Investigating the impact of non-gated thoracic CT prior to CTCA to reduce layered testing.

AIM: To determine the proportion of computed tomography (CT) coronary angiography (CTCA) referrals with coronary artery calcification (CAC) evident on previous non-cardiac CT imaging and how this impacted the diagnostic yield for CTCA, the requirement for additional diagnostic testing, and the associated costs to confirm or refute obstructive coronary artery disease (CAD). MATERIALS AND METHODS: A retrospective review of CTCA examinations was undertaken between 01/05/2018 and 31/05/2020 in which the examinations were cross referenced for previous non-gated thoracic CT at Royal United Hospitals Bath. Major epicardial vessel CAC on baseline CT was re-evaluated by published semi-quantitative methods, giving a per-patient CAC score (mild = 1-3, moderate = 4-6, severe >6). Subsequent incomplete CTCA diagnostic yield, further testing, and cost implications were examined. RESULTS: Of the 2140 CTCA examinations identified, 13% (280/2140) had a preceding non-gated thoracic CT (53% female, age 63 ± 11 years). The incomplete diagnostic rate increased with CAC grade, mild 32%, (RR 12; 95% CI 4-40), moderate 64% (RR 25; 95% CI 8-80), severe 75%, (RR 29; 95% CI 9-94). Additional diagnostic testing occurred in 4% for the mild CAC category, and 14% and 42% for moderate and severe, respectively. When severe CAC was identified on a non-gated thoracic CT a cost saving of £171/patient (dobutamine stress echo [DSE]) and £61/patient (myocardial perfusion scintigraphy [MPS]) was established with a direct to functional testing pathway. CONCLUSIONS: In patients referred for CTCA where severe CAC was identified on a preceding non-gated thoracic CT a direct to functional testing altered management in 42% of cases and was cost-effective.

Transcriptome Analysis of Podoscypha petalodes Strain GGF6 Reveals the Diversity of Proteins Involved in Lignocellulose Degradation and Ligninolytic Function.

The present study reports transcriptomic profiling of a Basidiomycota fungus, Podoscypha petalodes strain GGF6 belonging to the family Podoscyphaceae, isolated from the North-Western Himalayan ranges in Himachal Pradesh, India. Podoscypha petalodes strain GGF6 possesses significant biotechnological potential as it has been reported for endocellulase, laccase, and other lignocellulolytic enzymes under submerged fermentation conditions. The present study attempts to enhance our knowledge of its lignocellulolytic potential as no previous omics-based analysis is available for this white-rot fungus. The transcriptomic analysis of P. petalodes GGF6 reveals the presence of 280 CAZy proteins. Furthermore, bioprospecting transcriptome signatures in the fungi revealed a diverse array of proteins associated with cellulose, hemicellulose, pectin, and lignin degradation. Interestingly, two copper-dependent lytic polysaccharide monooxygenases (AA14) and one pyrroloquinolinequinone-dependent oxidoreductase (AA12) were also identified, which are known to help in the lignocellulosic plant biomass degradation. Overall, this transcriptome profiling-based study provides deeper molecular-level insights into this Basidiomycota fungi, P. petalodes, for its potential application in diverse biotechnological applications, not only in the biofuel industry but also in the environmental biodegradation of recalcitrant molecules. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-022-01037-6.

Dynamic tracking of variant frequencies depicts the evolution of mutation sites amongst SARS-CoV-2 genomes from India.

With the exponential spread of the coronavirus disease 2019 (COVID-19) pandemic across the world within the 12 months, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains are continuously trying to adapt themselves to the host environment by random mutations. When doing so, some variants with evolutionary advantages such as better human to human transmissibility potential might get naturally selected. This short communication demonstrates how the mutation frequency patterns are evolving in 2457 SAR-CoV-2 strains isolated from COVID-19 patients across diverse Indian states. We have identified 19 such variants showing contrasting mutational probabilities in the span of 7 months. Out of these, 14 variants are showing increasing mutational probabilities suggesting their propagation with time due to their unexplored evolutionary advantages. However, the mutational probabilities of five variants have significantly decreased in June onward as compared to March/April, suggesting their termination with time. Further in-depth investigation of these identified variants will provide valuable knowledge about the evolution, infection strategies, transmission rates, and epidemiology of SARS-CoV-2.

