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Background It is unclear whether asthma and asthma medications increase or decrease the risk of severe COVID-19, and this is particularly true for patients with severe asthma receiving biologics. Objectives The aim of this study was to assess incidence and disease course of COVID-19 in patients with severe asthma on biologic therapy (omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab), as compared with COVID-19 data from the general Dutch population. Methods COVID-19 cases were identified through a prospective ongoing survey between March 17 and April 30, 2020 among all severe asthma specialists from 15 hospitals of the Dutch Severe Asthma Registry RAPSODI. From these cases, data was collected on patient characteristics, including co-morbidities, COVID-19 disease progression and asthma exacerbations. Findings were then compared with COVID-19 data from the general Dutch population. Results Of 634 severe asthma patients who received biologic therapy in RAPSODI, 9 (1.4%) were diagnosed with COVID-19. Seven patients (1.1%) required hospitalization for oxygen therapy, of which 5 were admitted to the intensive care for intubation and mechanical ventilation. One patient died (0.16%). All intubated patients had ≥1 co-morbidities. Odds (95%CI) for COVID-19 related hospitalization and intubations were 14 (6.6–29.5) and 41 (16.9–98.5) times higher, respectively, compared to the Dutch population. One patient presented with an asthma exacerbation. Conclusion Patients with severe asthma using biologic therapy showed to have a more severe course of COVID-19 compared to the general population. This may be due to co-morbidities, the severity of asthmatic airway inflammation, the use of biologics, or a combination of these.

The aim of the present study was to compare the effectiveness and safety of add-on treatment with dapagliflozin to placebo in patients with prednisone-induced hyperglycaemia during treatment for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We enrolled 46 patients hospitalized for an AECOPD in a multicentre double-blind randomized controlled study in which add-on treatment with dapagliflozin 10 mg was compared with placebo. Glycaemic control and incidence of hypoglycaemia were measured through a blinded subcutaneous continuous glucose monitoring device. Participants in the dapagliflozin group spent 54 ± 27.7% of the time in target range (3.9-10 mmol/L) and participants in the placebo group spent 53.6 ± 23.4% of the time in target range (P = .96). The mean glucose concentration was 10.1 mmol/L in the dapagliflozin group and 10.4 mmol/L in the placebo group (P = .66). One participant using dapagliflozin and 2 participants using placebo experienced symptomatic hypoglycaemia. Treatment with dapagliflozin was safe and there was no difference in risk of hypoglycaemia compared with placebo. Dapagliflozin did not result in better glycaemic control compared with placebo in participants with prednisone-induced hyperglycaemia during AECOPD.

Background— Calcium-insensitive transient outward current ( I to ) is important to the development of cardiac memory (CM), which itself reflects the capacity of the heart to remodel electrophysiologically. We used cardiac pacing to test the hypothesis that CM evolution can be explained by developmental maturation of I to . Methods and Results— Acutely anesthetized dogs from 1 day old to adult were paced from the left ventricle (VP, n=29) or left atrial appendage (AP, n=12) to induce CM. T-wave vector displacement (TVD) obtained during VP was greater than with AP (adults, 0.39±0.06 mV; neonates, 0.04±0.01 mV; P r =−0.65, P Conclusions— The inducibility of CM gradually increases with age in association with evolution of the epicardial action potential notch and mRNA expression for KChIP2 and Kv4.3. This suggests that the capacity of the heart to remodel electrophysiologically and to manifest memory during development depends in part on evolution of the determinants of I to .

Cardiac memory (CM) has short- (STCM) and long-term (LTCM) components modulated by calcium and angiotensin II. LTCM is associated with reducedItoand Kv4.3 mRNA levels. Because the cAMP response element binding protein, CREB, contributes to CNS memory transcription, we hypothesized that it might be a transcriptional factor in CM, influenced by calcium and angiotensin II. We studied STCM in dogs that were AV sequentially paced (AVP) for 2 hours or sham-operated. STCM was evaluated with ECG and vectorcardiogram (VCG), and subepicardial biopsies were taken at 5 to 120 minutes and investigated for CREB. LTCM was studied in dogs paced for 3 weeks and in sham controls. At 3 weeks the heart was excised, biopsies obtained, and CRE binding tested. STCM induction occurred in AVP dogs but not in sham or AVP dogs treated with saralasin or nifedipine. Nuclear CREB was significantly decreased at 2 hours in the AVP no-drug group only. LTCM dogs manifested reduced binding of nuclear proteins to CRE, and CRE binding activity in the promoter region of Kv4.3. In conclusion, there is an association between STCM induction and decreased nuclear CREB that is angiotensin-modulated and calcium-dependent. Moreover, the decreased CRE binding after 3 weeks of AVP combined with CRE binding activity in the Kv4.3 promoter can explain the Kv4.3 mRNA andItodownregulation that characterize LTCM.

