Soccer and Vocational Training are Ineffective Delivery Strategies to Prevent HIV and Substance Abuse by Young, South African Men: A Cluster Randomized Controlled Trial.

HIV and substance abuse are common among young men, associated with a cluster of risk behaviors. Yet, most services addressing these challenges are delivered in setting underutilized by men and are often inconsistent with male identity. This cluster randomized controlled trial aimed to reduce multiple risk behaviors found among young men township areas on the outskirts of Cape Town, South Africa. Young men aged 18-29 years (N = 1193) across 27 neighborhoods were randomized by area to receive HIV-related skills training during either: (1) a 12-month soccer league (SL) intervention; (2) 6-month SL followed by 6 months of vocational training (VT) intervention (SL/VT, n = 9); or 3) a control condition (CC). Bayesian longitudinal mixture models were used to evaluate behaviors over time. Because we targeted multiple outcomes as our primary outcome, we analyzed if the number of significantly different outcomes between conditions exceeded chance for 13 measures over 18 months (with 83%, 76%, and 61% follow-up). Only if there were three significant benefits favoring the SL/VT over the SL would benefits be significant. Outcome measures included substance use, HIV-testing, protective sexual behaviors, violence, community engagement and mental health. Consistent participation in the SL was typically around 45% over time across conditions, however, only 17% of men completed SL/VT. There were no significant differences between conditions over time based on the number of study outcomes. These structural interventions were ineffective in addressing young men's substance abuse and risk for HIV.Clinical Trial Registration: This trial was prospectively registered on 24 November 2014 with ClinicalTrials.gov (NCT02358226).

Ten-year trends, disparities, and clinical impact of stroke thrombectomy and thrombolysis: A single center experience 2012-2021.

OBJECTIVES: As indications for acute ischemic stroke treatment expand, it is unclear whether disparities in treatment utilization and outcome still exist. The main objective of this study was to investigate disparities in acute ischemic stroke treatment and determine impact on outcome. MATERIALS AND METHODS: Retrospective observational cohort study of consecutive ischemic stroke admissions to a comprehensive stroke center from 2012-2021 was performed. Primary exposure was intravenous thrombolysis and/or endovascular thrombectomy. Primary end points were discharge modified Rankin Scale, home disposition, and expired/hospice. Multivariable logistic regression analyses were conducted to elucidate disparities in treatment utilization and determine impact on outcome. RESULTS: Of 517,615 inpatient visits, there were 7,540 (1.46 %) ischemic stroke admissions, increasing from 1.14 % to 1.79 % from 2012-2021. Intravenous thrombolysis significantly decreased from 14.4 % to 9.8 % while endovascular thrombectomy significantly increased from 0.8 % to 10.5 %. Both intravenous thrombolysis and endovascular thrombectomy increased odds of discharge home and modified Rankin Scale 0-2, and thrombectomy decreased odds of expired/hospice. After adjusting for covariates, decreased odds of thrombectomy was associated with Medicaid insurance (Odds Ratio [95 % Confidence Interval] 0.55 [0.32-0.93]), age 80+ (0.49 [0.35-0.69]), prior stroke (0.49 [0.31-0.77]), and diabetes mellitus (0.55 [0.39-0.79]), while low median household income (<$80,000/year) increased odds of no acute treatment (1.34 [1.16-1.56]). No sex or racial disparities were observed. Medicaid and low-income were not associated with worse clinical outcomes. CONCLUSIONS: Less endovascular thrombectomy occurred in Medicaid, older, prior stroke, and diabetic patients, while low-income was associated with no treatment. The observed socioeconomic disparities did not impact discharge outcome.

An enantioselective and modular platform for C4'-modified nucleoside analogue synthesis enabled by intramolecular trans-acetalizations.