Real-world clinical and cost analysis of CT coronary angiography and CT coronary angiography-derived fractional flow reserve (FFRCT)-guided care in the National Health Service.

AIM: To quantify the real-world clinical and cost impact of computed tomography (CT) coronary angiography (CTCA)-derived fractional flow reserve (FFRCT) in the National Health Service (NHS). MATERIALS AND METHODS: Consecutive clinical CTCA examinations from September to December 2018 with ≥1 stenosis of ≥25% underwent FFRCT analysis. The Heart Team reviewed clinical data and CTCA findings, blinded to FFRCT values, and documented hypothetical consensus management. FFRCT results were then unblinded and hypothetical consensus management re-recorded. Diagnostic waiting times for management pathways were estimated. A per-patient cost analysis for diagnostic certainty regarding coronary artery disease (CAD) management was performed using 2014-2020 NHS tariffs for pre- and post-FFRCT pathways. RESULTS: Two hundred and fifty-one CTCAs were performed during the study period. Fifty-seven percent (145/251) had no CAD or stenosis <25%. One study was non-diagnostic. Of the remaining 42% (105/251), two were ineligible for FFRCT and there was a 5% (5/103) failure rate. FFRCT led to a change in hypothetical management in 65% (64/98; p<0.001) patients with a functional imaging test cancelled in 17% (17/98) and a diagnostic angiogram cancelled in 47% (46/98). FFRCT-guided management had a reduced mean time to definitive investigation compared with CTCA alone (28 ± 4 versus 44 ± 4 days; p=0.004). Using the proposed 2020/21 tariff, CTCA + FFRCT for stenosis ≥50% resulted in a diagnostic pathway £44.97 more expensive per patient than usual care without FFRCT. CONCLUSIONS: In the real-world NHS setting, FFRCT-guided management has the potential to rationalise patient management, accelerate diagnostic pathways, and depending on the stenosis severity modelled, may be cost-effective.

UK undergraduate aspirations and attitudes survey: do we have a perception problem in clinical radiology?

AIM: To understand medical students' potential long-term career choices, with particular reference to radiology, and their current perceptions and experiences of radiology and radiologists, with the aim to help inform future initiatives for undergraduate and early postgraduate medical education and workforce strategies. MATERIALS AND METHODS: An invitation to an online survey was sent to all undergraduate medical students at a large UK medical school, using Likert-style, multiple choice and ranking questions. A quantitative approach was used to explore these responses (n=328). RESULTS: Radiology ranked only 10th out of 14 specialties for long-term career preference amongst medical student respondents (n=328). Radiology was judged as being "low status", but enabled a "good" work-life balance. Medical students considered making an impact on patient diagnosis and level of intellectual challenge as positive influences of a potential career in radiology. Perception of radiology by the public, patient relationship/contact time, perception of radiology by other clinicians, variation of work, and radiology work environment were all perceived more negatively. CONCLUSION: Radiology remains a specialty with limited exposure and experience for undergraduate students, who appear to be incompletely aware of the scope and range of the work of modern radiologists. Greater exposure to radiology teaching in the undergraduate curriculum and placements in radiology departments may increase and expedite medical students' understanding and enjoyment of radiology at a juncture where demand for radiology services is increasing rapidly in the UK.

Computed tomographic and clinical features of pulmonary veno-occlusive disease: raising the radiologist's awareness.

Pulmonary veno-occlusive disease (PVOD) is a rare subtype of pulmonary arterial hypertension (PAH) characterised by preferential remodelling of the pulmonary venules. Differentiation from other subtypes of PAH is essential as the management can differ significantly; for example, initiation of vasodilator therapy may cause fatal pulmonary oedema in a patient with PVOD misdiagnosed with idiopathic PAH. PVOD also carries a substantially worse prognosis. Lung biopsy is required for definitive diagnosis, but this is hazardous, and ideally, should be avoided in pulmonary hypertension. Computed tomography (CT) may suggest the diagnosis, directing the patient towards specialist review. Potential distinguishing CT features between PVOD and other subtypes of PAH include interlobular septal thickening, mediastinal lymphadenopathy, and centrilobular ground-glass opacities. No evidence-based medical therapy exists for PVOD at present and lung transplantation remains the definitive treatment for eligible patients. Therefore, early radiological identification of this challenging diagnosis facilitates timely referral for transplant.