Background— We tested the hypothesis that I Ca,L is important to the development of cardiac memory. Methods and Results— The effects of L-type Ca 2+ channel blockade and β-blockade were tested on acutely anesthetized and on chronically instrumented, conscious dogs. Short-term memory (STM) was induced by 2 hours of ventricular pacing and long-term memory (LTM) by ventricular pacing for 21 days. STM dogs received placebo, nifedipine, or propranolol, and LTM dogs received placebo, atenolol, or amlodipine. AT 1 receptor blockade (candesartan) and ACE inhibition (trandolapril) were also tested in LTM. Microelectrodes were used to record transmembrane potentials from isolated epicardial and endocardial slabs using a protocol simulating STM in intact animals. Left ventricular epicardial myocytes from LTM or sham control dogs were dissociated, and I Ca,L was recorded (whole-cell patch-clamp technique). Evolution of STM and LTM was attenuated by I Ca,L blockers but not β-blockers. Neither AT 1 receptor blockade nor ACE inhibition suppressed LTM. In microelectrode experiments, pacing induced an epicardial-endocardial gradient change mimicking STM that was suppressed by nifedipine. In patch-clamp experiments, peak I Ca,L density in LTM and control were equivalent, but activation was more positive and time constants of inactivation longer in LTM ( P Conclusions— I Ca,L blockade but not β-adrenergic blockade suppresses cardiac memory. LTM evolution is unaffected by angiotensin II blockade and is associated with altered I Ca,L kinetics.

Cardiac memory is characterized by an altered T-wave on electrocardiogram or vectorcardiogram recorded during sinus rhythm, having been induced by a preceding period of abnormal ventricular activation. This phenomenon reflects the dynamic ability of the heart to adapt to new circumstances, in this instance, an altered electrical activation pattern. The result of this adaptation is a changed electrical substrate expressed in cardiac repolarization. The signal transduction mechanisms and ion channel changes that are initiated by altered activation and that contribute to the expression of cardiac memory are the major focus of this review. Studies of non-cognitive memory in central nervous system have provided a paradigm for much of this research.

To the Editor: Cardiac memory (CM) has been investigated extensively over the last decades.1–3⇓⇓ Whereas early studies focused on electrotonus as a central determinant of cardiac memory,3 more recent work has considered changes in ion channels driven by to-be-determined transcriptional events.4,5⇓ However, any transcriptional mechanisms involved remained largely unidentified. In the September 5 issue of the journal, we reported our first study investigating transcriptional mechanisms of CM.6 Based on previously shown parallels between CM and memory in the CNS,7 which incorporates the cAMP response element binding protein (CREB) as an important transcription factor,8 we investigated the role of CREB in …

Up to now, the only technique capable of generating millijoule-level sub-10-fs pulses is based on spectral broadening in a gas-filled capillary with subsequent compression. Even though this technique is routinely being used, the exact nature of the processes involved in white-light generation processes is not fully understood. We present a measurement approach that opens up a new window to understanding femtosecond continuum generation processes. Aside from yielding a better understanding of the underlying physical principles, this has direct implications in how the pulses are subsequently compressed. More importantly, it might provide the answer to the question of whether a phase-locked pulse keeps its lock during this process.

