Medical Student Competence in Eliciting a History for “Chronic Fatigue”

Purpose: We report an observational study of medical students abilities in taking a complex history for which sleep disorders is one of several possible conditions. Methods: Students are observed taking a focused history from a simulated patient whose chief complaint is I am tired. I cannot get anything done. Nine groups of students (n = 360) completing the internal medicine core-clerkship were evaluated by one of three examiners. Students received full, partial, or no credit for each item on a uniform behavioral checklist, which included prompts for common medical and psychiatric disorders associated with chronic fatigue. Results: Observed means were lowest for items pertaining to sleep behaviors and head trauma. Fewer than half of the students inquired about whether or not the person had difficulty falling asleep at night, family history of sleep apnea, and frequency and length of naps. In contrast, the majority of students inquired about heart disease, metabolic disorders, the use of illicit drugs, alcohol consumption, and the taking of medications. Examiners accounted for a significant source of variance in scores; yet the station discriminated among top and bottom students as measured by the Objective Structured Clinical Examination (OSCE) overall. No statistically significant differences were observed on the basis of clerkship site, primary care versus traditional-track students, time of year, or gender. Conclusion: A majority of students do not adequately cover issues relevant to sleep in contrast to other associated disorders when taking a focused history for chronic fatigue.     

Genomic Analysis of SARS-CoV-2 Alpha,Beta and Delta Variants of Concern Uncovers Signatures of Neutral and Non-Neutral Evolution

Due to the emergence of new variants of the SARS-CoV-2 coronavirus, the question of how the viral genomes evolved, leading to the formation of highly infectious strains, becomes particularly important. Three major emergent strains, Alpha, Beta and Delta, characterized by a significant number of missense mutations, provide a natural test field. We accumulated and aligned 4.7 million SARS-CoV-2 genomes from the GISAID database and carried out a comprehensive set of analyses. This collection covers the period until the end of October 2021, i.e., the beginnings of the Omicron variant. First, we explored combinatorial complexity of the genomic variants emerging and their timing, indicating very strong, albeit hidden, selection forces. Our analyses show that the mutations that define variants of concern did not arise gradually but rather co-evolved rapidly, leading to the emergence of the full variant strain. To explore in more detail the evolutionary forces at work, we developed time trajectories of mutations at all 29,903 sites of the SARS-CoV-2 genome, week by week, and stratified them into trends related to (i) point substitutions, (ii) deletions and (iii) non-sequenceable regions. We focused on classifying the genetic forces active at different ranges of the mutational spectrum. We observed the agreement of the lowest-frequency mutation spectrum with the Griffiths–Tavaré theory, under the Infinite Sites Model and neutrality. If we widen the frequency range, we observe the site frequency spectra much more consistently with the Tung–Durrett model assuming clone competition and selection. The coefficients of the fitting model indicate the possibility of selection acting to promote gradual growth slowdown, as observed in the history of the variants of concern. These results add up to a model of genomic evolution, which partly fits into the classical drift barrier ideas. Certain observations, such as mutation “bands” persistent over the epidemic history, suggest contribution of genetic forces different from mutation, drift and selection, including recombination or other genome transformations. In addition, we show that a “toy” mathematical model can qualitatively reproduce how new variants (clones) stem from rare advantageous driver mutations, and then acquire neutral or disadvantageous passenger mutations which gradually reduce their fitness so they can be then outcompeted by new variants due to other driver mutations.     

Nebivolol and metoprolol for treating migraine: an advance on beta-blocker treatment?

OBJECTIVE: To evaluate the efficacy of oral treatment with nebivolol and metoprolol in the prophylaxis of migraine attacks. BACKGROUND: Beta-blockers such as propranolol and metoprolol are known to be effective in preventing migraine attacks. Following earlier observations of successful use of nebivolol in a few hypertensive patients with concomitant migraine, we conducted a prospective study to ascertain whether nebivolol would be effective and better tolerated, in a methodologically strict, randomized and double-blind setting. DESIGN AND METHODS: Randomized, double-blind study in 30 patients with confirmed migraine diagnosis, a minimum 1-year history, onset prior to 50 years of age, written records of attacks for the previous 3 months, and minimum 2 attacks per month. Primary endpoint was frequency of attacks (prevention of migraine attacks) in the final 4 weeks of a 14-week treatment on full dose of metoprolol and nebivolol. Secondary endpoints were time to therapeutic effect, duration of attacks, intensity of headache, consumption of analgesics, evaluation of accompanying symptoms, migraine disability assessment, clinical global impression, quality of life, and responder rates. The statistical analysis was prospectively planned and conducted for all randomized patients. RESULTS: Both metoprolol and nebivolol where similarly effective regarding the main endpoint (prevention of migraine attacks) as well as the secondary ones, and both had a fast onset of action, typically within 4 weeks from starting therapy, with responder rates increasing relatively little over time after the first 4 weeks. Use of acute pain medication decreased on both drugs, as well as accompanying symptoms. Both patients' and physicians' evaluations of disability and disease status were similarly favorable to the 2 treatments. Regarding safety, nebivolol was considerably better tolerated than metoprolol in terms of all reported events, treatment-related events, and event severity. CONCLUSIONS: Our results suggest that nebivolol is as effective as metoprolol in the prophylaxis of migraine attacks, with the advantages of being better tolerated and not requiring up-titration to achieve therapeutic levels. Further and larger trials should be conducted on nebivolol in the prevention of migraine attacks as it may provide an improvement in current migraine prophylaxis with beta-blockers.     