C4'-modified nucleoside analogues continue to attract global attention for their use in antiviral drug development and oligonucleotide-based therapeutics. However, current approaches to C4'-modified nucleoside analogues still involve lengthy (9-16 steps), non-modular routes that are unamenable to library synthesis. Towards addressing the challenges associated with their syntheses, we report a modular 5-step process to a diverse collection of C4'-modified nucleoside analogues through a sequence of intramolecular trans-acetalizations of readily assembled polyhydroxylated frameworks. Overall, the 2-3 fold reduction in step-count compares favorably to even recently reported biocatalytic approaches and should ultimately enable new opportunities in drug design around this popular chemotype.

Mitochondria in Retinal Ganglion Cells: Unraveling the Metabolic Nexus and Oxidative Stress.

This review explored the role of mitochondria in retinal ganglion cells (RGCs), which are essential for visual processing. Mitochondrial dysfunction is a key factor in the pathogenesis of various vision-related disorders, including glaucoma, hereditary optic neuropathy, and age-related macular degeneration. This review highlighted the critical role of mitochondria in RGCs, which provide metabolic support, regulate cellular health, and respond to cellular stress while also producing reactive oxygen species (ROS) that can damage cellular components. Maintaining mitochondrial function is essential for meeting RGCs' high metabolic demands and ensuring redox homeostasis, which is crucial for their proper function and visual health. Oxidative stress, exacerbated by factors like elevated intraocular pressure and environmental factors, contributes to diseases such as glaucoma and age-related vision loss by triggering cellular damage pathways. Strategies targeting mitochondrial function or bolstering antioxidant defenses include mitochondrial-based therapies, gene therapies, and mitochondrial transplantation. These advances can offer potential strategies for addressing mitochondrial dysfunction in the retina, with implications that extend beyond ocular diseases.

Diagnostic Accuracy of Cone-Beam CT for Acute Intracranial Hemorrhage: A Systematic Review and Meta-Analysis.

OBJECTIVE: Our purpose was to synthesize evidence in the literature to determine the diagnostic accuracy of cone-beam CT (CBCT) for the detection of intracranial hemorrhage (ICH) and hemorrhage types, including intraparenchymal hemorrhage (IPH), subarachnoid hemorrhage (SAH), and intraventricular hemorrhage (IVH). METHODS: We performed a meta-analysis following the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Our protocol was registered with International Prospective Register of Systematic Reviews (PROSPERO-CRD42021261915). Systematic searches were last performed on April 30, 2024, in EMBASE, PubMed, Web-of-Science, Scopus, and Cumulative Index to Nursing and Allied Health Literature databases. Inclusion criteria were (1) studies reporting diagnostic metrics of CBCT for ICH and (2) studies using a reference standard to determine ICH. Exclusion criteria were (1) case reports, abstracts, reviews and (2) studies without patient-level data. Pooled estimates and 95% confidence intervals (CIs) were calculated for diagnostic odds ratios (DORs), sensitivity, and specificity using random-effects and common-effects models. Mixed methods appraisal tool was used to evaluate risk of bias. RESULTS: Seven studies were included in the meta-analysis yielding 466 patients. Mean or median age ranged from 54 to 75 years. Female patients represented 51.4% (222 of 432) in reported studies. Multidetector CT was the reference standard in all studies. DOR, pooled sensitivity, and pooled specificity for ICH were 5.28 (95% CI: 4.11-6.46), 0.88 (95% CI: 0.79-0.97), and 0.99 (95% CI: 0.98-1.0). Pooled sensitivity for IPH, SAH, and IVH was 0.98 (95% CI: 0.95-1.0), 0.82 (95% CI: 0.57-1.0), and 0.78 (95% CI: 0.55-1.0). Pooled specificity for IPH, SAH, and IVH was 0.99 (95% CI: 0.98-1.0), 0.99 (95% CI: 0.97-1.0), and 1.0 (95% CI: 0.98-1.0). DISCUSSION: CBCT had moderate DOR and high pooled specificity for ICH and hemorrhage types. However, pooled sensitivity varied by hemorrhage type, with the highest sensitivity for IPH, followed by SAH and IVH.

