RNA-binding protein Nocte regulates Drosophila development by promoting translation reinitiation on mRNAs with long upstream open reading frames.

RNA-binding proteins (RBPs) with intrinsically disordered regions (IDRs) are linked to multiple human disorders, but their mechanisms of action remain unclear. Here, we report that one such protein, Nocte, is essential for Drosophila eye development by regulating a critical gene expression cascade at translational level. Knockout of nocte in flies leads to lethality, and its eye-specific depletion impairs eye size and morphology. Nocte preferentially enhances translation of mRNAs with long upstream open reading frames (uORFs). One of the key Nocte targets, glass mRNA, encodes a transcription factor critical for differentiation of photoreceptor neurons and accessory cells, and re-expression of Glass largely rescued the eye defects caused by Nocte depletion. Mechanistically, Nocte counteracts long uORF-mediated translational suppression by promoting translation reinitiation downstream of the uORF. Nocte interacts with translation factors eIF3 and Rack1 through its BAT2 domain, and a Nocte mutant lacking this domain fails to promote translation of glass mRNA. Notably, de novo mutations of human orthologs of Nocte have been detected in schizophrenia patients. Our data suggest that Nocte family of proteins can promote translation reinitiation to overcome long uORFs-mediated translational suppression, and disruption of this function can lead to developmental defects and neurological disorders.

A systematic review of robotic surgery curricula using a contemporary educational framework.

BACKGROUND: There has been a rising trend in robotic surgery. Thus, there is demand for a robotic surgery curriculum (RSC) for training surgical trainees and practicing surgeons. There are limited data available about current curricular designs and the extent to which they have incorporated educational frameworks. Our aim was to study the existing robotic surgery curricula using Kern's 6-step approach in curriculum development. METHODS: A systematic review was conducted using PubMed, PubMed Central, Cochrane, Embase, and Scopus (we searched studies from 2001 to 2021). PRISMA Guidelines was used to guide the search. Curriculum designed for general surgery and its subspecialties were included. Urology and gynecology were excluded. The articles were reviewed by five reviewers. RESULTS: Our review yielded 71 articles, including 39 curricula at 9 different settings. Using Kern's framework, we demonstrated that the majority of robotic surgery curricula contained all the elements of Kern's curricular design. However, there were significant deficiencies in important aspects of these curricula i.e., implementation, the quality of assessment tools for measurement of performance and evaluation of the educational value of these interventions. Most institutions used commercial virtual reality simulators (VRS) as the main component of their RSC and 23% of curricula only used VRS. CONCLUSIONS: Although majority of these studies contained all the elements of Kern's framework, there are critical deficiencies in the components of existing curricula. Future curricula should be designed using established educational frameworks to improve the quality of robotic surgery training.

Minimally invasive vs open pancreatoduodenectomy on oncological adequacy: a propensity score-matched analysis.

BACKGROUND: The adoption of minimally invasive pancreatoduodenectomy (MIPD) has increased over the last decade. Most of the data on perioperative and oncological outcomes derives from single-center high-volume hospitals. The impact of MIPD on oncological outcomes in a multicenter setting is poorly understood. METHODS: The National Cancer Database was utilized to perform a propensity score matching analysis between MIPD vs open pancreatoduodenectomy (OPD). The primary outcomes were lymphadenectomy ≥ 15 nodes and surgical margins. Secondary outcomes were 90-day mortality, length of stay, and overall survival. RESULTS: A total of 10,246 patients underwent pancreatoduodenectomy for ductal adenocarcinoma between 2010 and 2016. Among these patients, 1739 underwent MIPD. A propensity score matching analysis with a 1:2 ratio showed that the rate of lymphadenectomy ≥ 15 nodes was significantly higher for MIPD compared to OPD, 68.4% vs 62.5% (P < .0001), respectively. There was no statistically significant difference in the rate of positive margins, 90-day mortality, and overall survival. OPD was associated with an increased rate of length of stay > 10 days, 36.6% vs 33% for MIPD (P < .01). Trend analysis for the patients who underwent MIPD revealed that the rate of adequate lymphadenectomy increased during the study period, 73.1% between 2015 and 2016 vs 63.2% between 2010 and 2012 (P < .001). In addition, the rate of conversion to OPD decreased over time, 29.3% between 2010 and 2012 vs 20.2% between 2015 and 2016 (P < .001). CONCLUSION: In this propensity score matching analysis, the MIPD approach was associated with a higher rate of adequate lymphadenectomy and a shorter length of stay compared to OPD. The surgical margins status, 90-day mortality, and overall survival were similar between the groups.

