Research Spotlight

Wang, F., X. Qi, J. Zhang and J. H. Huang (2020). “Astrocytic modulation of potassium under seizures.” Neural Regen Res 15(6): 980-987.

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The contribution of an impaired astrocytic K(+) regulation system to epileptic neuronal hyperexcitability has been increasingly recognized in the last decade. A defective K(+) regulation leads to an elevated extracellular K(+) concentration ([K(+)](o)). When [K(+)](o) reaches peaks of 10-12 mM, it is strongly associated with seizure initiation during hypersynchronous neuronal activities. On the other hand, reactive astrocytes during a seizure attack restrict influx of K(+) across the membrane both passively and actively. In addition to decreased K(+) buffering, aberrant Ca(2+) signaling and declined glutamate transport have also been observed in astrogliosis in epileptic specimens, precipitating an increased neuronal discharge and induction of seizures. This review aims to provide an overview of experimental findings that implicated astrocytic modulation of extracellular K(+) in the mechanism of epileptogenesis.

Van Der Pol, B., K. B. Waites, L. Xiao, S. N. Taylor, A. Rao, M. Nye, S. Chavoustie, A. Ermel, C. Kaplan, D. Eisenberg, P. A. Chan, L. Mena, S. Pacheco, S. Krishnamurthy, R. Mohan, R. Bertuzis, C. L. McGowin, R. Arcenas and E. M. Marlowe (2020). “Mycoplasma genitalium Detection in Urogenital Specimens from Symptomatic and Asymptomatic Men and Women by Use of the cobas TV/MG Test.” J Clin Microbiol 58(6).

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Mycoplasma genitalium (MG) infections are a growing concern within the field of sexually transmitted infections. However, diagnostic assays for M. genitalium have been limited in the United States. As most infections are asymptomatic, individuals can unknowingly pass the infection on, and the prevalence is likely to be underestimated. Diagnosis of M. genitalium infection is recommended using a nucleic acid test. This multicenter study assessed the performance of the cobas Trichomonas vaginalis (TV)/MG assay (cobas) for the detection of M. genitalium, using 22,150 urogenital specimens from both symptomatic and asymptomatic men and women collected at geographically diverse sites across the United States. The performance was compared to a reference standard of three laboratory-developed tests (LDTs). The specificity of the cobas assay for M. genitalium ranged from 96.0% to 99.8% across symptomatic and asymptomatic men and women. The sensitivities in female vaginal swabs and urine samples were 96.6% (95% confidence interval [CI], 88.5 to 99.1%) and 86.4% (95% CI, 75.5 to 93.0%), respectively. The sensitivities in male urine and meatal swab samples were 100% (95% CI, 94.0 to 100%) and 85.0% (95% CI, 73.9 to 91.9%), respectively. This study demonstrated that the cobas assay was highly sensitive and specific in all relevant clinical samples for the detection of M. genitalium.

Vaduganathan, M., B. L. Claggett, P. S. Jhund, J. W. Cunningham, J. Pedro Ferreira, F. Zannad, M. Packer, G. C. Fonarow, J. J. V. McMurray and S. D. Solomon (2020). “Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.” Lancet May 21;S0140-6736(20)30748-0. [Epub ahead of print].

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BACKGROUND: Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF. METHODS: In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker). FINDINGS: The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy. INTERPRETATION: Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.

Upchurch, K., M. Wiest, J. Cardenas, J. Skinner, D. Nattami, B. Lanier, M. Millard, H. Joo, J. Turner and S. Oh (2020). “Whole blood transcriptional variations between responders and non-responders in asthma patients receiving omalizumab.” Clin Exp Allergy May 29. [Epub ahead of print].

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BACKGROUND: Anti-IgE (omalizumab) has been used for the treatment of moderate-to-severe asthma that is not controlled by inhaled steroids. Despite its success, it does not always provide patients with significant clinical benefits. OBJECTIVE: To investigate transcriptional variations between omalizumab responders and non-responders and to study the mechanisms of action of omalizumab. METHODS: The whole blood transcriptomes of moderate-to-severe adult asthma patients (N=45: 34 responders and 11 non-responders) were analyzed over the course of omalizumab treatment. Non-asthmatic healthy controls (N=17) were used as controls. RESULTS: Transcriptome variations between responders and non-responders were identified using genes significant (FDR<0.05) in at least one comparison of each patient response status and time point compared to control subjects. Using gene ontology and network analysis, eight clusters of genes were identified. Longitudinal analyses of individual clusters revealed that responders could maintain changes induced with omalizumab treatment and become more similar to the control subjects, while non-responders tend to remain more similar to their pre-treatment baseline. Further analysis of an inflammatory gene cluster revealed that genes associated with neutrophil/eosinophil activities were upregulated in non-responders and, more importantly, omalizumab did not significantly alter their expression levels. The application of modular analysis supported our findings and further revealed variations between responders and non-responders. CONCLUSION & CLINICAL RELEVANCE: This study provides not only transcriptional variations between omalizumab responders and non-responders, but also molecular insights for controlling asthma by omalizumab.

Tanguturi, V. K., B. R. Lindman, P. Pibarot, J. J. Passeri, S. Kapadia, M. J. Mack, I. Inglessis, N. B. Langer, T. M. Sundt, J. Hung and S. Elmariah (2020). “Managing Severe Aortic Stenosis in the COVID-19 Era.” JACC Cardiovasc Interv Jun 1;S1936-8798(20)31265-6. [Epub ahead of print].

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The novel coronavirus-19 (COVID-19) pandemic has created uncertainty in the management of patients with severe aortic stenosis (AS). This population experiences high mortality from delays in treatment of valve disease but is largely overlapping with the population of highest mortality from COVID-19. We present strategies for managing patients with severe AS in the COVID-era. We suggest transitions to virtual assessments and consultation, careful pruning and planning of necessary testing, as well as fewer and shorter hospital admissions. These strategies center on minimizing patient exposure to COVID-19 and expenditure of human and health-care resources without significant sacrifice to patient outcomes during this public health emergency. Areas of innovation to improve our care during this time include increased use of wearable and remote devices to assess patient performance and vital signs, devices for facile cardiac assessment, and widespread use of clinical protocols for expedient discharge with virtual physical therapy and cardiac rehabilitation options.