Disaggregation of amyloid-beta fibrils via natural metabolites using long timescale replica exchange molecular dynamics simulation studies.

CONTEXT: Amyloid fibrils are self-assembled fibrous protein aggregates that are associated with several presently incurable diseases such as Alzheimer's. disease that is characterized by the accumulation of amyloid fibrils in the brain, which leads to the formation of plaques and the death of brain cells. Disaggregation of amyloid fibrils is considered a promising approach to cure Alzheimer's disease. The mechanism of amyloid fibril formation is complex and not fully understood, making it difficult to develop drugs that can target the process. Diacetonamine and cystathionine are potential lead compounds to induce disaggregation of amyloid fibrils. METHODS: In the current research, we have used long timescale molecular simulation studies and replica exchange molecular dynamics (REMD) for 1000 ns (1 µs) to examine the mechanisms by which natural metabolites can disaggregate amyloid-beta fibrils. Molecular docking was carried out using Glide and with prior protein minimization and ligand preparation. We focused on a screening a database of natural metabolites, as potential candidates for disaggregating amyloid fibrils. We used Desmond with OPLS 3e as a force field. MM-GBSA calculations were performed. Blood-brain barrier permeability, SASA, and radius of gyration parameters were calculated.

Rapid, tunable, and multiplexed detection of RNA using convective array PCR.

Detection of RNA targets is typically achieved through RT-qPCR or RNAseq. RT-qPCR is rapid but limited in number and complexity of targets detected, while RNAseq is high-throughput but takes multiple days. We demonstrate simultaneous amplification and detection of 28 distinct RNA targets from a single unsplit purified RNA sample in under 40 minutes using our convective array PCR (caPCR) technology. We integrate tunable strand displacement probes into caPCR to allow detection of RNA species with programmable sequence selectivity for either a single, perfectly matched target sequence or for targets with up to 2 single-nucleotide variants within the probe-binding regions. Tunable probes allow for robust detection of desired RNA species against high homology background sequences and robust detection of RNA species with significant sequence diversity due to community-acquired mutations. As a proof-of-concept, we experimentally demonstrated detection of 7 human coronaviruses and 7 key variants of concern of SARS-CoV-2 in a single assay.

Electronic referrals to the tobacco Quitline: implementation strategies in a large health system to optimize delivery of tobacco cessation to patients.

Electronic referrals provide an efficient solution for clinicians to connect patients to free tobacco cessation services, such as the tobacco Quitline. However, strategic planning is necessary for the successful adoption of this method across the health care system. The purpose of this study was to develop an implementation strategy for electronic referrals to the tobacco Quitline in a large health system. A clinical decision support tool created a closed-loop e-referral pathway between the electronic health record system and the Quitline. Multilevel strategies were developed to implement the e-referral process across the entire health system, including leadership buy-in, Epic tip sheets, newsletters, training for practice champions and staff, physician educator, patient-focused advertisements, and video clips distribution by the Maryland Department of Health Center for Tobacco Prevention and Control. The implementation of a system-wide e-referral pathway for tobacco cessation involved continuous clinician education and training, systematic quality control, and engaging "champion" clinicians. Postimplementation data analysis revealed that 1,790 e-referrals were received by the Quitline in 2018-2019, of which 18% accepted follow-up services, 18% declined, and 64% were not reached after multiple attempts. Among 322 patients who accepted Quitline services, 55% requested nicotine replacement therapy. Overall, 282 clinicians referred patients, including 107 primary care physicians and 175 specialists; 62 clinicians e-referred 72% patients, thereby emerging as "tobacco champions." The e-referral process is an efficient method for tobacco users to receive a cessation referral from clinicians. Sustainability can be achieved through leadership buy-in, physician ease of use, patient motivation, information technology supports, and reminders.

Management of Labor and Delivery After Fetoscopic Repair of an Open Neural Tube Defect.

OBJECTIVE: To report labor, delivery, and neonatal outcomes in a cohort of women delivering neonates who had undergone fetoscopic neural tube defect repair. METHODS: We conducted a retrospective cohort study from April 2014 to January 2018. All patients met Management of Myelomeningocele Study eligibility criteria. We included patients with completed second-trimester fetoscopic neural tube defect repair (laparotomy, uterine exteriorization, and minimally invasive access through two or three uterine ports) followed by standardized management of labor and delivery at our institution. Outcomes included rates of vaginal delivery, term delivery, and intrapartum cesarean delivery as well as obstetric and neonatal outcomes after oxytocin. Complications of interest included preterm prelabor rupture of membranes, chorioamnionitis, uterine dehiscence or rupture, 5-minute Apgar score less than 7, and neonatal acidosis (umbilical artery pH less than 7.15). RESULTS: Thirty-four patients had fetoscopic repair, followed by 17 vaginal deliveries (50%, 95% CI 32-68%). Median gestational age was 38 1/7 weeks at vaginal delivery (range 26 0/7-40 2/7 weeks of gestation) and 37 1/7 weeks of gestation at cesarean delivery (range 25 5/7-40 5/7 weeks of gestation); 62% of deliveries occurred at term. Eight patients had prelabor cesarean delivery: three nonurgent and five urgent (for nonreassuring fetal heart tracings). Twenty-six patients labored; six were induced and 20 labored spontaneously. Of the latter, five were augmented. Of 26 laboring patients, 17 delivered vaginally and nine underwent urgent cesarean delivery (35%, 95% CI 17-56%; seven nonreassuring fetal heart tracings and two breech). There were no cases of uterine rupture or dehiscence. Most (94%, 95% CI 80-99%) had normal 5-minute Apgar scores; one neonate (3%, 95% CI 0-15%) had acidosis but normal Apgar scores. CONCLUSION: Our data regarding trial of labor, use of low-dose oxytocin, and vaginal delivery after prenatal fetoscopic neural tube defect repair are reassuring. Importantly, fetoscopic repair may permit delivery at advanced gestational ages.