"Doc McStuffins: Doctor for a Day" Virtual Reality (DocVR) for Pediatric Preoperative Anxiety and Satisfaction: Pediatric Medical Technology Feasibility Study.

BACKGROUND: Preoperative anxiety is a common occurrence among children and is associated with a host of maladaptive postoperative behaviors. Consequently, increased attention has been placed on interventions to reduce preoperative anxiety and its associated outcomes. Child Life preparation prior to surgery includes evidence-based practices such as age-appropriate distraction and therapeutic play. Virtual reality (VR) is a promising addition to the Child Life toolbox to address anxiety prior to surgery. The current study evaluates the implementation and feasibility of a VR experience, "Doc McStuffins: Doctor for a Day Virtual Reality Experience" (DocVR), developed by Disney Junior in collaboration with Children's Hospital Los Angeles, to target pediatric preoperative anxiety. OBJECTIVE: The primary aim of this study was to examine the feasibility and efficacy of DocVR for preoperative anxiety. A secondary aim was to improve patient, caregiver, and health care provider satisfaction with the preoperative experience. METHODS: In this study, 51 patients (age 6-14 years) scheduled for surgery in the ambulatory surgery center and the main operating room at Children's Hospital Los Angeles were approached to participate in Disney's DocVR experience. The patients played the DocVR experience for an average of 18 minutes (3-55 minutes). Irrespective of surgical procedure, patients and their families were eligible, as long as they had no known marked cognitive or visual impairments that would interfere with completing the survey and engaging in the DocVR experience. RESULTS: Patients who tried the DocVR experience (n=51) responded overwhelmingly positively to both the VR technology and to the game itself. Patients experienced a statistically significant decrease in anxiety following DocVR game play (Z=-3.26, P=.001). On the Facial Affective Scale, the percentage of patients who chose the face with the most positive facial expression to represent their affect increased from 23% (12/51) pre-VR to 49% (25/47) post-VR. Furthermore, 97% (38/39) of patients reported feeling more comfortable at the hospital, and 74% (28/38) reported feeling less scared at the hospital after playing the game. The game was enjoyed by 94% (46/49) of patients, and 88% (30/34) of patients reported feeling both "Interested" and "Involved" in the game. CONCLUSIONS: DocVR is a feasible and beneficial VR experience to relieve pediatric preoperative anxiety and improve satisfaction in the preoperative area. The VR experience resulted in a decrease in overall anxiety and an increase in overall positive affect during the preoperative time. Patients also responded positively to the game, confirming their interest in the content and affirming the quality of the DocVR experience. The positive response to the game indicates that DocVR has the potential to make the overall preoperative experience less anxiety-producing and more comfortable, which leads to improved patient satisfaction. Naturally, improved patient outcomes lead to improved caregiver and health care provider satisfaction.

Trends in anticoagulant prescribing: a review of local policies in English primary care.

BACKGROUND: Oral anticoagulants are prescribed for stroke prophylaxis in patients with atrial fibrillation, which is the most common heart arrhythmia worldwide. The vitamin K antagonist (VKA) warfarin is a long-established anticoagulant. However, newer direct oral anticoagulants (DOACs) have been recently introduced as an alternative. Given the prevalence of atrial fibrillation, anticoagulant choice has substantial clinical and financial implications for healthcare systems. In this study, we explore trends and geographic variation in anticoagulant prescribing in English primary care. Because national guidelines in England do not specify a first-line anticoagulant, we investigate the association between local policies and prescribing data. METHODS: Primary care prescribing data of anticoagulants for all NHS practices from 2014 to 2019 in England was obtained from the ePACT2 database. Public formularies were accessed online to obtain local anticoagulation prescribing policies for 89.5% of clinical commissioning groups (CCGs). These were categorized according to their recommendations: no local policies, warfarin as first-line, or identification of a preferred DOAC (but not a preferred anticoagulant). Local policies were cross-tabulated with pooled prescribing data to measure the strength of association with Cramér's V. RESULTS: Nationally, prescribing of DOACs increased from 9% of all anticoagulants in 2014 to 74% in 2019, while that of warfarin declined accordingly. Still, there was significant local variation. Across geographical regions, DOACs ranged from 53 to 99% of all anticoagulants. Most CCGs (73%) did not specify a first-line choice, and 16% recommended warfarin first line. Only 11% designated a preferred DOAC. Policies with a preferred DOAC indeed correlated with increased prescribing of that DOAC (Cramér's V = 0.25, 0.27, 0.38 for rivaroxaban, apixaban, edoxaban respectively). However, local policies showed a negligible relationship with the classes of anticoagulants prescribed-DOAC or VKA (Cramér's V = 0.01). CONCLUSIONS: Nationally, the use of DOACs to treat atrial fibrillation has increased rapidly. Despite this, significant geographical variation in uptake remains. This study provides insights on how local policies relate to this variation. Our findings suggest that, in the absence of a nationally recommended first-line anticoagulant, local prescribing policies may aid in deciding between individual DOACs, but not in adjudicating between DOACs and vitamin K antagonists (i.e. warfarin) as general classes.

