Citations

Significance Lipid droplets (LDs) are specialized fat-storage organelles that can be used as a fuel source by many types of cells when nutrients are scarce. One mechanism used by hepatocytes (the functional cells of the liver) for the catabolism of these energy reserves is the lysosome-directed process of autophagy. Traditionally, autophagy necessitates the enclosure of cargo within a double-membrane autophagosome before delivery to the lysosome for degradation. Here, we use live-cell and electron microscopy to demonstrate that stable contacts between LDs and lysosomes in hepatocytes can result in the transfer of both proteins and lipids from LDs directly into the lysosome in the absence of an autophagosomal intermediate. These findings reveal a mechanism used for lipid homeostasis in the liver.

Abstract Background/Introduction TAILOR-PCI is the largest cardiovascular genotype-based randomized trial (NCT#01742117) investigating whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes after percutaneous coronary intervention (PCI). The TAILOR-PCI Digital Sub-Study tests the feasibility of extending original follow-up of 1 year to 2 years using state-of-the-art digital solutions. Deep phenotyping acquired during a clinical trial can be leveraged by extending follow-up in an efficient and cost-effective manner using digital technology. Purpose Our objective is to describe onboarding and engagement of participants initially recruited in a large, pragmatic, international, multi-center clinical trial to a digital registry. Methods TAILOR-PCI participants, within 23 months of their index PCI, were invited by letters containing a URL to the Digital Sub-Study website (http://tailorpci.eurekaplatform.org). These invitations were followed by phone calls, if no response to the letter, to determine reason for non-participation. A NIH-funded direct-to-participant digital research platform (the Eureka Research Platform) was used to onboard, consent and enroll participants for the digital follow-up. Participants were asked to answer health-related surveys at fixed intervals using the Eureka mobile app and desktop platform. To capture hospitalizations, participants could enable geofencing to allow background location tracking, which triggered surveys if a hospitalization was detected. Result(s) Letters were mailed to 893 of 929 eligible participants across 22 sites in the United States and Canada leading to 226 homepage visits and 118 registrations. There were 107 consents (12.0% of invited; mean age: 66.4±9.0; 19 females [18%]): 47 (44%) participants consented after the letter, 36 (34%) consented after the 1st call and 24 (22%) consented after a 2nd call. Among those who consented, 100 were eligible (7 did not have a smartphone) 81 downloaded the study mobile app and 73 agreed for geofencing (Figure 1). Among the 722 invited participants who were surveyed, 354 declined participation: due to lack of time (146; 20.2%), lack of smartphone (125; 17.3%), difficulty understanding (41; 5.7%), concern about using smartphone (34; 4.7%), concern of data privacy (14; 1.9%), concerns of location tracking (6; 0.8%) and other reasons (57; 7.9%). Conclusion Extended follow-up of a clinical trial using a digital platform is feasible but uptake in this study population was limited largely due to lack of time or a smartphone among participants. Based on data from other digital studies, uptake may also have been limited since digital follow-up consent was not incorporated at the time of consent for the main trial. Figure 1. Onboarding of the digital substudy Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institute of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)

Background: During awake craniotomy, securing the patient’s airway might be necessary electively or emergently. The objective of this study was to compare the feasibility of airway management using a laryngeal mask airway (LMA) and 4 alternative airway management techniques in an awake craniotomy simulation. Methods: After completing a questionnaire, 9 anesthesia providers attempted airway management in a cadaver positioned to simulate awake craniotomy conditions. Following the simulation, participants rated and ranked the devices in their order of preference. Results: Only 3 approaches resulted in the successful securement of an airway device for 100% of participants: LMA (median; interquartile range time to secure the airway 6 s, 5 to 10 s), fiberoptic bronchoscopy through an LMA (41 s; 23 to 51 s), and video laryngoscopy (49 s; 43 to 127 s). In contrast, the oral and nasal fiberoptic approaches demonstrated only 44.4% (154.5 s; 134.25 to 182 s) and 55.6% (75 s; 50 to 117 s) success rates, respectively. The LMA was the fastest and most reliable primary method to secure the airway (P=0.001). After the simulation, 100% of participants reported that an LMA would be their first choice for emergency airway management, followed by fiberoptic intubation through the LMA (7 of 9 participants) if the LMA failed to properly seat. Conclusions: We demonstrated that an LMA was the fastest and most reliable primary method to secure an airway in a laterally positioned cadaver with 3-pin skull fixation. Fiberoptic and video laryngoscope airway equipment should be readily available during awake craniotomy procedures, and an attempt to visualize the vocal cords through the LMA should be attempted before removing it for alternative techniques.

