Coevolved mutations reveal distinct architectures for two core proteins in the bacterial flagellar motor

Switching of bacterial flagellar rotation is caused by large domain movements of the FliG protein triggered by binding of the signal protein CheY to FliM. FliG and FliM form adjacent multi-subunit arrays within the basal body C-ring. The movements alter the interaction of the FliG C-terminal (FliGC) "torque" helix with the stator complexes. Atomic models based on the Salmonella entrovar C-ring electron microscopy reconstruction have implications for switching, but lack consensus on the relative locations of the FliG armadillo (ARM) domains (amino-terminal (FliGN), middle (FliGM) and FliGC) as well as changes during chemotaxis. The generality of the Salmonella model is challenged by the variation in motor morphology and response between species. We studied coevolved residue mutations to determine the unifying elements of switch architecture. Residue interactions, measured by their coevolution, were formalized as a network, guided by structural data. Our measurements reveal a common design with dedicated switch and motor modules. The FliM middle domain (FliMM) has extensive connectivity most simply explained by conserved intra and inter-subunit contacts. In contrast, FliG has patchy, complex architecture. Conserved structural motifs form interacting nodes in the coevolution network that wire FliMM to the FliGC C-terminal, four-helix motor module (C3-6). FliG C3-6 coevolution is organized around the torque helix, differently from other ARM domains. The nodes form separated, surface-proximal patches that are targeted by deleterious mutations as in other allosteric systems. The dominant node is formed by the EHPQ motif at the FliMMFliGM contact interface and adjacent helix residues at a central location within FliGM. The node interacts with nodes in the N-terminal FliGc α-helix triad (ARM-C) and FliGN. ARM-C, separated from C3-6 by the MFVF motif, has poor intra-network connectivity consistent with its variable orientation revealed by structural data. ARM-C could be the convertor element that provides mechanistic and species diversity.JK was supported by Medical Research Council grant U117581331. SK was supported by seed funds from Lahore University of Managment Sciences (LUMS) and the Molecular Biology Consortium

Anaphylactic response to topical fluorescein 2% eye drops: a case report

<p>Abstract</p> <p>Introduction</p> <p>The intravenous use of fluorescein 10% during retinal angiography can cause severe systemic reactions including, on rare occasions, anaphylaxis. Fluorescein 2% eye drops are used extensively for clinical examination and diagnosis, but to the best of our knowledge, they have only been reported as being responsible for a systemic anaphylactic response on two previous occasions.</p> <p>Case presentation</p> <p>We report the case of a 51-year-old woman who developed an anaphylactic reaction when she was administered fluorescein sodium 2% eye drops after cataract surgery. This was the second time she had been exposed to fluorescein. She had brittle asthma and a history of anaphylaxis following exposure to a variety of drug and food allergens. She was successfully resuscitated and recovered completely over a period of two days.</p> <p>Conclusions</p> <p>Fluorescein 2% drops are universally used in general practice, ophthalmology, optometry, and casualty departments. Our case report reveals the potential for this benign eye drop to cause a life-threatening systemic reaction and emphasises the importance of considering this consequence when administering topical fluorescein 2% to a patient with a history of anaphylaxis to other allergens.</p

Validation of a Smartphone-Based Approach to In Situ Cognitive Fatigue Assessment