Prompt engineering with a large language model to assist providers in responding to patient inquiries: a real-time implementation in the electronic health record.

Background: Large language models (LLMs) can assist providers in drafting responses to patient inquiries. We examined a prompt engineering strategy to draft responses for providers in the electronic health record. The aim was to evaluate the change in usability after prompt engineering. Materials and Methods: A pre-post study over 8 months was conducted across 27 providers. The primary outcome was the provider use of LLM-generated messages from Generative Pre-Trained Transformer 4 (GPT-4) in a mixed-effects model, and the secondary outcome was provider sentiment analysis. Results: Of the 7605 messages generated, 17.5% (n = 1327) were used. There was a reduction in negative sentiment with an odds ratio of 0.43 (95% CI, 0.36-0.52), but message use decreased (P < .01). The addition of nurses after the study period led to an increase in message use to 35.8% (P < .01). Discussion: The improvement in sentiment with prompt engineering suggests better content quality, but the initial decrease in usage highlights the need for integration with human factors design. Conclusion: Future studies should explore strategies for optimizing the integration of LLMs into the provider workflow to maximize both usability and effectiveness.

Exploring Health Inequalities and Presurgical Attitudes on Postsurgical Outcomes in Spine Surgery.

OBJECTIVE: The influence of social determinants of health on health disparities is substantial. However, their impact on postsurgical outcomes in spine can be challenging to ascertain at the community level. This study aims to explore the interplay between presurgical attitudes, area deprivation index (ADI), income, employment status, and body mass index (BMI) on postsurgical outcomes at 3, 6, 9, and 12 months after elective spine surgery. METHODS: The study involved 127 patients who underwent elective spine surgery between August 2021 and August 2022 at a large academic institution. The main objective involved a prospective analysis of presurgical attitudes, coupled with a retrospective assessment of ADI, income, employment status, and BMI over 3, 6, 9, and 12 months following elective spine surgery using a univariate analysis. RESULTS: Utilizing the univariate analyses, ADI displayed a significant correlation with increased Patient-Reported Outcomes Measurement Information System and Visual Analog Scale scores both before surgery and at the 3-, 6-, and 9-month postsurgical intervals (P < 0.05). One year after surgery, patients in the lowest income group (annual income under $25,000) consistently demonstrated the highest Patient-Reported Outcomes Measurement Information System pain (8.00, P = 0.022). Patients who were not employed had significantly lower levels of social support (P = 0.042) and confidence in the health care system (P = 0.009). Individuals who were unemployed were most likely to be readmitted six weeks after surgery (P < 0.001). CONCLUSIONS: Presurgical attitudes, ADI, income, employment status, and BMI were important factors associated with improved surgical outcome measurements, indicating potential focal points for combating health disparities in spinal surgery patients.

Association between Heat Vulnerability Index and Stroke Severity.

BACKGROUND: Socioeconomically disadvantaged neighborhoods are particularly vulnerable to heat-related illnesses. We aim to investigate the association between the heat vulnerability index (HVI), an established neighborhood-level metric of heat-related mortality risk, and acute ischemic stroke (AIS) severity. METHODS: We conducted a retrospective analysis of consecutive AIS admissions to a comprehensive stroke center between 2012 and 2021. Stroke severity was defined upon admission based on the National Institutes of Health Stroke Scale (NIHSS). Demographic, socioeconomic, and clinical characteristics were extracted from electronic health records. HVI status was assigned using residential ZIP codes. Multivariable logistic regression analyses were performed. RESULTS: Of 3429 AIS admissions, 1123 (32.8%) were from high-HVI (scores 4-5) neighborhoods and 868 (25.3%) had severe stroke (NIHSS score ≥ 10). In the multivariable regression model with stepwise selection, a high HVI was independently associated with severe stroke (adjusted odds ratio: 1.40 [95% confidence interval 1.16-1.69]). CONCLUSIONS: The association between a high HVI and severe stroke underscores the importance of targeting policy interventions to mitigate heat-related illness in socioeconomically disadvantaged neighborhoods.

