Pulmonary thromboembolism in hospitalised patients with COVID-19: a retrospective national study of patients managed in critical care and ward environments in Scotland.

OBJECTIVES: To assess for increase in pulmonary thromboembolism (PTE) in hospitalised patients with COVID-19, in both critical care and ward environments. SETTING: We reviewed all CT pulmonary angiograms (CTPA) performed in Scotland between 23 March 2020 and 31 May 2020 and identified those with COVID-19 using either classical radiological appearances or positive COVID-19 PCR swab. PARTICIPANTS: All hospitalised patients in Scotland with COVID-19 between 23 March 2020 and 31 May 2020 who underwent a CTPA. PRIMARY OUTCOME MEASURE: To assess if the rate of PTE was increased in those with COVID-19 compared with previously published figures of hospitalised patients. SECONDARY OUTCOME MEASURES: To assess the effect of right heart strain or requirement for critical care on mortality. RESULTS: 3401 CTPAs were reviewed. 192 were positive for PTE in patients with evidence of COVID-19 either real-time PCR swab positive for SARS-CoV-2 (n=104) or having radiological changes consistent with COVID-19 (n=88). The total number of hospital admissions in Scotland between 23rd March 2020 and 31st May 2020 with COVID-19 was 5195. The incidence of PTE during this time was 3.7% in all patients admitted to all hospitals in Scotland with COVID-19 during this period. 475 hospitalised patients were managed in critical care (both level 2 and level 3 care), in whom the incidence of PTE was 6% (n=29). 4720 patients did not require admission to critical care, in whom the incidence of PTE was 3.5% (n=163). There was increased risk of death with right heart strain (25/52 vs 128/140 (p<0.01)) and in critical care (15/29 vs 146/163 (p<0.01)). CONCLUSIONS: We have demonstrated an increased risk of PTE in critical care and ward-based environments. Further studies are required to establish effective prophylactic anticoagulation in this group.

Pearls and Pitfalls in MR Enterography Interpretation for Pediatric Patients.

Magnetic resonance (MR) enterography is now the preferred modality for evaluation of acute and chronic presentations of Crohn disease in pediatric patients. There has been increasing standardization in the performance and interpretation of these studies, given the growth in volume and impact on clinical management. This article will focus on technical considerations in the performance of MR enterography in children and adolescents, as well as "do not miss" findings on MR enterography that will impact clinical management and potential problems encountered with MR enterography that may limit its diagnostic utility in some patients.

Dosing obese cats based on body weight spuriously affects some measures of glucose tolerance.

The primary objective was to investigate whether dosing glucose by body weight results in spurious effects on measures of glucose tolerance in obese cats because volume of distribution does not increase linearly with body weight. Healthy research cats (n = 16; 6 castrated males, 10 spayed females) were used. A retrospective study was performed using glucose concentration data from glucose tolerance and insulin sensitivity tests before and after cats were fed ad libitum for 9 to 12 mo to promote weight gain. The higher dose of glucose (0.5 vs 0.3 g/kg body weight) in the glucose tolerance tests increased 2-min glucose concentrations (P < 0.001), and there was a positive correlation between 2-min and 2-h glucose (r = 0.65, P = 0.006). Two-min (P = 0.016 and 0.019, respectively), and 2-h (P = 0.057 and 0.003, respectively) glucose concentrations, and glucose half-life (T1/2; P = 0.034 and <0.001 respectively) were positively associated with body weight and body condition score. Glucose dose should be decreased by 0.05 g for every kg above ideal body weight. Alternatively, for every unit of body condition score above 5 on a 9-point scale, observed 2-h glucose concentration should be adjusted down by 0.1 mmol/L. Dosing glucose based on body weight spuriously increases glucose concentrations at 2 h in obese cats and could lead to cats being incorrectly classified as having impaired glucose tolerance. This has important implications for clinical studies assessing the effect of interventions on glucose tolerance when lean and obese cats are compared.

Diagnosis of prediabetes in cats: glucose concentration cut points for impaired fasting glucose and impaired glucose tolerance.

