J. Cornell, Phys. Rev. Lett. 77, 2867 (1996)]. In the case of an initial low density, rho(0)<<1, we find straight theta approximately 1/4 asymptotically. The probability that a site remains unvisited by any random walker (type II persistence) is also investigated and found to decay with a stretched exponential form, P(t) approximately exp(-constxrho(1/2)(0)t(1/4)), provided rho(0)<<1. A heuristic argument for this behavior, based on an exactly solvable toy model, is presented.

Comparison of ARM and HEAT protein repeats.

ARM and HEAT motifs are tandemly repeated sequences of approximately 50 amino acid residues that occur in a wide variety of eukaryotic proteins. An exhaustive search of sequence databases detected new family members and revealed that at least 1 in 500 eukaryotic protein sequences contain such repeats. It also rendered the similarity between ARM and HEAT repeats, believed to be evolutionarily related, readily apparent. All the proteins identified in the database searches could be clustered by sequence similarity into four groups: canonical ARM-repeat proteins and three groups of the more divergent HEAT-repeat proteins. This allowed us to build improved sequence profiles for the automatic detection of repeat motifs. Inspection of these profiles indicated that the individual repeat motifs of all four classes share a common set of seven highly conserved hydrophobic residues, which in proteins of known three-dimensional structure are buried within or between repeats. However, the motifs differ at several specific residue positions, suggesting important structural or functional differences among the classes. Our results illustrate that ARM and HEAT-repeat proteins, while having a common phylogenetic origin, have since diverged significantly. We discuss evolutionary scenarios that could account for the great diversity of repeats observed.

Levofloxacin induced polymorphic ventricular tachycardia with normal QT interval.

Polymorphic ventricular tachycardia (PVT) is a form of ventricular tachycardia characterized by QRS complexes that seem to change direction during the tachycardia. If associated with a prolonged QT interval, it is called torsades de pointes. In the absence of a congenital long QT syndrome, torsades is seen with certain drugs such as antiarrhythmic agents (Class IA, IC, III), psychotropic medications, antidepressants, antihistamines, and electrolyte disturbances. We report the first case of polymorphic ventricular tachycardia with normal QT interval associated with the oral use of levofloxacin in the absence of other etiologies known to cause these arrhythmias.

Unraveling the symmetry ambiguity in a hexamer: calculation of the R6 human insulin structure.

Crystallographic and NMR studies of insulin have revealed a highly flexible molecule with a range of different aggregation and structural states; the importance of these states for the function of the hormone is still unclear. To address this question, we have studied the solution structure of the insulin R6 symmetric hexamer using NMR spectroscopy. Structure determination of symmetric oligomers by NMR is complicated due to 'symmetry ambiguity' between intra- and intermonomer NOEs, and between different classes of intermonomer NOEs. Hence, to date, only two symmetric tetramers and one symmetric pentamer (VTB, B subunit of verotoxin) have been solved by NMR: there has been no other symmetric hexamer or higher-order oligomer. Recently, we reported a solution structure for R6 insulin hexamer. However, in that study, a crystal structure was used as a reference to resolve ambiguities caused by the threefold symmetry; the same method was used in solving VTB. Here, we have successfully recalculated R6 insulin using the symmetry-ADR method, a computational strategy in which ambiguities are resolved using the NMR data alone. Thus the obtained structure is a refinement of the previous R6 solution structure. Correlated motions in the final structural ensemble were analysed using a recently developed principal component method; this suggests the presence of two major conformational substates. The study demonstrates that the solution structure of higher-order symmetric oligomers can be determined unambiguously from NMR data alone, using the symmetry-ADR method. This success bodes well for future NMR studies of higher-order symmetric oligomers. The correlated motions observed in the structural ensemble suggest a new insight into the mechanism of phenol exchange and the T6 <--> R6 transition of insulin in solution.

Videofluoroscopic evaluation in the assessment of swallowing disorders in paediatric and adult populations.

Videofluoroscopic swallow studies (VFSS) are often considered the 'gold standard' technique to assess dysphagia. Despite this status, unanimous agreement has not been reached regarding the protocol for this procedure. Review of the literature reveals two main schools of thought. The first advocates a uniform, standardised protocol used with all patients. The second argues for functional, tailor-made studies, which aim to elicit a sample of swallowing representative of typical feeding patterns. This paper reviews the literature on VFSS methodology and evaluates the applicability of protocols to the paediatric population. Broadly speaking, adult protocols tend towards uniform procedures, whereas paediatric studies aim to be more individualised and tailor-made. Clinical recommendations based upon VFSS are examined in the light of validity and reliability issues. The need for standardisation of the VFSS procedure is highlighted. The question is raised whether it is possible to achieve uniformity and consistency between clinicians and still perform patient-centered, tailor-made VFSSs, which are truly representative of a patient's swallow function. It is revealed that dysphagia specialists should achieve greater consistency in the VFSS procedure before claiming to be implementing a 'gold standard' technique.

Molecular dynamics and accuracy of NMR structures: effects of error bounds and data removal.

The effect of internal dynamics on the accuracy of nuclear magnetic resonance (NMR) structures was studied in detail using model distance restraint sets (DRS) generated from a 6.6 nanosecond molecular dynamics trajectory of bovine pancreatic trypsin inhibitor. The model data included the effects of internal dynamics in a very realistic way. Structure calculations using different error estimates were performed with iterative removal of systematically violated restraints. The accuracy of each calculated structure was measured as the atomic root mean square (RMS) difference to the optimized average structure derived from the trajectory by structure factors refinement. Many of the distance restraints were derived from NOEs that were significantly affected by internal dynamics. Depending on the error bounds used, these distance restraints seriously distorted the structure, leading to deviations from the coordinate average of the dynamics trajectory even in rigid regions. Increasing error bounds uniformly for all distance restraints relieved the strain on the structures. However, the accuracy did not improve. Significant improvement of accuracy was obtained by identifying inconsistent restraints with violation analysis, and excluding them from the calculation. The highest accuracy was obtained by setting bounds rather tightly, and removing about a third of the restraints. The limiting accuracy for all backbone atoms was between 0.6 and 0.7 A. Also, the precision of the structures increased with removal of inconsistent restraints, indicating that a high precision is not simply the consequence of tight error bounds but of the consistency of the DRS. The precision consistently overestimated the accuracy.

Adaptation of protein surfaces to subcellular location.

In vivo, proteins occur in widely different physio-chemical environments, and, from in vitro studies, we know that protein structure can be very sensitive to environment. However, theoretical studies of protein structure have tended to ignore this complexity. In this paper, we have approached this problem by grouping proteins by their subcellular location and looking at structural properties that are characteristic to each location. We hypothesize that, throughout evolution, each subcellular location has maintained a characteristic physio-chemical environment, and that proteins in each location have adapted to these environments. If so, we would expect that protein structures from different locations will show characteristic differences, particularly at the surface, which is directly exposed to the environment. To test this hypothesis, we have examined all eukaryotic proteins with known three-dimensional structure and for which the subcellular location is known to be either nuclear, cytoplasmic, or extracellular. In agreement with previous studies, we find that the total amino acid composition carries a signal that identifies the subcellular location. This signal was due almost entirely to the surface residues. The surface residue signal was often strong enough to accurately predict subcellular location, given only a knowledge of which residues are at the protein surface. The results suggest how the accuracy of prediction of location from sequence can be improved. We concluded that protein surfaces show adaptation to their subcellular location. The nature of these adaptations suggests several principles that proteins may have used in adapting to particular physio-chemical environments; these principles may be useful for protein design.