IMPORTANCEThe role of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in the setting of the coronavirus disease 2019 (COVID-19) pandemic is hotly debated. There have been recommendations to discontinue these medications, which are essential in the treatment of several chronic disease conditions, while, in the absence of clinical evidence, professional societies have advocated their continued use. OBJECTIVE To study the association between use of ACEIs/ARBs with the likelihood of testing positive for COVID-19 and to study outcome data in subsets of patients taking ACEIs/ARBs who tested positive with severity of clinical outcomes of COVID-19 (eg, hospitalization, intensive care unit admission, and requirement for mechanical ventilation). DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study with overlap propensity score weighting was conducted at the Cleveland Clinic Health System in Ohio and Florida. All patients tested for COVID-19 between March 8 and April 12, 2020, were included. EXPOSURES History of taking ACEIs or ARBs at the time of COVID-19 testing. MAIN OUTCOMES AND MEASURES Results of COVID-19 testing in the entire cohort, number of patients requiring hospitalizations, intensive care unit admissions, and mechanical ventilation among those who tested positive.RESULTS A total of 18 472 patients tested for COVID-19. The mean (SD) age was 49 (21) years, 7384 (40%) were male, and 12 725 (69%) were white. Of 18 472 patients who underwent COVID-19 testing, 2285 (12.4%) were taking either ACEIs or ARBs. A positive COVID-19 test result was observed in 1735 of 18 472 patients (9.4%). Among patients who tested positive, 421 (24.3%) were admitted to the hospital, 161 (9.3%) were admitted to an intensive care unit, and 111 (6.4%) required mechanical ventilation. Overlap propensity score weighting showed no significant association of ACEI and/or ARB use with COVID-19 test positivity (overlap propensity score-weighted odds ratio, 0.97; 95% CI, 0.81-1.15). CONCLUSIONS AND RELEVANCEThis study found no association between ACEI or ARB use and COVID-19 test positivity. These clinical data support current professional society guidelines to not discontinue ACEIs or ARBs in the setting of the COVID-19 pandemic. However, further study in larger numbers of hospitalized patients receiving ACEI and ARB therapy is needed to determine the association with clinical measures of COVID-19 severity.

The MAPK kinase kinase Wallenda is regulated by the Highwire E3 ubiquitin ligase and initiates injury signaling in axons.

Long-distance organelle transport toward axon terminals, critical for neuron development and function, is driven along microtubules by kinesins [1, 2]. The biophysics of force production by various kinesins is known in detail. However, the mechanisms of in vivo transport processes are poorly understood because little is known about how motor-cargo linkages are controlled. A c-Jun N-terminal kinase (JNK)-interacting protein (JIP1) has been identified previously as a linker between kinesin-1 and certain vesicle membrane proteins, such as Alzheimer's APP protein and a reelin receptor ApoER2 [3, 4]. JIPs are also known to be scaffolding proteins for JNK pathway kinases [5, 6]. Here, we report evidence that a Drosophila ubiquitin-specific hydrolase and a JNK signaling pathway that it modulates can regulate a JIP1-kinesin linkage. The JNK pathway includes a MAPKKK (Wallenda/DLK), a MAPKK (Hemipterous/MKK7), and the Drosophila JNK homolog Basket. Genetic tests indicate that those kinases are required for normal axonal transport. Biochemical tests show that activation of Wallenda (DLK) and Hemipterous (MKK7) disrupts binding between kinesin-1 and APLIP1, which is the Drosophila JIP1 homolog. This suggests a control mechanism in which an activated JNK pathway influences axonal transport by functioning as a kinesin-cargo dissociation factor.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

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Cardiac sarcoidosis is a component of an often multiorgan granulomatous disease of still uncertain cause. It is being recognized with increasing frequency, mainly as the result of heightened awareness and new diagnostic tests, specifically cardiac magnetic resonance imaging and 18 F-fluorodeoxyglucose positron emission tomography scans. The purpose of this case-based review is to highlight the potentially life-saving importance of making the early diagnosis of cardiac sarcoidosis using these new tools and to provide a framework for the optimal care of patients with this disease. We will review disease mechanisms as currently understood, associated arrhythmias including conduction abnormalities, and atrial and ventricular tachyarrhythmias, guideline-directed diagnostic criteria, screening of patients with extracardiac sarcoidosis, and the use of pacemakers and defibrillators in this setting. Treatment options, including those related to heart failure, and those which may help clarify disease mechanisms are included.

Background Suboptimal colon preparation is a significant barrier to quality colonoscopy. The impact of pharmacologic agents associated with gastrointestinal dysmotility on quality of colon preparation has not been well characterized. Aims Evaluate impact of opiate pain medication and psychoactive medications on colon preparation quality in outpatient undergoing colonoscopy. Methods Outpatients undergoing colonoscopy at a single medical center during a 6-month period were retrospectively identified. Demographics, clinical characteristics and pharmacy records were extracted from electronic medical records. Colon preparation adequacy was evaluated using a validated composite colon preparation score. Results 2600 patients (57.3±12.9 years, 57% female) met the inclusion and exclusion criteria. 223 (8.6%) patients were regularly using opioids, 92 antipsychotics, 83 tricyclic antidepressants and 421 non-tricyclic antidepressants. Opioid use was associated with inadequate colon preparation both with low dose (OR=1.4, 95%CI 1.0-2.1, p=0.05) and high dose opioid users (OR=1.7, 95%CI 1.1-2.9, p=0.039) in a dose dependent manner. Other significant predictors of inadequate colon preparation included use of tricyclics (OR=1.9, 95%CI 1.1-3.0, p=0.012), non-tricyclic antidepressants (OR=1.5, 95%CI 1.1-2.0, p=0.013), and antipsychotic medications (OR=2.2, 95%CI 1.4-3.4, p=0.001). Conclusions Opiate pain medication use independently predict inadequate quality colon preparation in a dose dependent fashion; furthermore psychoactive medications have even more prominent effects and further potentate the negative impact of opiates with concurrent use.

Right ventricular (RV) failure remains a major complication after surgical implantation of a left ventricular assist device (LVAD). While the use of a percutaneous RV assist device has been described as a short-term bridge to recovery in end-stage heart failure patients with early post-operative RV failure after index LVAD implant, management of refractory late RV failure remains challenging in these patients. We report the first successful case of extended Impella RP use as a safe and effective bridge to orthotopic heart transplant in an LVAD patient with refractory, haemodynamically significant late RV failure. The Impella RP provided support for 37 days. Haemodynamically intolerant arrhythmia precluded use of inotropic support. No adverse complications related to percutaneous Impella RP support were seen. We also review potential considerations for mechanical circulatory support strategies in this setting: central RV assist device cannulation requires sternotomy incision that can impact subsequent cardiac surgeries, while percutaneous Protek Duo insertion requires adequate vessel size and patency. With an LVAD in situ, veno-arterial extracorporeal membrane oxygenation was not considered for isolated RV support in this case. The patient is currently over 6 months post-orthotopic heart transplant.