Citations

Abstract Introduction “Spring forward,” the start of daylight savings time (DST) reduces sleep opportunity by an hour. The resulting sleep deprivation in healthcare workers can increase the potential for medical errors. We examined the change in patient safety-related adverse events (AEs) following the time change in both spring and fall. Methods Self-reported AEs that occurred 7 days prior to and following the spring and fall time changes for years 2010–2017 in a large healthcare organization were ascertained. AEs likely resulting from human errors were identified. The change in the number of AEs (all AEs or restricted to those resulting from human error) following the spring and fall time change were modeled using negative binomial mixed models using a random effect to correct for non-independent observations in consecutive. Results Over the 8 year period, there were more AEs (all and human) in the 7 days following the change in time both in spring (All: 2812 V. 2699; Human: 1902 V. 1625) and fall (All: 3207 V. 3007; Human: 2189 V. 2087). However, the only statistically significant increase was for the estimated 18% increase in human errors following time change in spring (95% CI: 6% to 34%; p = 0.004). The 18% AE increase in spring was also significantly greater than the 5% increase in AE in fall (p = 0.018). Conclusion There is a significant increase in human error related AEs following the “spring forward” clock change which can jeopardize patient safety. Based on safety considerations, DST might best be eliminated; alternatively, policy makers and healthcare organizations should evaluate measures to mitigate the increased risk during this period. Support NA

Abstract Introduction Patients presenting with excessive sleepiness are frequently on antidepressant medication(s). While practice parameters recommend discontinuation of antidepressants prior to multiple sleep latency testing (MSLT), data examining the impact of tapering these medications on MSLT results are limited. Methods Adult patients who underwent MSLT at Mayo Clinic Rochester, Minnesota, between 2014-2018 were included. Clinical and demographic characteristics, medications, including use of rapid eye movement suppressing antidepressants (REMS-AD) at assessment and during testing, actigraphy and polysomnography data were manually abstracted. The difference in number of sleep-onset rapid eye movement periods (SOREMS), proportion with ≥2 SOREMS and mean sleep latency (MSL) in patients who were on REMS-AD and discontinued prior to testing versus those who remained on REMS-AD were examined. At our center, all antidepressants are discontinued 2 weeks prior to MSLT wherever feasible; fluoxetine is stopped 4 weeks prior. Regression analyses accounting for demographic, clinical and other medication-related confounders were performed. Results A total of 502 patients (age=38.18±15.90 years; 67% female) underwent MSLT; 178 (35%) were on REMS-AD at the time of assessment. REMS-AD were discontinued prior to testing in 121/178 (70%) patients. Patients tapered off REMS-AD were more likely to have ≥2 SOREMS (OR-12.20; 95%CI=1.60-92.94) compared to patients who remained on REMS-AD at the time of the MSLT. They also had shorter MSL (8.77±0.46 vs 10.21±0.28; p>0.009) and higher odds of having ≥2 SOREMS (OR=2.22; 95%CI=1.23-3.98) compared to patients not on REMS-AD at initial assessment. These differences persisted after regression analyses accounting for confounders. Conclusion Patients who taper off REMS-AD prior to MSLT are more likely to demonstrate ≥2SOREMs and have a shorter MSL. Pending further prospective investigations, clinicians should preferably withdraw REMs-AD before an MSLT. If this is not done, the test interpretation should include a statement regarding the potential effect of the drugs on the results. Support None