The visual impact of fractionated stereotactic conformal radiotherapy on seven eyes with optic nerve sheath meningiomas.

BACKGROUND: Treatment of primary optic nerve sheath meningiomas (ONSMs) remains controversial. Although recent studies have suggested a favorable outcome of radiotherapy, controlled data on the efficacy of fractionated stereotactic conformal radiotherapy (SCRT) in primary ONSMs are still lacking. METHODS: Seven eyes treated with SCRT (total dose: 54 Gy) were compared with six eyes that were not treated because of patient or physician preference. The indication for intervention was deterioration of visual function with or without imaging evidence of tumor progression. Patients with secondary ONSMs and those with neurofibromatosis type 2 were excluded. The mean follow-up period was 57 months for the treated eyes and 61 months for the untreated eyes. RESULTS: Among the seven treated eyes, visual acuity improved in six, five of which sustained improvement of three or more Snellen lines. One eye deteriorated by two lines. Visual field improved in four eyes, remained stable in two, and deteriorated in one. Four untreated eyes showed worsening of visual acuity and two remained stable. Visual field deteriorated in three eyes and was stable in three. None of the untreated eyes experienced improvement in visual acuity or visual field. No complications of treatment were documented. CONCLUSIONS: In agreement with previous reports, these results indicate that SCRT is superior to observation in its impact on visual function in eyes with primary ONSMs.     

Effects of the Ca2+ sensitizers EMD 57033 and CGP 48506 on myocardial contractility and Ca2+ transients in human ventricular and atrial myocardium

Zusammenfassung Ca²⁺-Sensitizer, wie z.B. EMD 57033 (EMD) und CGP 48506 (CGP) erhöhen die Kontraktionskraft ohne dabei den intrazellulären Ca²⁺-Transienten zu erhöhen und sind somit möglicherweise für die Behandlung der menschlichen Herzinsuffizienz von Bedeutung. Es ist jedoch unklar, ob sich Ca²⁺-Sensitizer in ihrem pharmakokinetischen Wirkprinzip am menschlichen Myokard unterscheiden. Daher wurde der Einfluss von EMD und CGP auf die Kontraktionskraft und den intrazellulären Ca²⁺-Transienten (Fura 2) an linksventrikulären Papillarmuskelstreifen (PAP) von menschlichem insuffizientem Myokard sowie in rechtsatrialen Trabekeln (RA) von Patienten untersucht, die sich einer aortokoronaren Bypass-Operation unterziehen mussten. In PAP wurde die Kraft effizienter und stärker nach Applikation von EMD (EC₅₀ EMD: 4,7ǃ,0 7mol/l, max. PIE EMD: +12,0DŽ,0 mN/mm²) erhöht als nach CGP (EC₅₀: 16,9lj,6 7mol/l, max. PIE: +6,4DŽ,8 mN/mm²). Ähnliche Ergebnisse wurden an RA erhalten. Carbachol (100 7mol/l) hatte keinen Einfluss auf die positiv inotrope Wirkung von EMD und CGP. Beide Ca²⁺-Sensitizer erhöhten signifikant die Relaxationszeit und die diastolischen Spannung. EMD und CGP veränderten den intrazellulären Ca²⁺-Transienten nicht. Schlussfolgerung Die Ca²⁺-Sensitizer EMD und CGP erhöhen cAMP- und Ca²⁺-unabhängig die Kontraktionskraft am menschlichen Myokard. Da sie die Relaxation beeinträchtigen, ist ihr therapeutischer Nutzen für die Herzinsuffizienz begrenzt. Summary Ca²⁺ sensitizers like EMD 57033 (EMD) and CGP 48506 (CGP) may be advantageous for the treatment of human heart failure, as they increase force of contraction without increasing the intracellular Ca²⁺ transients or energy consumption. However, whether or not Ca²⁺ sensitizers differ in their mode of action in human myocardium is not fully understood. The present study investigates the influence of EMD and CGP on force of contraction (FOC) and the intracellular Ca²⁺ transient (fura-2 ratio method) in left ventricular papillary muscle strips from left ventricular failing human myocardium (DCM, n=28) as well as in right atrial trabeculae (RA, n=21) obtained from patients undergoing cardiac bypass surgery. In isolated trabeculae of DCM, FOC was more efficacious and potently increased after application of EMD (EC₅₀ EMD: 4.7ǃ.0 7mol/l, max. PIE EMD: +12.0DŽ.0 mN/mm²) than CGP (EC₅₀: 16.9lj.6 7mol/l, max. PIE: +6.4DŽ.8 mN/mm²). Similar results were obtained in RA. Application of carbachol (100 7mol/l) had no effect on the positive inotropic effect of EMD or CGP. Both Ca²⁺ sensitizers significantly increased time to half peak relaxation as well as diastolic tension in DCM. EMD (10 7mol/l) and CGP (30 7mol/l) did not affect the Ca²⁺ transients in RA. The Ca²⁺ sensitizers EMD and CGP increase cAMP and Ca²⁺ independently from the force of contraction in the human myocardium. However, their therapeutic use in human heart failure may be limited as they impair relaxation.     