As a critical factor in the built environment, lighting presents considerable influence on occupants. Previous research across static lighting conditions has found that both illuminance and correlated color temperature (CCT) affect occupants’ physiological and psychological functioning. However, little research has been conducted on the non-visual impacts of dynamic lighting with daily variation in illuminance and CCT levels. The purpose of this study is to better understand the impact of dynamic lighting on office occupants’ health, well-being and experience at a living lab. Fifteen participants were recruited to work in three office modules for four months. Four lighting conditions were designed and implemented in this study, including two static lighting conditions and two dynamic lighting conditions with a specific predefined control scheme. A prototype lighting system with enhanced control capabilities was configured and implemented to ensure the desired lighting environment protocol. Both objective methods and subjective surveys were used to assess the behavioral and physiological outcomes of interest, including mental stress, sleep, productivity, satisfaction, mood, visual comfort and perceived naturalness. The results showed that the daytime behavioral impacts were either positive or mixed. Specifically, a significant alertness increase was observed in the afternoon, indicating a potential solution to reduce the natural feelings of sleepiness during the workday. There was also a marginal benefit for mood. The nighttime impacts include a significant decrease in perceived sleep quality and sleep time after subjects were exposed to dynamic lighting. No significant differences were observed for mental stress, productivity, visual comfort, or perceived naturalness. The findings present additional insights into the non-visual impacts of dynamic lighting and give recommendations for further investigations.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Circumstances of the COVID-19 pandemic have mandated a change to standard management of infantile spasms. On April 6, 2020, the Child Neurology Society issued an online statement of immediate recommendations to streamline diagnosis and treatment of infantile spasms with utilization of telemedicine, outpatient studies, and selection of first-line oral therapies as initial treatment. The rationale for the recommendations and specific guidance including follow-up assessment are provided in this manuscript. These recommendations are indicated as enduring if intended to outlast the pandemic, and limited if intended only for the pandemic health care crisis but may be applicable to future disruptions of health care delivery.

e13535 Background: Pediatric patients (pts) receiving long-term vincristine treatment for acute lymphoblastic leukemia (ALL) who carry two variant alleles of CEP72 rs924607 experience more severe peripheral neuropathy (PN) at lower cumulative vincristine doses. The objective of this retrospective pharmacogenetic analysis was to determine if pts homozygous for rs924607 have increased PN risk when receiving short-term vincristine treatment for diffuse large B-cell lymphoma (DLBCL). Methods: Caucasian pts with DLBCL randomized to either of two vincristine-containing regimens (R-CHOP or DA-EPOCH-R) on the CALGB 50303 (Alliance) trial were genotyped for germline rs924607 via TaqMan. Vincristine was administered intravenously 1.4 mg/m2 (2 mg cap) on day 1 of each R-CHOP cycle (1.4 mg/m2/cycle) or 0.4 mg/m2/day (no cap) on days 1-4 of each DA-EPOCH-R cycle (1.6 mg/m2/cycle). Dosing was repeated every 21 days for 6 treatment cycles, for a maximum cumulative vincristine dose of 8.4 (R-CHOP) or 9.6 (DA-EPOCH-R) mg/m2 over 18 weeks. The primary analysis compared risk of NCI CTCAE grade 3 or higher PN in rs924607 homozygous variant pts versus wild-type allele carriers using multivariable Cox proportional hazards regression adjusted for treatment received (R-CHOP vs. DA-EPOCH-R), age (continuous), and sex (male vs. female). A secondary analysis was conducted only in pts assigned to the DA-EPOCH-R arm. Results: Of 307 pts included in the analysis, 32 (10.4%) experienced grade 3+ PN. PN occurrence was nominally lower in homozygous pts (5/59 = 8.5%) than wild-type carriers (27/248 = 10.9%). In the primary analysis, homozygous pts did not experience PN earlier in treatment (Hazard ratio (HR) = 1.04, (95% confidence interval: 0.39-2.75), one-sided p-value = 0.47). There was no significant difference between groups in dose-at-PN occurrence (homozygous (n = 5): 8.81 mg/m2 vs. wild-type carrier (n = 27):6.74 mg/m2, p > 0.05). The secondary analysis in pts on the DA-EPOCH-R arm (n = 147), in which the majority of PN events occurred (n = 27/32 = 84%), homozygous pts (n = 26) did not have significantly increased PN risk (HR = 1.30, p = 0.56). Conclusions: This retrospective analysis of the prospective CALGB 50303 trial did not find that pts homozygous for CEP72 rs924607 had increased PN risk during short-term vincristine treatment for DLBCL. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org . ClinicalTrials.gov Id: NCT00118209.