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.

Cost effectiveness of intraoperative laparoscopic ultrasound for suspected choledocholithiasis; outcomes from a specialist benign upper gastrointestinal unit.

INTRODUCTION: Common bile duct stones are present in 10% of patients with symptomatic gallstones. One-third of UK patients undergoing cholecystectomy will have preoperative ductal imaging, commonly with magnetic resonance cholangiopancreatography. Intraoperative laparoscopic ultrasound is a valid alternative but is not widely used. The primary aim of this study was to assess cost effectiveness of laparoscopic ultrasound compared with magnetic resonance cholangiopancreatography. MATERIALS AND METHODS: A prospective database of all patients undergoing laparoscopic cholecystectomy between 2015 and 2018 at a district general hospital was assessed. Inclusion criteria were all patients, emergency and elective, with symptomatic gallstones and suspicion of common bile duct stones (derangement of liver function tests with or without dilated common bile duct on preoperative ultrasound, or history of pancreatitis). Patients with known common bile duct stones (magnetic resonance cholangiopancreatography or failed endoscopic retrograde cholangiogram) were excluded. Ninety-day morbidity data were also collected. RESULTS: A total of 420 (334 elective and 86 emergency) patients were suspected to have common bile duct stones and were included in the study. The cost of a laparoscopic ultrasound was £183 per use. The cost of using the magnetic resonance cholangiopancreatography unit was £365 per use. Ten postoperative magnetic resonance cholangiopancreatographies were performed for inconclusive intraoperative imaging. The estimated cost saving was £74,650. Some 128 patients had common bile duct stones detected intraoperatively and treated. There was a false positive rate of 4.7%, and the false negative rate at 90 days was 0.7%. laparoscopic ultrasound use saved 129 bed days for emergency patients and 240 magnetic resonance cholangiopancreatography hours of magnetic resonance imaging. CONCLUSION: The use of laparoscopic ultrasound during laparoscopic cholecystectomy for the detection of common bile duct stone is safe, accurate and cost effective. Equipment and maintenance costs are quickly offset and hospital bed days can be saved with its use.

Malignant brain tumors in patients with glutaric aciduria type I.

Three young patients with glutaric aciduria type I (age 6-23 years) of different ethnic origins, treated for their metabolic disease since early childhood, presented with malignant central nervous system tumors. We recommend continuing clinical follow-up, including monitoring of neurological manifestations and neuroradiological findings, in all patients with glutaric aciduria type I beyond early childhood, especially if adherence to diet is poor or the treatment was not started neonatally.

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.

Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD.

BACKGROUND: Abeta42-immunization reduces plaque burden and improves cognition in transgenic mouse models of Alzheimer disease (AD). This phase 1 study evaluated the safety, tolerability, and immunogenicity of AN1792 (human aggregated Abeta42) in patients with mild to moderate AD. METHODS: Twenty patients were enrolled into each of four dose groups and randomly assigned to receive IM AN1792 (50 or 225 microg) with QS-21 adjuvant (50 or 100 microg) or QS-21 only (control) in a 4:1 active:control ratio on day 0 and at weeks 4, 12, and 24. Patients could receive up to four additional injections of a polysorbate 80 modified formulation at weeks 36, 48, 60, and 72. Safety, tolerability, immunogenicity, and exploratory evidence of efficacy were evaluated. RESULTS: Treatment-related adverse events were reported in 19 (23.8%) patients, but no relationship was observed between AN1792 dose and incidence. One patient developed meningoencephalitis that was diagnosed after death (not directly related to study treatment) and 219 days after discontinuing from the study. Five deaths occurred during the study follow-up, but none was considered to be directly related to study treatment. During the period of the first four injections, 23.4% of AN1792-treated patients had a positive anti-AN1792 antibody titer (an anti-AN1792 antibody titer of > or =1:1,000). This increased to 58.8% after additional injections with the modified formulation. Disability Assessment for Dementia scores showed less decline among active compared with control patients at week 84 (p = 0.002). No treatment differences were observed in three other efficacy measures. CONCLUSIONS: AN1792 + QS-21 elicited a positive antibody response to Abeta42 in more than half of this elderly study population.

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).

A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin.

BACKGROUND: Alpha-4 integrins facilitate leucocyte migration across vascular endothelium. AIM: To assess the safety and efficacy of natalizumab (Antegren), a humanized antibody to alpha-4 integrin, in patients with active ulcerative colitis. METHODS: Ten patients with active ulcerative colitis, defined by a Powell-Tuck activity score > 4, received a single 3 mg/kg natalizumab infusion. The primary end-point was the change in Powell-Tuck score at 2 weeks post-infusion. RESULTS: Significant decreases in the median Powell-Tuck score were observed at 2 and 4 weeks post-infusion (7.5 and 6, respectively) compared to the median baseline score (10). Five of 10 patients achieved a good clinical response at 2 weeks and one more patient by 4 weeks, defined by a Powell-Tuck score of < or = 5. Significant improvements in quality of life scores were found at week 4. Rescue medication was required by two (20%), three (30%) and eight (80%) patients by weeks 2, 4 and 8, respectively (median, 34 days; range, 8-43 days). One patient remained in remission at 12 weeks. The median C-reactive protein at 2 weeks (6 mg/L) was lower than that pre-treatment (16 mg/L). CONCLUSIONS: A single 3 mg/kg infusion of natalizumab was well tolerated by ulcerative colitis patients. The positive efficacy demonstrated in this study merits further investigation by randomized, placebo-controlled trials.

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.

Is first trimester exposure to the combination of antiretroviral therapy and folate antagonists a risk factor for congenital abnormalities?

OBJECTIVES: To assess use of antiretroviral therapy (ART) by HIV positive pregnant women in London since 1994 and the risk of congenital abnormalities associated with multidrug exposure during the first trimester of pregnancy. METHODS: Retrospective multicentre study of medical, obstetric, and paediatric notes of all mother-infant pairs, where the mother was known to be HIV infected before delivery, using a standardised proforma. RESULTS: In this study of 195 mother-infant pairs, use of ART during any stage of pregnancy increased from 33.3% in 1994 to 92.5% in 1999 (p=0.01, trend). First trimester exposure increased from 0% in 1994 to 27.5% in 1999 (p=0.00045, trend). Congenital malformations were observed in nine infants (4.6%). Compared with infants not exposed to ART or folate antagonists during the first trimester (n=148), exposure to both ART and folate antagonists during the first trimester (n=13) was associated with an increased risk of congenital abnormalities (4% v 23.1%; OR 7.10, 95% CI 1.5, 34.2). No malformations were observed in the 34 children exposed to either ART or folate antagonists alone during the first trimester. CONCLUSION: An increasing number of HIV infected women conceived while on ART. Although there is no evidence of teratogenicity caused by ART if given alone during the first trimester, exposure to the combination of ART and folate antagonists was associated with a significantly higher risk of congenital abnormalities in this cohort.

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.