Shot in the dark.

A 43-year-old woman presented with decreased vision in the right eye associated with painful eye movements 10 days after receiving her first dose of Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine (Pfizer Inc, New York, NY). Two days later she developed painful loss of vision in the left eye. Clinical presentation and magnetic resonance imaging findings were consistent with bilateral optic perineuritis transitioning to optic neuritis. Extensive evaluation including aquaporin-4 immunoglobin G (IgG), myelin oligodendrocyte glycoprotein IgG, and lumbar puncture was unrevealing. Visual acuity at nadir was counting fingers in both eyes, but after receiving intravenous steroids and plasma exchange vision eventually improved to 20/20 in each eye, although she was left with inferior visual field defects and bilateral optic disc pallor. This case highlights the diagnostic challenge in the evaluation of atypical optic neuritis with a review of post-COVID-19 vaccination-associated optic neuritis.

Structural interplay between DNA-shape protein recognition and supercoiling: The case of IHF.

The integration host factor (IHF) is a prominent example of indirect readout as it imposes one of the strongest bends on relaxed linear DNA. However, the relation between IHF and torsionally constrained DNA, as occurs physiologically, remains unclear. By using atomistic molecular dynamics simulations on DNA minicircles, we reveal, for the first time, the reciprocal influence between a DNA-bending protein and supercoiling. On one hand, the increased curvature of supercoiled DNA enhances wrapping around IHF making the final complex topologically dependent. On the other hand, IHF acts as a 'supercoiling relief' factor by compacting relaxed DNA loops and, when supercoiled, it pins the position of plectonemes in a unique and specific manner. In addition, IHF restrains under- or overtwisted DNA depending on whether the complex is formed in negatively or positively supercoiled DNA, becoming effectively a 'supercoiling buffer'. We finally provide evidence of DNA bridging by IHF and reveal that these bridges divide DNA into independent topological domains. We anticipate that the crosstalk detected here between the 'active' DNA and the multifaceted IHF could be common to other DNA-protein complexes relying on the deformation of DNA.

Atomistic Molecular Dynamics Simulations of DNA in Complex 3D Arrangements for Comparison with Lower Resolution Structural Experiments.

Atomic-level computer simulations are a very useful tool for describing the structure and dynamics of complex biomolecules such as DNA and for providing detail at a resolution where experimental techniques cannot arrive. Molecular dynamics (MD) simulations of mechanically distorted DNA caused by agents like supercoiling and protein binding are computationally challenging due to the large size of the associated systems and timescales. However, nowadays they are achievable thanks to the efficient usage of GPU and to the improvements of continuum solvation models. This together with the concurrent improvements in the resolution of single-molecule experiments, such as atomic force microscopy (AFM), makes possible the convergence between the two. Here we present detailed protocols for doing so: for performing molecular dynamics (MD) simulations of DNA adopting complex three-dimensional arrangements and for comparing the outcome of the calculations with single-molecule experimental data with a lower resolution than atomic.

Fruit lead concentrations of tomato (Solanum lycopersicum L.) grown in lead-contaminated soils are unaffected by phosphate amendments and can vary by season, but are below risk thresholds.

Urban agriculture in post-industrial cities faces concerns on human health risks posed by elevated lead (Pb) concentrations of edible plant tissues grown in Pb-enriched soils. A recommended mitigation strategy to decrease soil Pb bioavailability to humans is the addition of soluble phosphate (PO43--P), but it is unclear if this strategy can also reduce crop Pb uptake and accumulation in edible tissues. Across urban agriculture sites in Chicago, Illinois (6 site-years) with elevated total soil Pb, we tested the hypothesized decrease in tomato fruit Pb following soil-based application of three phosphate-based mitigation amendments: triple superphosphate, composted biosolids, and air dried biosolids. Fruit Pb concentrations (mg Pb kg-1 dry mass) and loads (mg Pb m-2) were unaffected by mitigation amendments. However, fruit Pb concentrations were higher by an order of magnitude in 2020 (≥0.13 mg kg-1) compared to 2019 (0.01 mg kg-1) for two of the three sites. Though highly variable across site-years, the bioconcentration factor (BCF) of Pb from soil to fruit varied was unaffected by mitigation amendments. Relatively low BCF values were consistent with fruit Pb concentrations being below FAO/WHO risk limits. Collectively, our findings support previous propositions that fruits of plants grown in soils with elevated Pb generally pose lower risk to consumers. To mitigate health risks of consuming tomatoes grown in soils with Pb contamination, the seasonality of Pb uptake should be investigated, and greater focus should be placed on where tomatoes are grown rather than phosphate-based immobilization strategies originally designed to mitigate human bioavailability.

A randomised cross-over trial of QT response to hyperventilation-induced anxiety and diaphragmatic breathing in patients with stress cardiomyopathy and in control patients.