Abstract Introduction Sleep disordered breathing (SDB) is associated with adverse cardiovascular outcomes and decreased cardiorespiratory fitness (CRF). The risk of long-term major adverse cardiovascular events (MACE) when SDB and decreased CRF co-occur has not been determined. Methods We included consecutive patients that underwent a symptom-limited cardiopulmonary exercise test followed by first-time diagnostic polysomnography within 6 months. Patients were stratified based on the presence of moderate-severe SDB (apnea/hypopnea index ≥15/hour) and decreased CRF defined as <70% predicted peak oxygen consumption (VO2). MACE was a composite outcome of myocardial infarction (MI), coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), stroke/transient ischemic attack (TIA) and death. Cox-proportional hazard models adjusting for factors known to influence CRF and MACE were constructed. Results Of 498 included patients (60±13 years, 28.1% female), 175 (35%) had MACE (MI=17, PCI=14, CABG=13, stroke=20, TIA=12, deaths=99) at a median follow-up of 8.7 years (interquartile range=6.5-10.3 years). After adjusting for age, sex, beta-blockers, systemic hypertension, diabetes mellitus, coronary artery disease, cardiac arrhythmia, chronic obstructive pulmonary disease, smoking and positive airway pressure (PAP) usage, decreased CRF alone (HR=1.91, 95%CI=1.15-3.18, p=0.012), but not SDB alone (HR=1.26, 95%CI=0.75-2.13, p=0.389) was associated with increased risk of MACE. Those with SDB and decreased CRF had increased risk of MACE compared to patients with decreased CRF alone (HR=1.85, 95%CI=1.21-2.84, p<0.005) after accounting for these confounders; the risk was attenuated after additionally adjusting for adequate adherence to PAP (HR=1.85, 95%CI=0.99-3.05, p=0.05). Conclusion The incidence of MACE, including mortality, was high in this sample. Moderate-severe SDB with concurrent decreased CRF was associated with higher risk of MACE than decreased CRF alone. These results highlight the importance of including CRF in the risk assessment of patients with SDB, and conversely, that of screening for SDB in patients with low peak VO2. Support None.

There is marked sexual dimorphism in the current coronavirus disease 2019 (COVID-19) pandemic. Here we report that estrogen can regulate the expression of angiotensin-converting enzyme 2 (ACE2), a key component for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry, in differentiated airway epithelial cells. Further studies are required to elucidate the mechanisms by which sex steroids regulate SARS-CoV-2 infectivity.

Abstract We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Supplemental O 2 is a primary mode of respiratory therapy for preterm infants. Numerous studies, however, have shown that supplemental O 2 may contribute to the pathophysiology of airway hyperreactivity (AHR) associated with wheezing disorders such as asthma later in childhood. The calcium‐sensitive receptor (CaSR) is a potent modulator of smooth muscle contractility and may be an underlying feature of childhood asthma. In the present study, we investigated whether CaSR is involved in neonatal hyperoxia induced AHR in a mouse model of BPD. We hypothesize that inhibition (CaSR antagonism), downregulation of expression (siRNA), or deletion (CaSR KO mice) of CaSR will attenuate the AHR induced by hyperoxia in neonatal mice. Newborn C57BL/6 wild‐type (background) or CaSR −/− (knockout) mice were randomized on the second day of life and assigned to room air (21% O 2 ) or hyperoxic (40% O 2 ) groups and exposed for seven days, then recovered in room air for two additional weeks. At day P21, AHR was assessed in vitro using precision‐cut living lung slice preparations in response to increasing doses of methacholine (MCh, 0.25–8 μM). Wild‐type lung slices were pre‐incubated for 48 h in a CaSR siRNA sequence (40 nM) or scrambled RNA as a negative control. In another set of experiments, slices were pre‐incubated in a CaSR antagonist – NPS 2143 (10 nM) for 1 h. Airways were imaged and airway reactivity was expressed as percent change from baseline airway lumen area (± SEM). Neonatal hyperoxia significantly increased airway contractile responses to MCh in wild‐type mice with a mean maximal effect (Emax) of 68.4±8.7% decrease in airway lumen area compared to room air controls (47.3±5.8%, p<0.001), indicating AHR. Pre‐incubation (48hrs) with siRNA targeting CaSR or pharmacologic inhibition (NPS 2143, 1hr incubation) of CaSR reversed the hyperoxia‐induced AHR and the contractile responses were normalized to control level, with hyperoxic groups Emax of 44.0±5.2% and 41.3±3.1%, respectively. AHR was not observed in CaSR knockout mice suggesting resistance to hyperoxia exposure. These data suggest that CaSR plays an important role in the long‐term effects of neonatal hyperoxia on AHR. We speculate that CaSR may be a novel therapeutic target to reverse airway hyperreactivity in former preterm infants who had received prior supplemental O 2 therapy. Support or Funding Information Funding: NIH: HL R01 138402 and NIH R01 HL 056470