Diabetes is typically diagnosed in cats once clinical signs are evident. Diagnostic criteria for prediabetes in cats have not been defined. The objective of the study was to establish methodology and cut points for fasting and 2-h blood glucose concentrations in healthy client-owned senior cats (≥8 yr) using ear/paw samples and a portable glucose meter calibrated for feline blood. Of the 78 cats, 27 were ideal (body condition score [BCS] 4 or 5 of 9), 31 overweight (BCS 6 or 7), and 20 obese (BCS 8 or 9); 19 were Burmese and 59 non-Burmese. After an 18-24-h fast and an ear/paw blood glucose measurement using a portable glucose meter, glucose (0.5 g/kg bodyweight) was administered intravenous and blood glucose measured at 2 min and 2 h. Cut points for fasting and 2-h glucose concentrations were defined as the upper limits of 95% reference intervals using cats with BCS 4 or 5. The upper cut point for fasting glucose was 6.5 mmol/L. Of the overweight and obese cats, 1 (BCS 7) was above this cut point indicating evidence of impaired fasting glucose. The cut point for 2-h glucose was 9.8 mmol/L. A total of 7 cats (4 with BCS 8 or 9 including 1 Burmese; 3 with BCS 6 or 7, non-Burmese) were above this cut point and thus had evidence of impaired glucose tolerance. In conclusion, the methodology and cutpoints for diagnosis of prediabetes are defined for use in healthy cats 8 yr and older with a range of BCSs.

Hypoxaemia in patients with pulmonary arterial hypertension during simulated air travel.

BACKGROUND: Recent air travel recommendations suggest patients with precapillary pulmonary hypertension (PCPH) in New York Heart Association (NYHA) functional class 3 and 4 should have in-flight oxygen without the need for pre-flight testing. However it remains unclear as to how best to determine patients fitness to fly. METHODS: This study (i) investigates the effect of hypoxic challenge testing (HCT) on the arterial oxygen levels in a cohort of 36 patients with PCPH and (ii) compares the relative frequency with which FC and HCT predict the requirement for in-flight oxygen. RESULTS: The degree of arterial hypoxaemia induced by HCT (fall in partial pressure of oxygen in arterial blood (PaO(2)) 2.36 kPa, 95% CI 2.06-2.66 kPa) was similar to the drop observed in other published studies of chronic respiratory diseases. Following current air travel recommendations based on FC, 25 patients of the cohort would require in-flight oxygen whilst 10 subjects failed the HCT. Fourteen subjects had flown post-diagnosis. Of these, nine subjects should have had in-flight oxygen based on FC but were asymptomatic without. Also one who passed the HCT had developed symptoms during the flight whilst three who failed the HCT were asymptomatic flying without in-flight oxygen. CONCLUSIONS: Hypoxaemia induced by simulated air travel in patients with PCPH is similar to that seen in published studies of patients with other chronic respiratory diseases. HCT failed to predict correctly who had developed symptoms during an aircraft flight in a significant minority of the study subjects. Similarly guidelines based on functional class result in a major increase in the proportion of patients being advised to use oxygen, many of whom had been asymptomatic on previous flights without it. More work is required to improve prediction of need for in-flight oxygen in patients with PCPH.

The role of per cent predicted 6-min walk distance in pulmonary arterial hypertension.

Absolute 6-min walk distance (6MWD) predicts mortality in pulmonary arterial hypertension (PAH), but varies greatly between normal individuals due to physiological factors such as age, sex, height and weight. The % predicted 6MWD adjusts for these factors and may predict mortality more reliably. The aim of the study was to compare the strength of mortality prediction by absolute and % predicted 6MWD in PAH at baseline and on treatment. % predicted 6MWD was calculated using four different reference equations in 137 PAH patients (idiopathic and connective tissue disease associated) diagnosed between November 2000 and November 2009. Cox proportional hazards and receiver-operating characteristic (ROC) analyses were used to compare the prognostic strength of absolute and % predicted 6MWD. % predicted 6MWD was predictive of all-cause mortality at baseline (hazard ratio 0.74-0.83 per 10% increase; p<0.05) and on treatment (0.67-0.75 per 10% increase; p<0.01), but each respective area under the ROC curve was not different from that of absolute 6MWD for predicting 2-yr mortality at baseline (absolute versus % predicted: 0.74 versus 0.71-0.75) or on treatment (0.77 versus 0.72-0.78). In conclusion, % predicted 6MWD may help clinicians interpret the 6-min walk test, but its prognostic value is not superior to that of absolute 6MWD.

Identification of novel candidate genes associated with cleft lip and palate using array comparative genomic hybridisation.