OBJECTIVES: The most perfect example of the mind-body interaction in all of medicine is provided by stress cardiomyopathy. In stress cardiomyopathy, what is initially a purely emotional event may become rapidly fatal. Prolongation of the QT interval is a cardinal feature of the condition, but the mechanism of the prolongation is unknown. We undertook a randomised controlled trial of stress with a cross-over design, comparing the cardiac response of women with a history of stress cardiomyopathy to age-matched controls to explore the mind-body interaction. Our hypothesis is that the hearts of women with a history of stress cardiomyopathy will respond differently to emotional stress than those of the controls. METHOD: This is a randomised cross-over study. Each patient underwent two separate 24-hour Holter monitors performed at least 5 days apart. Baseline recording was followed by either the stress intervention (hyperventilation) or control (diaphragmatic breathing). Our primary endpoint is change in QTc interval over the first hour. Secondary endpoints were change in QTc over 24 hours, and change in SDNN, a measure of heart rate variability. As a secondary stressor, each participant was telephoned four times during their stressed recording and asked to complete a questionnaire. RESULTS: Twelve stress cardiomyopathy patients and twelve control patients were recruited. Baseline characteristics did not differ between cases and controls. With hyperventilation, there was a significant initial difference in anxiety (p<0.001), heart rate response (p<0.0001), and QTc (p<0.0002) compared to diaphragmatic breathing, but no differences between the cases and controls. Only first phone call caused an increase in QTc in cases and controls (p = 0.0098). SDNN increased with hyperventilation (p<0.0001) but did not differ between cases and controls. CONCLUSIONS: QTc response in women with a history of stress cardiomyopathy does not differ from controls. The relevance of QT prolongation and sensitivity in the autonomic response to the pathogenesis of stress cardiomyopathy remains uncertain.

Integration host factor bends and bridges DNA in a multiplicity of binding modes with varying specificity.

Nucleoid-associated proteins (NAPs) are crucial in organizing prokaryotic DNA and regulating genes. Vital to these activities are complex nucleoprotein structures, however, how these form remains unclear. Integration host factor (IHF) is an Escherichia coli NAP that creates very sharp bends in DNA at sequences relevant to several functions including transcription and recombination, and is also responsible for general DNA compaction when bound non-specifically. We show that IHF-DNA structural multimodality is more elaborate than previously thought, and provide insights into how this drives mechanical switching towards strongly bent DNA. Using single-molecule atomic force microscopy and atomic molecular dynamics simulations we find three binding modes in roughly equal proportions: 'associated' (73° of DNA bend), 'half-wrapped' (107°) and 'fully-wrapped' (147°), only the latter occurring with sequence specificity. We show IHF bridges two DNA double helices through non-specific recognition that gives IHF a stoichiometry greater than one and enables DNA mesh assembly. We observe that IHF-DNA structural multiplicity is driven through non-specific electrostatic interactions that we anticipate to be a general NAP feature for physical organization of chromosomes.

The effects of beta-blockers in patients with stress cardiomyopathy.

Beta-blockers are often used in the treatment of patients with stress cardiomyopathy without firm evidence of benefit. We conducted a retrospective case note review investigating the effects of beta-blockers on QT interval and heart rate in patients with stress cardiomyopathy over 3 days of hospital admission. We found no evidence of effects on QT interval from beta-blocker treatment in this condition.

Comparing the variants of takotsubo syndrome: an observational study of the ECG and structural changes from a New Zealand tertiary hospital.

OBJECTIVES: In takotsubo syndrome, QTc prolongation is a measure of risk of potentially fatal arrhythmia. It is not known how this risk, or derangement of other markers, differs across the echo variants of takotsubo syndrome. Therefore, we sought to explore whether apical takotsubo syndrome differs from the variants of the syndrome in more ways than just regional wall motion pattern. As the region of affected myocardium is usually larger, we hypothesised that patients with the classic apical ballooning form of takotsubo syndrome would have more severe derangement of their markers. DESIGN: Observational study of patients gathered from a prospective database (2010-2018) and by retrospective review (2006-2009). SETTING: The sole tertiary hospital from a New Zealand region in which case clusters of takotsubo syndrome were precipitated by large earthquakes in 2010, 2011 and 2016. PARTICIPANTS: A total of 222 patients who met a modified version of the Mayo criteria for takotsubo syndrome were included. All patients had digitally archived echocardiograms that were over-read by a second echocardiologist blinded to the clinical report. PRIMARY OUTCOME MEASURES: Ejection fraction, peak troponin and QTc interval. RESULTS: Patients with the apical form were older (p=0.011), had a lower initial left ventricular ejection fraction (35% vs 44%, p<0.0001) and a higher peak high-sensitivity troponin I (hsTnI) (p=0.01) than those with variant forms. There was no difference in the electrical abnormalities between the variants (QTc interval, heart rate, PR interval, QRS duration or T-wave axis). There was also no correlation between any of peak hsTnI, peak QTc and ejection fraction. QTc interval increased on day 2 and peaked on day 3 before falling steeply (p<0.0001). CONCLUSIONS: The variants of takotsubo syndrome differ in more ways than just their echo pattern but do not differ in their electrical abnormalities. There is a dissociation between the structural and electrical abnormalities. QTc peaks on day 3 and then falls steeply.