County-level geographic disparities in cardiovascular disease mortality among US breast cancer survivors, 2000-2018.

BACKGROUND: Disparities in cardiovascular disease mortality among breast cancer survivors are documented, but geographic factors by county-level socioeconomic status (SES) and rurality are not well described. METHODS: We analyzed 724 518 women diagnosed with localized or regional stage breast cancer between 2000 and 2017 within Surveillance, Epidemiology, and End Results Program-18 with follow-up until 2018. We calculated relative risks (RRs) of cardiovascular disease mortality using Poisson regression, accounting for age- and race-specific rates in the general population, according to county-level quintiles of SES (measured by Yost index), median income, and rurality at breast cancer diagnosis. We also calculated 10-year cumulative mortality risk of cardiovascular disease accounting for competing risks. RESULTS: Cardiovascular disease mortality was 41% higher among breast cancer survivors living in the lowest SES (RR = 1.41, 95% confidence interval [CI] = 1.36 to 1.46, Ptrend < .001) and poorest (RR = 1.41, 95% CI = 1.36 to 1.47, Ptrend < .001) counties compared with the highest SES and wealthiest counties, and 24% higher for most rural relative to most urban counties (RR = 1.24, 95% CI = 1.17 to 1.30, Ptrend < .001). Disparities for the lowest SES relative to highest SES counties were greatest among younger women aged 18-49 years (RR = 2.32, 95% CI = 1.90 to 2.83) and aged 50-59 years (RR = 2.01, 95% CI = 1.77 to 2.28) and within the first 5 years of breast cancer diagnosis (RR = 1.53, 95% CI = 1.44 to 1.64). In absolute terms, however, disparities were widest for women aged 60+ years, with approximately 2% higher 10-year cumulative cardiovascular disease mortality risk in the poorest compared with wealthiest counties. CONCLUSIONS: Geographic factors at breast cancer diagnosis were associated with increased cardiovascular disease mortality risk. Studies with individual- and county-level information are needed to inform public health interventions and reduce disparities among breast cancer survivors.

Racial and ethnic disparities in treatment-related heart disease mortality among US breast cancer survivors.

BACKGROUND: Racial and ethnic disparities in heart disease mortality by initial treatment type among breast cancer survivors have not been well described. METHODS: We included 739 557 women diagnosed with first primary invasive breast cancer between 2000 and 2017 (aged 18-84 years, received surgery, survived ≥1 year, followed through 2018) in the Surveillance, Epidemiology, and End Results-18 database. Standardized mortality ratios (SMRs; observed over expected) were calculated by race and ethnicity (non-Hispanic/Latina Asian American, Native Hawaiians, and other Pacific Islanders [AANHPI]; non-Hispanic/Latina Black [Black]; Hispanic/Latina [Latina]; and non-Hispanic/Latina White [White]) and initial treatment (surgery only; chemotherapy with surgery; chemotherapy, radiotherapy, with surgery; and radiotherapy with surgery) compared with the racial- and ethnic-matched general population, and by clinical characteristics. Cumulative heart disease mortality was estimated accounting for competing risks. RESULTS: SMRs were elevated for Black and Latina women treated with surgery only and chemotherapy with surgery (SMR range = 1.15-1.21) and AANHPI women treated with chemotherapy, radiotherapy, with surgery (SMR = 1.29; 95% confidence interval [CI] = 1.11 to 1.48), whereas SMRs were less than 1 for White women (SMR range = 0.70-0.96). SMRs were especially high for women with advanced (regional or distant) stage among Black women for all treatment (range = 1.15-2.89) and for AANHPI and Latina women treated with chemotherapy with surgery (range = 1.28-3.61). Non-White women diagnosed at younger than age 60 years had higher SMRs, as did Black and AANHPI women diagnosed with estrogen receptor-positive breast cancers. Black women had the highest 10-year cumulative risk of heart disease mortality: aged younger than 60 years (Black: 1.78%, 95% CI = 1.63% to 1.94%) compared with White, AANHPI, and Latina women (<1%) and aged 60 years and older (Black: 7.92%, 95% CI = 7.53% to 8.33%) compared with White, AANHPI, and Latina women (range = 3.90%-6.48%). CONCLUSIONS: Our findings illuminated striking racial and ethnic disparities in heart disease mortality among Black, AANHPI, and Latina breast cancer survivors, especially after initial chemotherapy receipt.