Inspiring a convergent engineering approach to measure and model the tissue microenvironment.

Understanding the molecular and physical complexity of the tissue microenvironment (TiME) in the context of its spatiotemporal organization has remained an enduring challenge. Recent advances in engineering and data science are now promising the ability to study the structure, functions, and dynamics of the TiME in unprecedented detail; however, many advances still occur in silos that rarely integrate information to study the TiME in its full detail. This review provides an integrative overview of the engineering principles underlying chemical, optical, electrical, mechanical, and computational science to probe, sense, model, and fabricate the TiME. In individual sections, we first summarize the underlying principles, capabilities, and scope of emerging technologies, the breakthrough discoveries enabled by each technology and recent, promising innovations. We provide perspectives on the potential of these advances in answering critical questions about the TiME and its role in various disease and developmental processes. Finally, we present an integrative view that appreciates the major scientific and educational aspects in the study of the TiME.

Neurologic Quality of Life Outcomes in Patients with Normal Pressure Hydrocephalus After Ventriculoperitoneal Shunt Placement: A Prospective Assessment of Cognition, Mobility, and Social Participation.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) typically presents with gait disturbances, cognitive decline, and urinary incontinence. Symptomatic improvement generally occurs following shunt placement, but limited evidence exists on the quality of life (QOL) metrics in iNPH. Therefore, we conducted a prospective study of the effect of shunt placement on QOL in iNPH patients, using Quality of Life in Neurologic Disorders (Neuro-QOL) metrics. METHODS: Eligible patients underwent shunt placement after evidence of symptomatic improvement following temporary cerebrospinal fluid diversion via inpatient lumbar drain trial. Patients were administered short- and long-form Neuro-QOL assessments prior to shunt placement and at 6-month and 1-year postoperative timepoints to evaluate lower extremity mobility, cognitive function, and social roles and activities participation. Changes in QOL measures were analyzed using a repeated-measures linear mixed effects model. RESULTS: There were 48 patients with a mean age of 75.4 ± 6.3 years. Average short-form mobility scores improved by 3.9 points (14.6%) at 6-month follow-up and by 6.2 points (23.2%) at 1-year follow-up compared with preoperative baseline (P = 0.027 and P = 0.0002, respectively). Short-form cognition scores increased by 5.2 points (22.4%) at 6 months and 10.9 points (47.0%) at 1 year postoperatively (P = 0.007 and P < 0.0001, respectively). On long-form assessment, social roles and activity participation scores improved by 29.3 points (23.4%) at 6 months and 31.6 points (25.2%) at 1 year after surgery compared to baseline (P = 0.028 and P = 0.02, respectively). CONCLUSIONS: Our findings demonstrate that shunt placement leads to improved QOL in iNPH patients across multiple domains. Significant improvements in mobility, cognition, and social roles and activity participation are realized within the first 6 months and are sustained on 1-year follow-up.

Analysis of Arc/Arg3.1 Oligomerization In Vitro and in Living Cells.

Arc (also known as Arg3.1) is an activity-dependent immediate early gene product enriched in neuronal dendrites. Arc plays essential roles in long-term potentiation, long-term depression, and synaptic scaling. Although its mechanisms of action in these forms of synaptic plasticity are not completely well established, the activities of Arc include the remodeling of the actin cytoskeleton, the facilitation of AMPA receptor (AMPAR) endocytosis, and the regulation of the transcription of AMPAR subunits. In addition, Arc has sequence and structural similarity to retroviral Gag proteins and self-associates into virus-like particles that encapsulate mRNA and perhaps other cargo for intercellular transport. Each of these activities is likely to be influenced by Arc's reversible self-association into multiple oligomeric species. Here, we used mass photometry to show that Arc exists predominantly as monomers, dimers, and trimers at approximately 20 nM concentration in vitro. Fluorescence fluctuation spectroscopy revealed that Arc is almost exclusively present as low-order (monomer to tetramer) oligomers in the cytoplasm of living cells, over a 200 nM to 5 µM concentration range. We also confirmed that an α-helical segment in the N-terminal domain contains essential determinants of Arc's self-association.