BackgroundAcquired Brain Injury can result in multiple detrimental cognitive effects such as reduced memory capability, concentration and planning. These effects can lead to cognitive fatigue, which can exacerbate the symptoms of Acquired Brain Injury and hinder management and recovery. Assessing cognitive fatigue is difficult due to the largely subjective nature of the condition and existing assessment approaches. Traditional methods of assessment use self-assessment questionnaires delivered in a medical setting. However, recent work has attempted to employ more objective cognitive tests as a way of evaluating cognitive fatigue. However, these tests are still predominantly delivered within a medical environment, limiting their utility and efficacy. ObjectiveThe aim of the research was to investigate how cognitive fatigue can be accurately assessed in-situ, during the quotidian activities of life. It was hypothesised that this could be achieved through the use of mobile assistive technology to assess: working memory, sustained attention, information processing speed, reaction time, and cognitive throughput.Methods:The study used a bespoke smartphone application to track daily cognitive performance in order to assess potential levels of cognitive fatigue. 21 participants with no prior reported brain injuries took place in a two-week study, resulting in 81 individual testing instances being collected. The smartphone application delivered three cognitive tests on a daily basis: (1) Spatial Span to measure visuospatial working memory; (2) Psychomotor Vigilance Task to measure sustained attention, information processing speed and reaction time; (3) a Mental Arithmetic test to measure cognitive throughput. A smartphone optimised version of the Mental Fatigue Scale self-assessment questionnaire was used as a baseline to assess the validity of the three cognitive tests, as the questionnaire has already been validated in multiple peer reviewed studies. ResultsHighest correlated results were from the Psychomotor Vigilance Task, and showed a positive correlation with those from the pre-validated Mental Fatigue Scale, measuring 0.342, p &lt; .008. Scores from the cognitive tests were entered into a regression model and showed that only reaction time in the Psychomotor Vigilance Task was a significant predictor of fatigue (p = .016, F = 2.682, 95% CI 9.0 to 84.2). Higher scores on the Mental Fatigue Scale were related to increases in reaction time during our mobile variant of the Psychomotor Vigilance Task.Conclusions:The results show that the Psychomotor Vigilance Task mobile cognitive test developed for this study could be used as a valid and reliable in-situ method for measuring cognitive fatigue. This would remove the subjectivity associated with established self-assessment approaches and the need for assessment to be performed in a medical setting. Based on our findings, future work could explore delivering a small set of tests with increased duration to further improve measurement reliability. Moreover, as the smartphone assessment tool can be used as part of everyday life, additional sources of data relating to physiological, psychological and environmental context could be included within the analysis to improve the nature and precision of the assessment process

In-hospital mortality of COVID-19 patients hospitalized with ST-segment elevation myocardial infarction: A meta-analysis

Introduction: Coronavirus Disease 2019 (COVID-19) has been associated with an increased risk of adverse cardiovascular events including arteriovenous thrombosis, myocarditis and acute myocardial injury. Relevant literature to date has reported widely varying estimates of mortality, ranging from approximately 2 to 11 times higher odds of mortality in COVID-19-positive STEMI (ST-segment elevation myocardial infarction) patients. Hence, we conducted this meta-analysis to resolve these inconsistencies and assess the impact of COVID-19 infection on mortality and other clinical outcomes in patients presenting with STEMI. Methods: This meta-analysis was registered in PROSPERO (CRD42021297458) and performed according to the Cochrane Handbook for Systematic Reviews of Interventions. PubMed and Embase were searched from inception to November 2021 (updated on April 2022) using a search strategy consisting of terms relating to COVID-19, STEMI, and mortality. Results: We identified 435 studies through our initial search. After screening according to our eligibility criteria, a total of 11 studies were included. Compared with the non-COVID-19 STEMI patients, the in-hospital mortality rate was higher in COVID-19-positive STEMI patients. Similarly, the risk of cardiogenic shock was higher in the COVID-19-positive patients. Length of hospital stay was longer in STEMI patients with COVID-19. Conclusions: Our study highlights the necessity for early evaluation of COVID-19 status in all STEMI patients followed by risk stratification, prompt reperfusion and more aggressive management of COVID-19-positive patients. Further research is needed to elucidate the mechanisms behind poorer prognosis in such patients.Lewis Katz School of MedicineMedicin

Effects of composition and phase relations on mechanical properties and crystallisation of silicate glasses

Crystallization, mechanical properties and workability are all important for commercialization and optimization of silicate glass compositions. However, the inter-relations of these properties as a function of glass composition have received little investigation. Soda-lime-silica glasses with Na2O-MgO-CaO-Al2O3-SiO2 compositions relevant to commercial glass manufacture were experimentally studied and multiple liquidus temperature and viscosity models were used to complement the experimental results. Liquidus temperatures of the fabricated glasses were measured by the temperature gradient technique, and Rietveld refinements were applied to X-Ray powder diffraction (XRD) data for devitrified glasses, enabling quantitative determination of the crystalline and amorphous fractions and the nature of the crystals. Structural properties were investigated by Raman spectroscopy. Acoustic echography, micro-Vicker’s indentation and single-edge notched bend testing methods were used to measure Young’s moduli, hardness and fracture toughness, respectively. It is shown that it is possible to design lower-melting soda-lime-silica glass compositions without compromising their mechanical and crystallization properties. Unlike Young’s modulus, brittleness is highly responsive to the composition in soda-lime-silica glasses, and notably low brittleness values can be obtained in glasses with compositions in the wollastonite primary phase field: an effect that is more pronounced in the silica primary phase field. The measured bulk crystal fractions of the glasses subjected to devitrification at the lowest possible industrial conditioning temperatures, indicate that soda-lime-silica glass melts can be conditioned close to their liquidus temperatures within the compositional ranges of the primary phase fields of cristobalite, wollastonite or their combinations