Modeling and dynamic simulation of a two-stage pre-denitrification MBBR system under increasing organic loading rates.

Biofilm-based wastewater treatment systems have become attractive due to their numerous advantages when compared to other suspended growth processes. However, the mathematical modeling of these reactors is relatively complex, since it has to consider a wide range of phenomena to accurately describe the process behavior. This work deals with the modeling of a two-stage MBBR system run in pre-denitrification mode for the removal of organic matter and nitrogen from wastewater. The model development took into account diffusive phenomena and kinetics in a homogeneous biofilm composed of different bacterial functional groups (namely heterotrophs and nitrifiers). The thickness of the biofilm was treated as a variable, given that detachment of adhered biomass took place. The suspended biomass fraction was also considered to remove the pollutants by means of Monod-type kinetics associated with the activated sludge model. The dynamic behavior of the components involved in the system and their spatial distribution in the biofilm obtained from simulated data showed good agreement with those reported in the literature, demonstrating the reproducibility of the model and encouraging future applications in full-scale MBBR plants.

Elevated S100A8 protein expression in breast cancer cells and breast tumor stroma is prognostic of poor disease outcome.

PURPOSE: Elevated S100A8 expression has been observed in cancers of the bladder, esophagus, colon, ovary, and breast. S100A8 is expressed by breast cancer cells as well as by infiltrating immune and myeloid cells. Here we investigate the association of elevated S100A8 protein expression in breast cancer cells and in breast tumor stroma with survival outcomes in a cohort of breast cancer patients. PATIENTS AND METHODS: Tissue microarrays (TMA) were constructed from breast cancer specimens from 417 patients with stage I-III breast cancer treated at the University of Michigan Comprehensive Cancer Center between 2004 and 2006. Representative regions of non-necrotic tumor and distant normal tissue from each patient were used to construct the TMA. Automated quantitative immunofluorescence (AQUA) was used to measure S100A8 protein expression, and samples were scored for breast cancer cell and stromal S100A8 expression. S100A8 staining intensity was assessed as a continuous value and by exploratory dichotomous cutoffs. Associations between breast cancer cell and stromal S100A8 expression with disease-free survival and overall survival were determined using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: High breast cancer cell S100A8 protein expression (as indicated by AQUA scores), as a continuous measure, was a significant prognostic factor for OS [univariable hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.00-1.55, p = 0.05] in this patient cohort. Exploratory analyses identified optimal S100A8 AQUA score cutoffs within the breast cancer cell and stromal compartments that significantly separated survival curves for the complete cohort. Elevated breast cancer cell and stromal S100A8 expression, indicated by higher S100A8 AQUA scores, significantly associates with poorer breast cancer outcomes, regardless of estrogen receptor status. CONCLUSIONS: Elevated breast cancer cell and stromal S1008 protein expression are significant indicators of poorer outcomes in early stage breast cancer patients. Evaluation of S100A8 protein expression may provide additional prognostic information beyond traditional breast cancer prognostic biomarkers.

The influence of intramolecular sulfur-lone pair interactions on small-molecule drug design and receptor binding.

Sulfur-lone pair interactions are important conformational control elements in sulfur-containing heterocycles that abound in pharmaceuticals, natural products, agrochemicals, polymers and other important classes of organic molecules. Nonetheless, the role of intramolecular sulfur-lone pair interactions in the binding of small molecules to receptors is often overlooked. Here we analyze the magnitudes and origins of these interactions for a variety of biologically relevant small molecules using quantum chemical and automated docking calculations. In most cases examined in this study, the lowest energy conformation of the small molecule displays a sulfur-lone pair close contact. However, docking studies, both published and new, often predict that conformations without sulfur-lone pair contacts have the best binding affinity for their respective receptors. This is a serious problem. Since many of these predicted bound conformations are not actually energetically accessible, pursuing design (e.g., drug design) around these binding modes necessarily will lead, serendipity aside, to dead end designs. Our results constitute a caution that one best not neglect these interactions when predicting the binding affinities of potential ligands (drugs or not) for hosts (enzymes, receptors, DNA, RNA, synthetic hosts). Moreover, a better understanding and awareness of sulfur-lone pair interactions should facilitate the rational modulation of host-guest interactions involving sulfur-containing molecules.