AIM AND METHOD: We analysed DNA samples isolated from individuals born with cleft lip and cleft palate to identify deletions and duplications of candidate gene loci using array comparative genomic hybridisation (array-CGH). RESULTS: Of 83 syndromic cases analysed we identified one subject with a previously unknown 2.7 Mb deletion at 22q11.21 coinciding with the DiGeorge syndrome region. Eighteen of the syndromic cases had clinical features of Van der Woude syndrome and deletions were identified in five of these, all of which encompassed the interferon regulatory factor 6 (IRF6) gene. In a series of 104 non-syndromic cases we found one subject with a 3.2 Mb deletion at chromosome 6q25.1-25.2 and another with a 2.2 Mb deletion at 10q26.11-26.13. Analyses of parental DNA demonstrated that the two deletion cases at 22q11.21 and 6q25.1-25.2 were de novo, while the deletion of 10q26.11-26.13 was inherited from the mother, who also has a cleft lip. These deletions appear likely to be causally associated with the phenotypes of the subjects. Estrogen receptor 1 (ESR1) and fibroblast growth factor receptor 2 (FGFR2) genes from the 6q25.1-25.2 and 10q26.11-26.13, respectively, were identified as likely causative genes using a gene prioritization software. CONCLUSION: We have shown that array-CGH analysis of DNA samples derived from cleft lip and palate subjects is an efficient and productive method for identifying candidate chromosomal loci and genes, complementing traditional genetic mapping strategies.

Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma.

Activating mutations of the genes for NRAS and BRAF, components of the p44/42 mitogen-activated protein kinase (MAPK) pathway, are common findings in melanoma. Recent evidence in several nonmelanoma cell systems supports the regulation of the inducible nitric oxide synthase (iNOS) gene by this pathway. On the basis of our data showing that melanoma iNOS expression predicts shortened patient survival, we formulated the hypothesis that activating mutations of NRAS or BRAF, which lead to constitutive activation of the p44/42 MAPK pathway, drive iNOS expression in human melanoma. In the present study, we have shown that inhibition of melanoma iNOS activity by S-methylisothiourea leads to decreased cell proliferation, confirming the importance of iNOS activity for melanoma cell growth. Regulation of melanoma iNOS expression by the p44/42 MAPK pathway was demonstrated by inhibition of the pathway by U0126, and by BRAF RNA interference. To explore this regulatory pathway in human tissue, 20 melanoma tumors were examined for NRAS and BRAF mutations, immunohistochemical evidence of ERK phosphorylation, and iNOS expression. A significant association was found among these three features. We conclude that in human melanoma, activating mutations of NRAS and BRAF drive constitutive iNOS expression and, implicitly, nitric oxide production, contributing to the poor survival of these patients.

Use of reactance to estimate transpulmonary resistance.

This study examines the relationship of respiratory system resistance (R(rs)) and reactance (X(rs)) measured by forced oscillometry with transpulmonary resistance (R(L)) measured by oesophageal manometry. Simultaneous forced oscillometry using a single frequency of 5 Hz and oesophageal manometry were performed on five asthmatics during bronchoprovocation. The data obtained were used to derive prediction equations for R(L) from oscillometric parameters, which were tested on a further six asthmatics and 35 nonasthmatic subjects. In the first five asthmatic subjects, R(L) correlated more strongly with X(rs) than with R(rs). In the second set of asthmatics, R(L) ranged 0.0005-4.57 kPa.s.L(-1), with a median of 0.21 kPa.s.L(-1). The R(L) values predicted from X(rs) showed a mean+/-sd difference of -0.067+/-0.25 kPa.s.L(-1) compared with the values measured in this set of patients. X(rs) in subjects with other respiratory conditions appeared to follow the same relationship with R(L) as in asthmatics. Lumped element modelling suggested that the linear relationship between X(rs) and R(L) was a consequence of the increasing contribution of central and upper airway wall shunts as peripheral airway resistance rose, and that this effect was much larger than that due to changes in static elastance. In conclusion, the reactance of the respiratory system can predict transpulmonary resistance more accurately than can the resistance of the respiratory system.

Long-term continuous positive airway pressure (CPAP) outcomes from a sleep service using limited sleep studies and daycase CPAP titration in the management of obstructive sleep apnoea/hypopnoea syndrome.