The Liverpool Peritonsillar abscess Score: Development of a predictive score through a prospective multicentre observational study.

OBJECTIVES: While uncommon in the population at large, peritonsillar abscess (PTA) is a common subject of ENT referrals. Missed or uncertain diagnosis is a source of concern for non-specialist referrers. In line with the NHS England Second Sepsis Action Plan, we aimed to develop a predictive score for the presence of PTA. This would help to improve non-specialist colleagues' diagnostic certainty as well as to support ENT surgeons' triage of these referrals. DESIGN: Prospective, multicentre observational study. SETTING: Primary and secondary care. PARTICIPANTS: Patients >16 years with symptoms of sore throat. DATA: We prospectively collected comprehensive data on patient demographics, symptoms and clinical status. We documented whether the patient had aspiration-proven PTA or not. We performed binary logistic regression analysis, iterative development of a predictive score which we validated internally. RESULTS: 100 patients were included (46 PTA and 54 tonsillitis). Five variables added significantly to the logistic regression model: unilateral sore throat; trismus; male gender; pharyngeal voice change; and uvular deviation. Using the odds ratio outputs, we developed the Liverpool Peritonsillar abscess Score (LPS) iteratively. We validated the latest (third) iteration of the LPS internally (ie, on the same sample), yielding sensitivity 96%; specificity 85%; positive predictive value 85%; and negative predictive value 96%. The area under the receiver operating characteristics (AUROC) curve was 0.970. CONCLUSIONS: We have developed the first predictive score for PTA based on symptoms and signs that do not require the user to have specialist experience. Its high negative predictive value may be particularly helpful to non-specialist colleagues.

Comparison of retinal nerve fiber layer and central macular thickness measurements among five different optical coherence tomography instruments in patients with multiple sclerosis and optic neuritis.

BACKGROUND: To compare the mean central macular thickness (CMT) and the mean average optic nerve retinal nerve fiber layer (RNFL) thickness in the eyes of patients with a history of optic neuritis and/or multiple sclerosis (MS) using 5 commercially available optical coherence tomography (OCT) instruments. METHODS: Cross-sectional study including 46 patients (92 eyes) with a history of optic neuritis and/or MS. Both eyes were imaged on the same day with 5 OCT instruments: 1 time-domain OCT (Stratus) and 4 different Fourier-domain (spectral-domain) OCT (3D OCT-1000, Cirrus, RTVue-100, and Spectralis). RESULTS: Twenty-five patients (50 eyes) were included in the final analysis after excluding patients with diabetes, glaucoma, ocular hypertension, or retinal pathology and inadequate scan quality. Randomized block analysis of variance revealed statistically significant differences across instruments (P < 0.001) for both eyes for mean CMT and mean average optic nerve RNFL. When testing for significant differences in measurements from instrument to instrument, some difference was noted between the right and left eyes. CONCLUSIONS: Statistically significant differences exist among commercially available OCT instruments in measuring mean CMT and mean average RNFL thickness in patients with optic neuritis and/or MS. These findings likely result from the differences in data acquisition and segmentation algorithm software among OCT instruments. Awareness of these variations among OCT instruments will be important in using these instruments for clinical trials and management of patients with optic neuritis and/or MS.

Evaluation of stigmatizing language and medical errors in neurology coverage by US newspapers.

OBJECTIVES: To analyze US newspaper coverage of neurologic diseases to determine whether stigmatizing language is used in describing patients and examine its sources where found and to examine stories for medical errors. METHODS: A content analysis of newspaper articles was performed for 2003 using the Lexis-Nexis database. Keyword searches for 11 common neurologic conditions were performed for The New York Times and 8 regional newspapers with circulation greater than 200,000. RESULTS: A total of 1203 stories focusing on 11 neurologic conditions were recovered. Newspaper coverage did not reflect disease prevalence (rank correlation, p=-0.009; P=.98). The topics most covered were Alzheimer disease and other dementias (400 stories, 33% of total), which were eventually combined Into 1 category for purposes of data analysis. Conditions with the highest prevalence were among the least covered topics, including migraine (34 stories, 3% of total) and head trauma (19 stories, 2% of total). Stigmatizing language was found in 15% of all stories. Excluding wire stories, the average among locally produced newspaper stories was higher (21%). Stories on epilepsy (30%) and migraine (29%) contained the highest frequency of stigmatizing language. Sources of stigma within a story included reporters (55%), patients (26%), family (17%), and physicians (16%). In an accuracy analysis, 20% of sampled stories contained medical errors or exaggerations, with half of these concerning neurodegenerative conditions. CONCLUSION: A total of 21% of all stories (excluding wire stories) contained language judged stigmatizing, with reporters as the most common source of the stigmatizing language. A total of 20% of analyzed stories had medical errors or exaggerations, the latter most often overstating treatment effectiveness.