Continuous positive airway pressure (CPAP) is a common mode of respiratory support for preterm infants. Recent studies from our lab, however, have shown that CPAP may contribute to the pathophysiology of airway hyperreactivity (AHR) associated with wheezing disorders in former preterm infants. The long‐term effects of CPAP on lung‐development, however, still remain largely unknown. Both hyaluronan synthase 3 (HAS3) and the calcium‐sensitive receptor (CaSR) have been associated with various respiratory morbidities. In the present study, we used a neonatal mouse model of daily CPAP treatment to investigate whether the long‐term effects on AHR are associated with changes in airway HAS3 and CaSR expression. Neonatal mice were exposed to CPAP (6cm H 2 O) for 3 hours per day for the first 7 postnatal days. Control animals experienced the same conditions as experimental animals only with no CPAP. On postnatal day 21, the lungs from these animals were harvested for either real time rt‐PCR or immunohistochemistry to assess changes in HAS3 and CaSR expression. We observed increased expression of multiple genes involved in hylauraonan synthesis, most notably has3 , as well as increased CaSR expression, in the lungs of mice two weeks after CPAP ended when compared to control mice. The increased gene expression of has3 and CaSR was also reflected in increased protein expression as confirmed by immunohistochemistry. HAS3 was expressed predominantly in airway epithelium and the increased CaSR expression correlated with increased αSM actin. To further investigate the role of CaSR in CPAP‐induced AHR, CaSR KO mice ( CaSR (−/−) ) were exposed to CPAP and airway reactivity to methacholine challenge was assessed two weeks later (P21 days). Compared to control mice, AHR was not expressed in CaSR (−/−) mice suggesting resistance to CPAP treatment. These data suggest increased airway HAS3 and CaSR may be important modulators of CPAP‐induced AHR and remodeling. Support or Funding Information HLR01138402 HLR01056470

Purpose Epidemiological evidences suggest higher incidence and severity of asthma in pre‐menopausal women and aging men, indicating the role of sex steroids, especially estrogen. Our recent studies demonstrated that airway smooth muscle (ASM) cells from both male and female expresses estrogen receptors (ERα and β) and these receptors differentially regulate intracellular calcium ([Ca 2+ ] i ) which is a key role player in contraction. The degree of force for contraction can also be altered in a Ca 2+ ‐independent manner via RhoA. Both Ca 2+ ‐dependent and Ca 2+ ‐independent pathways in ASM thus together contribute towards the airway contractility. In this study, we hypothesized that the ERs differentially regulate cyclic adenosine monophosphate (cAMP) and RhoA mechanisms, thereby affecting the overall contractility of human ASM cells. Methods Asthmatic and non‐asthmatic primary human ASM cells (isolated from lung tissue, Mayo Clinic, IRB‐approved) were seeded and grown to 70% confluence. After serum‐deprivation, cells were exposed to 1nM 17β‐estradiol (E 2 ), 10nM PPT (ERα agonist) or WAY (ERβ agonist) for 24hr. IBMX (10μM) was used as phosphodiesterase inhibitor and Isoproterol (100nM for 10min) served as a positive control group for estimation of cAMP. In parallel studies, phosphorylation of myosin light chain (MLC 20 ) and myosin phosphatase targeting subunit‐1 (MYPT1) was assessed through Western analyses. Activated RhoA and cAMP measurements were done through ELISA kits. Cell contraction was accessed through traction force microscopy (TFM) using softgel plates coated with collagen and fluorescent beads. Upon treatments, phase‐contrast and fluorescent images were captured before, during and after 10μM histamine exposure and net traction force was calculated using advanced software. Results Prolonged (24h) activation of ERβ significantly increased the baseline cAMP levels whereas ERα activation decreased it. This effect was more profound in asthmatic ASM cells compared to non‐asthmatics. Furthermore, ERβ activation lowered the active RhoA levels in non‐asthmatic human ASM cells. The phosphorylation of MLC 20 and MYPT1 was significantly attenuated with ERβ activation compared to vehicle. TFM studies demonstrated reduced traction force in non‐asthmatic ASM cells treated with ERβ agonist compared to the vehicle, whereas ERα activation did not show any significant changes. Conclusion Our findings highlight the crucial role of divergent ER signaling in regulating Ca 2+ ‐dependent and Ca 2+ ‐independent pathways, which together govern the contractile function of ASM. Particularly, ERβ activation (and not ERα) mediates ASM relaxation by increasing the cAMP, reducing active RhoA and decreasing phosphorylation of MLC 20 /MYPT1. Thus, ERβ activation might serve as a novel target to manage the increased ASM contractility in asthma. Support or Funding Information Acknowledgement Supported by NIH grants R01‐HL0123494 (Venkatachalem), R01‐HL 088029 (Prakash) and R01‐HL142061 (Pabelick, Prakash).