In a recently published study by Morice et al. [1] cough hypersensitivity syndrome (CHS) is put forward as a distinct disease entity, an exciting concept. Within their definition, the lion’s share of patients referred to a specialized cough clinic would fit the diagnosis of CHS (as assessed by the newly presented Hull Airway Reflux Questionnaire [1]). This single clinical entity includes several phenotypes like rhinitis-dominant CHS or the predominantly Th2 response CHS (also known as cough-variant asthma). However, the hypothesis is that a single precipitant predisposes these patients to cough. The authors speculate that this is a gaseous nonacid reflux that has been undetectable thus far with the currently available techniques. An alternative (or complementary) predisposing factor one could think of is upregulation of the receptor-channel transient receptor potential vanilloid (TRPV) type 1. Morice et al. have done a vast amount of work exploring the role of this ion channel in chronic cough and so have others [2–4]. This channel has gained popularity as a “cough-mediating receptor” since it triggers afferent nerve activity in response to cough-provoking stimuli, including heat, acid, and certain arachidonic acid derivatives. The channel is also indirectly activated by inflammatory mediators like bradykinin, nerve growth factor, and prostaglandin [5]. Furthermore, TRPV1 expression is increased in chronic coughers and the channel is upregulated in reaction to inflammation [3, 4]. From the data presented in Morice et al., I think another clue to the involvement of TRPV1 might be derived. As shown before by others [6, 7], the study by Morice et al. shows a female preponderance for developing CHS. Hitherto this female predilection to CHS has not been elucidated. However, the literature offers the ingredients for a plausible hypothesis which is in line with a role for TRPV1 in CHS. A female predominance for afflictions involving ion channels is not unusual in nature. The influence of sex hormones on ion channels has long been recognized, explaining many pathogenic differences between men and women. For example, women are at greater risk for drug-induced cardiac arrhythmias, and the female gender itself is an independent risk factor for sudden death. This is, at least in part, explained by an effect of estrogen on mRNA levels of several potassium and calcium channels (reviewed in [8]). Estrogen also influences TRPV1 activation/sensitization. Although some controversy exists, most studies describe a gain of function. Not surprisingly, most reports on this subject stem from the field of gynaecology and describe the importance of the channel in activating afferent nerve fibers in gynecologic pain. Yan et al. [9] show that in ovariectomized rats TRPV1 becomes important only in activating afferent nerve fibers in response to uterine cervical distension after estrogen replacement therapy. Peng et al. [10] show that the sensitization of TRPV1 as a nociceptive activator of C fibers in rats is dependent on the estrous cycle. Moreover, they demonstrated that capsaicin-induced activation of C fibers is significantly greater in the proestrus stage (high estradiol, low progesterone) than in the metestrus stage (low estradiol, high progesterone), favoring estradiol over progesterone as a hormonal mediator of TRPV1. Kiasalari et al. [11] identified a population of C-fiber cells that express high levels of TRPV1 and more than 75% of these cells express estrogen receptor α, suggesting a role for estrogen in regulating these cells. From the above, it is hypothesized that the influence of estrogen on TRPV1 predisposes the female sex to CHS, thus explaining the higher prevalence of CHS among women. This association would strengthen the hypothesis that TRPV1 is important in CHS.

Atrial fibrillation (AF) shortens the atrial effective refractory period (AERP). To investigate the role of the autonomic nervous system during this so-called electrical remodeling of the atria (ERA) and during recovery from ERA we analyzed heart rate variability (HRV). In 12 goats atrioventricular (300:150 beats/min) pacing was performed for 24 hours, interrupted at 4, 8, 16, and 24 hours for recording of 500 atrial (AA) intervals during sin us rhythm and measurement of the AERP(430 ms) at 7. 4 +/- 0.6 sites. After 24 hours, pacing was stopped and the electrophysiological study and recording of the AA intervals was repeated at 4, 8, 16, and 24 hours after cessation of pacing. Time- and frequency-domain parameters were computed from each 500 AA interval recording. After 24 hours of rapid pacing the AERP had shortened significantly (247 +/- 5.6 to 102 +/- 6.4 ms, P

Background —Atrial fibrillation (AF) induces electrical remodeling, which is thought to be responsible for the low success rate of antiarrhythmic treatment in AF of longer duration. Electrical remodeling seems to be related to tachycardia-induced intracellular calcium overload. Due to its vagomimetic action, digoxin is widely used to control the ventricular rate during AF, but it also increases intracellular calcium. On the basis of these characteristics, we hypothesized that digoxin would aggravate tachycardia-induced electrical remodeling. Methods and Results —We analyzed the atrial effective refractory period (AERP) at cycle lengths of 430, 300, and 200 ms during 24 hours of rapid atrio/ventricular (300/150 bpm) pacing in 7 chronically instrumented conscious goats treated with digoxin or saline. Digoxin decreased the spontaneous heart rate but had no other effects on baseline electrophysiological characteristics. In addition to a moderate increase in the rate of electrical remodeling during rapid pacing, digoxin significantly delayed the recovery from electrical remodeling after cessation of pacing (at 430, 300, and 200 ms: P =0.001, P =0.0015, and P =0.007, respectively). This was paralleled by an increased inducibility and duration of AF during digoxin. Multivariate analysis revealed that both a short AERP and treatment with digoxin were independent predictors of inducibility ( P =0.001 and P =0.03, respectively) and duration ( P =0.001 for both) of AF. Conclusions —Digoxin aggravates tachycardia-induced atrial electrical remodeling and delays recovery from electrical remodeling in the goat, which increases the inducibility and duration of AF.