Brain imaging in lung cancer patients without symptoms of brain metastases: a national survey of current practice in England.

AIM: To determine current practice regarding brain imaging for newly diagnosed lung cancer patients without symptoms of brain metastases. MATERIALS AND METHODS: A survey questionnaire was sent by e-mail to all the lung cancer lead clinicians in England currently on the National Cancer Intelligence Network database. The survey asked whether brain imaging was used in new lung cancer patients without symptoms or signs to suggest brain metastases; and if so, which patient subgroups were imaged according to cell type, stage of disease, and intention to treat, and which techniques were used to image these patients. Responses were received between February and May 2014. RESULTS: Fifty-nine of 154 centres replied to the survey (38%). Thirty of the 59 centres (51%) did not image the brain in these patients. Twenty-nine of the 59 (49%) centres imaged the brain in at least certain subgroups. Of those centres that did image the brain 21 (72%) used CT as the first-line imaging technique and six (20%) used MRI. Twenty-five of 59 (42%) centres stated that the 2011 NICE guidelines had led to a change in their practice. CONCLUSION: There is wide variation in practice regarding brain imaging in this patient group in England, with no brain imaging at all in approximately half of centres and a spectrum of imaging in the other half. When the brain is imaged, CT is the technique most commonly used. The 2011 NICE guidelines have led to some change in practice but not to national uniformity.

Delusional infestation: an Australian multicentre study of 23 consecutive cases.

Delusional infestation remains a debilitating condition that is therapeutically challenging for clinicians. This case series identifies 23 patients with delusional infestation in an Australian setting. The majority of patients are women and unlikely to have a psychiatric comorbid background. The use of unnecessary anti-parasitic medication is prevalent.

Under-mask beard covers achieve an adequate seal with tight-fitting disposable respirators using quantitative fit testing.

BACKGROUND: Tight-fitting respirators are a critical component of respiratory protection against airborne diseases for health workers. However, they are not recommended for health workers with facial hair. Some health workers are unable to shave for religious or medical reasons. Under-mask beard covers have been proposed as a solution to allow health workers with facial hair to wear tight-fitting respirators. However, studies to date have been limited by their predominant reliance on qualitative rather than quantitative fit testing techniques. AIM: To assess the efficacy of under-mask beard covers in achieving an adequate seal with tight-fitting disposable P2/N95 respirators using quantitative fit testing. METHODS: Bearded adult males underwent quantitative fit testing with an under-mask beard cover using either a TSI PortaCount Respirator Fit Tester 8038 or an AccuFit 9000 PRO fit testing device on up to five disposable P2/N95 respirators (3M 1860, 3M 1870+, BYD N95 Healthcare Particulate Respirator, BSN Medical ProShield N-95 Medium and Trident RTCFFP2). The primary outcome was the proportion of subjects that passed or failed quantitative fit testing with an under-mask beard cover. FINDINGS: Thirty subjects were assessed; of these, 24 (80%) passed quantitative fit testing with at least one tight-fitting P2/N95 disposable respirator. Among these subjects, the median best-achieved fit factor was 200 (interquartile range 178-200). None of the subjects had an adverse reaction to the under-mask beard cover. CONCLUSION: The under-mask beard cover technique may be used to achieve a satisfactory seal with tight-fitting P2/N95 respirators in health workers with facial hair who cannot shave.

Improving Cry8Ka toxin activity towards the cotton boll weevil (Anthonomus grandis).

BACKGROUND: The cotton boll weevil (Anthonomus grandis) is a serious insect-pest in the Americas, particularly in Brazil. The use of chemical or biological insect control is not effective against the cotton boll weevil because of its endophytic life style. Therefore, the use of biotechnological tools to produce insect-resistant transgenic plants represents an important strategy to reduce the damage to cotton plants caused by the boll weevil. The present study focuses on the identification of novel molecules that show improved toxicity against the cotton boll weevil. In vitro directed molecular evolution through DNA shuffling and phage display screening was applied to enhance the insecticidal activity of variants of the Cry8Ka1 protein of Bacillus thuringiensis. RESULTS: Bioassays carried out with A. grandis larvae revealed that the LC50 of the screened mutant Cry8Ka5 toxin was 3.15-fold higher than the wild-type Cry8Ka1 toxin. Homology modelling of Cry8Ka1 and the Cry8Ka5 mutant suggested that both proteins retained the typical three-domain Cry family structure. The mutated residues were located mostly in loops and appeared unlikely to interfere with molecular stability. CONCLUSIONS: The improved toxicity of the Cry8Ka5 mutant obtained in this study will allow the generation of a transgenic cotton event with improved potential to control A. grandis.