BACKGROUND: Detailed polysomnography (PSG) and overnight continuous positive airway pressure (CPAP) titration as the basis for investigation and treatment of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) incurs high costs from inpatient stays and technician attendance, even when split night studies are employed. Responding to rapidly increasing demand, from 1996 the sleep service at Glasgow Royal Infirmary adopted limited sleep studies and daycase CPAP titration as first line management. Here we describe the outcomes of this service between 1996 and 1999. METHODS: Data were collected from prospective records made at follow up by sleep technicians and by casenote review. RESULTS: Results were available for 158 subjects (97.5%) of 162 commenced on CPAP during this period. One hundred and forty-eight (91%) were diagnosed by limited sleep studies and 80 (50%) were diagnosed at home. The median follow up was 23 months (interquartile range (IQR), 13-35). Median use of CPAP in those continuing therapy was 5.3 hours/night (IQR, 3.1 to 6.5) and 77% were still using CPAP at three years. Only initial low CPAP compliance (< 2 hours/night) significantly predicted early CPAP cessation. In those still on CPAP in 1999, the mean drop in Epworth Sleepiness Scale score was 4.6 points (95% confidence intervals, 3.2 to 6.0). CONCLUSION: These data from the CPAP population at Glasgow Royal Infirmary provide information on longterm outcomes using a diagnostic protocol based on limited sleep studies and daycase CPAP titration.

IscA, an alternate scaffold for Fe-S cluster biosynthesis.

An IscA homologue within the nif regulon of Azotobacter vinelandii, designated (Nif)IscA, was expressed in Escherichia coli and purified to homogeneity. Purified (Nif)IscA was found to be a homodimer of 11-kDa subunits that contained no metal centers or other prosthetic groups in its as-isolated form. Possible roles for (Nif)IscA in Fe-S cluster biosynthesis were assessed by investigating the ability to bind iron and to assemble Fe-S clusters in a NifS-directed process, as monitored by the combination of UV-vis absorption, Mössbauer, resonance Raman, variable-temperature magnetic circular dichroism, and EPR spectroscopies. Although (Nif)IscA was found to bind ferrous ion in a tetrahedral, predominantly cysteinyl-ligated coordination environment, the low-binding affinity argues against a specific role as a metallochaperone for the delivery of ferrous ion to other Fe-S cluster assembly proteins. Rather, a role for (Nif)IscA as an alternate scaffold protein for Fe-S cluster biosynthesis is proposed, based on the NifS-directed assembly of approximately one labile [4Fe-4S](2+) cluster per (Nif)IscA homodimer, via a transient [2Fe-2S](2+) cluster intermediate. The cluster assembly process was monitored temporally using UV-vis absorption and Mössbauer spectroscopy, and the intermediate [2Fe-2S](2+)-containing species was additionally characterized by resonance Raman spectroscopy. The Mössbauer and resonance Raman properties of the [2Fe-2S](2+) center are consistent with complete cysteinyl ligation. The presence of three conserved cysteine residues in all IscA proteins and the observed cluster stoichiometry of approximately one [2Fe-2S](2+) or one [4Fe-4S](2+) per homodimer suggest that both cluster types are subunit bridging. In addition, (Nif)IscA was shown to couple delivery of iron and sulfur by using ferrous ion to reduce sulfane sulfur. The ability of Fe-S scaffold proteins to couple the delivery of these two toxic and reactive Fe-S cluster precursors is likely to be important for minimizing the cellular concentrations of free ferrous and sulfide ions. On the basis of the spectroscopic and analytical results, mechanistic schemes for NifS-directed cluster assembly on (Nif)IscA are proposed. It is proposed that the IscA family of proteins provide alternative scaffolds to the NifU and IscU proteins for mediating nif-specific and general Fe-S cluster assembly.

Source ROCs are (typically) curvilinear: comment on Yonelinas (1999).

On the basis of his assumption that recollection is a threshold process, A. P. Yonelinas (1999) predicted linear source-identification receiver operating characteristics (ROCs) and recently reported data that were consistent with this prediction. In this article, the authors present data showing curvilinear source-identification ROCs across various encoding and test conditions. On the basis of the source-monitoring framework (e.g., M. K. Johnson, S. Hashtroudi, & D. S. Lindsay, 1993), the authors argue that curvilinearity of source-identification ROCs is a result of differences in the qualitative characteristics of memories rather than simply the influence of undifferentiated familiarity as the dual-process model might suggest.

A paramagnetic species with unique EPR characteristics in the active site of heterodisulfide reductase from methanogenic archaea.