Brain activity and connectivity in response to negative affective stimuli: Impact of dysphoric mood and sex across diagnoses

Negative affective stimuli elicit behavioral and neural responses which vary on a continuum from adaptive to maladaptive, yet are typically investigated in a dichotomous manner (healthy controls vs. psychiatric diagnoses). This practice may limit our ability to fully capture variance from acute responses to negative affective stimuli to psychopathology at the extreme end. To address this, we conducted a functional magnetic resonance imaging study to examine the neural responses to negative valence/high arousal and neutral valence/low arousal images as a function of dysphoric mood and sex across individuals (n = 99) who represented traditional categories of healthy controls, major depressive disorder, bipolar psychosis, and schizophrenia. Observation of negative (vs. neutral) stimuli elicited blood oxygen‐level dependent responses in the following circuitry: periaqueductal gray, hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and greater connectivity between AMYG and mPFC. Across all subjects, severity of dysphoric mood was associated with hyperactivity of HYPO, and, among females, right (R) AMYG. Females also demonstrated inverse relationships between severity of dysphoric mood and connectivity between HYPO ‐ R OFC, R AMYG ‐ R OFC, and R AMYG ‐ R HIPP. Overall, our findings demonstrated sex‐dependent deficits in response to negative affective stimuli increasing as a function of dysphoric mood state. Females demonstrated greater inability to regulate arousal as mood became more dysphoric. These findings contribute to elucidating biosignatures associated with response to negative stimuli across disorders and suggest the importance of a sex‐dependent lens in determining these biosignatures. Hum Brain Mapp 37:3733–3744, 2016. © 2016 Wiley Periodicals, Inc .     

Prenatal exposure to a pro-inflammatory stimulus causes delays in the development of the innate immune response to LPS in the offspring

Growing evidence suggests that maternal health during the prenatal period is a critical determinant of adult immuno-competence. This study aimed to characterise the innate immune response to bacterial exposure in rat offspring following maternal exposure to a pro-inflammatory stimulus. The offspring's innate immune responses were investigated at four developmental timepoints in the rat by determination of immune cell subtypes and TNF-alpha and IL-1beta response to in-vivo LPS exposure. The pre-weaned offspring of exposed dams demonstrated no immune response to the LPS challenge, whereas control offspring responded with a typical elevation in cytokine levels. In pubescence no differences were observed between the responses of the control and exposed offspring. In adulthood and senescence, offspring of endotoxin treated dams had significantly less monocytes in circulation than control offspring and differential sex effects were only evident in these older animals. The developmental profile of immune functioning following prenatal immune activation has not previously been demonstrated. This study highlights the prenatal period as one of importance in determining later immune function.     

Can oats be taken in a gluten-free diet? A systematic review

OBJECTIVE: There has long been doubt about the need to exclude oats from a gluten-free diet (GFD). The objective of this study was to review the literature in order to arrive at a firm recommendation. MATERIAL AND METHODS: Electronic databases were searched up to February 2006 using the terms "oats" and "coeliac disease". RESULTS: Twenty relevant studies were found and presented. Early studies were small and uncontrolled and mostly indirect. In 10 studies involving 165 patients, only 1 patient was shown to have histological damage as a result of consuming oats. CONCLUSIONS: Coeliac patients can, to some advantage, include oats in a GFD although there may be the occasional patient who is also oats sensitive. Previous conflicting results may have been partly due to contamination of oats by wheat. Lest contamination is present and exceeds the safe threshold, we recommend that coeliac patients should only add oats to their GFD when they are established on a conventional GFD, and stop eating oats if they develop any symptoms.     

A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies

Extensive crosstalk among ErbB/HER receptors suggests that blocking signaling from more than one family member may be essential to effectively treat cancer and limit drug resistance. We generated a conventional IgG molecule MEHD7945A with dual HER3/EGFR specificity by phage display engineering and used structural and mutational studies to understand how a single antigen recognition surface binds two epitopes with high affinity. As a human IgG1, MEHD7945A exhibited dual action by inhibiting EGFR- and HER3-mediated signaling in?vitro and in?vivo and the ability to engage immune effector functions. Compared with monospecific anti-HER antibodies, MEHD7945A was more broadly efficacious in multiple tumor models, showing that combined inhibition of EGFR and HER3 with a single antibody is beneficial.