Sulphilimine cross-links in Goodpasture's disease.

The sulphilimine cross-link of the Goodpasture (GP) autoantigen is a novel molecular mechanism (structural constraint) for conferring immune privilege to a site which otherwise is susceptible to structural changes that induce an immunogenic and pathogenic conformation. Perturbation of the assembly or cleavage of the sulphilimine cross-links could be a key factor in the aetiology of Goodpasture's disease in susceptible individuals.

The angiotensin IV analog Nle-Tyr-Leu-psi-(CH2-NH2)3-4-His-Pro-Phe (norleual) can act as a hepatocyte growth factor/c-Met inhibitor.

The angiotensin (Ang) IV analog norleual [Nle-Tyr-Leu-psi-(CH2-NH2)(3-4)-His-Pro-Phe] exhibits structural homology with the hinge (linker) region of hepatocyte growth factor (HGF) and is hypothesized to act as a hinge region mimic. Norleual competitively inhibited the binding of HGF to its receptor c-Met in mouse liver membranes, with an IC(50) value of 3 pM. Predictably, norleual was able to inhibit HGF-dependent signaling, proliferation, migration, and invasion in multiple cell types at concentrations in the picomolar range. Ex vivo studies demonstrated that norleual exhibited potent antiangiogenic activity, an attribute that would be predicted for a HGF/c-Met antagonist. Furthermore, norleual suppressed pulmonary colonization by B16-F10 murine melanoma cells, which are characterized by an overactive HGF/c-Met system. Together, these data suggest that AngIV analogs exert at least some of their biological activity through interference with the HGF/c-Met system and may have utility as therapeutic agents in disorders that are dependent on an intact HGF/c-Met system. Finally, the ability of norleual to induce marked biological responses in human embryonic kidney cells, which do not express insulin-responsive aminopeptidase (IRAP), coupled with the observed effects of norleual on the HGF/c-Met system, casts doubt on the physiological significance of AngIV-dependent inhibition of IRAP. [Corrected]

Analysis of Cry8Ka5-binding proteins from Anthonomus grandis (Coleoptera: Curculionidae) midgut.

Biotech crops expressing Bacillus thuringiensis Cry toxins present a valuable approach for insect control. Cry8Ka5, which is highly toxic to the cotton boll weevil (Anthonomus grandis), was used as a model to study toxin-ligand interactions. Three Cry-binding proteins were detected after toxin overlay assays. Following de novo sequencing, a heat-shock cognate protein and a V-ATPase were identified, whilst a approximately 120 kDa protein remained unknown. Additional Cry8Ka5-binding proteins were visualized by two-dimensional gel electrophoresis ligand blots.

Noble gases in stratospheric dust particles: confirmation of extraterrestrial origin.

Noble gas elemental and isotopic ratios were measured in a group of 13 "chondritic" stratospheric dust particles. Neon and argon are present in "solar" proportions; xenon appears to be dominated by contributions from "planetary" sources. The apparent xenon concentration is higher than that measured in any bulk meteorite, approaching the concentration found in the noble gas-rich, acid-insoluble residues from carbonaceous chondrites.

Infectious arthritis of the knee caused by Mycobacterium terrae: a case report.

Mycobacterium terrae is ubiquitous in our environment. M terrae infections most commonly involve tendon sheaths, bones, bursae, and joints. We report a case of infectious arthritis of the knee caused by M terrae in a 21-year-old man who had non-specific chronic synovitis. No organism was seen on microscopy or isolated from cultures until months later. Initially the M terrae culture was considered a contaminant and specific anti-mycobacterial treatment was not advised. The patient was commenced on suppressive therapy for persistent effusion and discomfort. Eventually, the M terrae infection was confirmed and he was commenced on clarithromycin, ciprofloxacin, and ethambutol. The triple antibiotic regimen was continued for 2 years. The knee improved but never completely settled. The patient chose to cease all antibiotic medication. The knee remained swollen and irritable, with little chance of eradicating the organism.