Breast screening attendance of Aboriginal and Torres Strait Islander women in the Northern Territory of Australia

Objective: To compare breast screening attendances of Indigenous and non-Indigenous women. Methods: A total of 4,093 BreastScreen cases were used including 857 self-identified Indigenous women. Chi-squared analysis compared data between Indigenous and non-Indigenous women. Logistic regression was used for groupings based on visits-to-screening frequency. Odds ratios and 95% confidence intervals were calculated for associations with low attendance. Results: Indigenous women were younger and had fewer visits to screening compared with non-Indigenous women. Non-English speaking was mainly associated with fewer visits for Indigenous women only (OR 1.9, 95%CI 1.3-2.9). Living remotely was associated with fewer visits for non-Indigenous women only (OR 1.3, 95%CI 1.1-1.5). Shared predictors were younger age (OR 12.3, 95%CI 8.1-18.8; and OR 11.5, 95%CI 9.6-13.7, respectively) and having no family history of breast cancer (OR 2.1, 95%CI 1.3-3.3; and OR 1.8, 95%CI 1.5-2.1, respectively). Conclusions: Factors associated with fewer visits to screening were similar for both groups of women, except for language which was significant only for Indigenous women, and remoteness which was significant only for non-Indigenous women. Implications for public health: Health communication in Indigenous languages may be key in encouraging participation and retaining Indigenous women in BreastScreen; improving access for remote-living non-Indigenous women should also be addressed

Australia's National Bowel Cancer Screening Program: does it work for Indigenous Australians?

<p>Abstract</p> <p>Background</p> <p>Despite a lower incidence of bowel cancer overall, Indigenous Australians are more likely to be diagnosed at an advanced stage when prognosis is poor. Bowel cancer screening is an effective means of reducing incidence and mortality from bowel cancer through early identification and prompt treatment. In 2006, Australia began rolling out a population-based National Bowel Cancer Screening Program (NBCSP) using the Faecal Occult Blood Test. Initial evaluation of the program revealed substantial disparities in bowel cancer screening uptake with Indigenous Australians significantly less likely to participate in screening than the non-Indigenous population.</p> <p>This paper critically reviews characteristics of the program which may contribute to the discrepancy in screening uptake, and includes an analysis of organisational, structural, and socio-cultural barriers that play a part in the poorer participation of Indigenous and other disadvantaged and minority groups.</p> <p>Methods</p> <p>A search was undertaken of peer-reviewed journal articles, government reports, and other grey literature using electronic databases and citation snowballing. Articles were critically evaluated for relevance to themes that addressed the research questions.</p> <p>Results</p> <p>The NBCSP is not reaching many Indigenous Australians in the target group, with factors contributing to sub-optimal participation including how participants are selected, the way the screening kit is distributed, the nature of the test and comprehensiveness of its contents, cultural perceptions of cancer and prevailing low levels of knowledge and awareness of bowel cancer and the importance of screening.</p> <p>Conclusions</p> <p>Our findings suggest that the population-based approach to implementing bowel cancer screening to the Australian population unintentionally excludes vulnerable minorities, particularly Indigenous and other culturally and linguistically diverse groups. This potentially contributes to exacerbating the already widening disparities in cancer outcomes that exist among Indigenous Australians. Modifications to the program are recommended to facilitate access and participation by Indigenous and other minority populations. Further research is also needed to understand the needs and social and cultural sensitivities of these groups around cancer screening and inform alternative approaches to bowel cancer screening.</p