Heterodisulfide reductase (Hdr) from methanogenic archaea is an iron-sulfur protein that catalyses the reversible reduction of the heterodisulfide (CoM-S-S-CoB) of the methanogenic thiol coenzymes, coenzyme M (H-S-CoM) and coenzyme B (H-S-CoB). In EPR spectroscopic studies with the enzyme from Methanothermobacter marburgensis, we have identified a unique paramagnetic species that is formed upon reaction of the oxidized enzyme with H-S-CoM in the absence of H-S-CoB. This paramagnetic species can be reduced in a one-electron step with a midpoint-potential of -185 mV but not further oxidized. A broadening of the EPR signal in the 57Fe-enriched enzyme indicates that it is at least partially iron based. The g values (gxyz = 2.013, 1.991 and 1.938) and the midpoint potential argue against a conventional [2Fe-2S]+, [3Fe-4S]+, [4Fe-4S]+ or [4Fe-4S]3+ cluster. This species reacts with H-S-CoB to form an EPR silent form. Hence, we propose that only a half reaction is catalysed in the presence of H-S-CoM and that a reaction intermediate is trapped. This reaction intermediate is thought to be a [4Fe-4S]3+ cluster that is coordinated by one of the cysteines of a nearby active-site disulfide or by the sulfur of H-S-CoM. A paramagnetic species with similar EPR properties was also identified in Hdr from Methanosarcina barkeri.

Brain potentials reflect behavioral differences in true and false recognition.

People often falsely recognize nonstudied lures that are semantically similar to previously studied words. Behavioral research suggests that such false recognition is based on high semantic overlap between studied items and lures that yield a feeling of familiarity, whereas true recognition is more often associated with the recollection of details. Despite this behavioral evidence for differences between true and false recognition, research measuring brain activity (PET, fMRI, ERP) has not clearly differentiated corresponding differences in brain activity. A median split was used to separate subjects into Good and Poor performers based on their discrimination of studied targets from similar lures. Only Good performers showed late (1000--1500 msec), right frontal event-related brain potentials (ERPs) that were more positive for targets and lures compared with new items. The right frontal differences are interpreted as reflecting postretrieval evaluation processes that were more likely to be engaged by Good than Poor performers. Both Good and Poor performers showed a parietal ERP old/new effect (400--800 msec), but only Poor performers showed a parietal old/lure difference. These results are consistent with the view that the parietal and frontal ERP old/new effects reflect dissociable processes related to recollection.

Hospital at home services for acute exacerbation of chronic obstructive pulmonary disease: a survey of British practice.

OBJECTIVES: To identify the prevalence of and attitudes towards hospital at home services for acute exacerbation of chronic obstructive pulmonary disease (COPD) in Great Britain. To identify the models of service in existence, in particular staff numbers and the workload experienced. DESIGN: A postal survey was used to locate existing schemes. Telephone interviews were conducted with each of the hospital at home services identified. SUBJECTS & SETTING: A questionnaire was sent to one consultant in each of 223 respiratory departments in Great Britain. Thirty six departments were subsequently contacted by telephone. OUTCOME MEASURES: Awareness and prevalence of hospital at home services. Perceived problems with starting a service. Details of organisation of existing services. RESULTS: We received 186 replies to the postal questionnaire. Of these respiratory departments, 179 (96%) were aware of hospital at home services for acute exacerbation of COPD and, in November 1999, 30 (16%) were running such a service. Difficulty in obtaining funding was the main reason for not setting up a service rather than lack of evidence of benefit or unsuitability of local circumstances. Median staffing level was two nurses (range one to six) looking after a median number of new patients of five per week (range 0.5 to 12). There was wide variation in the organisation of services. CONCLUSIONS: Despite lack of objective evidence of effectiveness, there was a high level of awareness of and interest in starting hospital at home services for acute exacerbation of COPD in British respiratory departments when assessed in November 1999.

Collaborative practice: a successful model.

Recognizing the need for better collaboration, nursing personnel from two nonrelated health care facilities, acute care and rehabilitation hospitals, came together to establish a methodology to improve outcomes for patients with spinal cord injury (SCI). Focus areas were to facilitate communication and transition between hospitals. A collaborative practice model evolved for the patient with tetraplegia who is ventilator-dependent. This model has been successfully instituted in both institutions. This article describes the processes used in developing this model. It also includes recommendations for the reader to create a workable process in his or her respective institution.