Operative Time and 30-Day Outcomes in Bariatric Surgery: Comparison between Robotic and Laparoscopic Approach: 4-Year MBSAQIP Database Analysis.

BACKGROUND: The main criticism of robotic surgery is longer operative time (OT). The aim of this study was to examine the variables that determine OT, the association between OT and 30-day outcomes, and the effect of the robotic approach in bariatric surgery. STUDY DESIGN: MBSAQIP data for 2016 to 2019 were queried. Logistic regression was performed to examine the association between OT and outcomes for each surgical approach while adjusting for patients' characteristics. The results of each fitted logistic regression model were reported as odds ratio and the associated 95% CI. RESULTS: A total of 666,182 patients underwent robotic sleeve gastrectomy (R-SG), laparoscopic sleeve gastrectomy, robotic Roux-en-Y gastric bypass (R-RYGB), laparoscopic Roux-en-Y gastric bypass, robotic duodenal switch (R-DS), and laparoscopic duodenal switch). More patients underwent laparoscopic surgery (89.7%) than robotic surgery (10.3%). OT for robotic cases was longer than for laparoscopic cases (p < 0.0001). Longer OT was associated with increased odds of adverse 30-day outcomes irrespective of the surgical approach. The association between OT and adverse outcomes was stronger in the laparoscopic cohort. There was no significant difference in postoperative outcomes when comparing the laparoscopic and robotic approaches after adjusting for OT, except a lower reoperation rate for R-SG (p = 0.03) and readmission rates in R-RYGB and R-DS (p < 0.01). The variability of OT was higher in the laparoscopic group and was more affected by the first assistant. CONCLUSIONS: The outcomes in robotic bariatric surgery were comparable with the laparoscopic approach despite longer OT. Use of robotic surgery decreased the variability in OT.

Identification of Distinct Inflammatory Programs and Biomarkers in Systemic Juvenile Idiopathic Arthritis and Related Lung Disease by Serum Proteome Analysis.

OBJECTIVE: Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high-mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA-LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA-LD. METHODS: We used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA-LD, or other related diseases. We verified selected findings by enzyme-linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA-LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort. RESULTS: Proteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat-shock proteins and glycolytic enzymes. Interleukin-18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA-LD. We also identified an MAS-independent SJIA-LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM-5), matrix metalloproteinase 7 (MMP-7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM-5 and MMP-7 in the lungs of patients with SJIA-LD. The ability of ICAM-5 to distinguish SJIA-LD from systemic JIA/MAS was independently validated. CONCLUSION: Serum proteins support a systemic JIA-to-MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA-LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM-5, could aid in early detection and management of SJIA-LD.

Insurer-Provider Networks in the Medical Care Market.

I use data on the hospital networks offered by managed care health insurers to estimate the expected division of profits between insurers and providers. I include a simple profit-maximization framework and an additional effect: hospitals that can secure demand without contracting with all insurers (e.g., those most attractive to consumers and those that are capacity constrained) may demand high prices that some insurers refuse to pay. Hospital mergers may also affect price bargaining. I estimate that all three types of hospitals capture higher markups than other providers. These results provide information on the hospital investment incentives generated by bargaining.

Non-enzymatic primer extension with strand displacement.

Non-enzymatic RNA self-replication is integral to the emergence of the 'RNA World'. Despite considerable progress in non-enzymatic template copying, demonstrating a full replication cycle remains challenging due to the difficulty of separating the strands of the product duplex. Here, we report a prebiotically plausible approach to strand displacement synthesis in which short 'invader' oligonucleotides unwind an RNA duplex through a toehold/branch migration mechanism, allowing non-enzymatic primer extension on a template that was previously occupied by its complementary strand. Kinetic studies of single-step reactions suggest that following invader binding, branch migration results in a 2:3 partition of the template between open and closed states. Finally, we demonstrate continued primer extension with strand displacement by employing activated 3'-aminonucleotides, a more reactive proxy for ribonucleotides. Our study suggests that complete cycles of non-enzymatic replication of the primordial genetic material may have been facilitated by short RNA oligonucleotides.