Global Health Initiatives: International Physician-to-Physician Consultation Programs.

PURPOSE: The goal of this article is to provide technical and operational blueprints for two successful global telehealth programs. METHODS: The authors designed a physician-to-physician consultation program to provide subspecialty expertise to physicians in war-torn Ukraine. Leveraging secure web applications, telehealth platforms, and image-sharing platforms, the authors repeatedly iterated upon infrastructure and workflows, which in turn facilitated the development of a parallel international program for US Department of State (DOS) employees and families. The authors provide descriptive statistics and metrics of both programs' successes and failures and detail iterative improvements with workflow visuals. To measure the added value of subspecialty imaging consultation, two radiologists performed a retrospective comparative review of the DOS program imaging reports, comparing the initial report to the consult report in consensus, measuring diagnostic report agreement, and rating the clinical impact of identified discrepancies on a three-point scale (mild, moderate, or major). Bivariate analyses using χ2 tests were conducted to assess associations between diagnostic discrepancies and patient or imaging factors. P values <.05 were considered to indicate statistical significance. RESULTS: The Ukraine program (May 2022 to August 2023) provided 114 patient consultations with 77 subspecialty radiology consults, >50 WhatsApp chats, and >1,000 messages exchanged, with a 92% overall consult request response rate. The DOS program (November 2022 to July 2023) provided 275 consultations with 70 subspecialty radiology consults and a 36% to 38% rate of alternative diagnoses, with 20% rated as incurring moderate or major clinical impact. Bivariate analyses demonstrated no significant patient or imaging association with diagnostic disagreements (P > .05 for all). CONCLUSIONS: Global telehealth infrastructure and multiple applications and platforms can be optimized in a workflow to provide efficient, high-level clinical and imaging consultation services across the globe.

Differential Interactions of the Proteasome Inhibitor PI31 with Constitutive and Immuno-20S Proteasomes.

PI31 (Proteasome Inhibitor of 31,000 Da) is a 20S proteasome binding protein originally identified as an in vitro inhibitor of 20S proteasome proteolytic activity. Recently reported cryo-electron microscopy structures of 20S-PI31 complexes have revealed that the natively disordered proline-rich C-terminus of PI31 enters the central chamber in the interior of the 20S proteasome and interacts directly with the proteasome's multiple catalytic threonine residues in a manner predicted to inhibit their enzymatic function while evading its own proteolysis. Higher eukaryotes express an alternative form of the 20S proteasome (termed "immuno-proteasome") that features genetically and functionally distinct catalytic subunits. The effect of PI31 on immuno-proteasome function is unknown. We examine the relative inhibitory effects of PI31 on purified constitutive (20Sc) and immuno-(20Si) 20S proteasomes in vitro and show that PI31 inhibits 20Si hydrolytic activity to a significantly lesser degree than that of 20Sc. Unlike 20Sc, 20Si hydrolyzes the carboxyl-terminus of PI31 and this effect contributes to the reduced inhibitory activity of PI31 toward 20Si. Conversely, loss of 20Sc inhibition by PI31 point mutants leads to PI31 degradation by 20Sc. These results demonstrate unexpected differential interactions of PI31 with 20Sc and 20Si and document their functional consequences.

Efficacy and Safety of Systemic Corticosteroids for Urticaria: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Short courses of adjunctive systemic corticosteroids are commonly used to treat acute urticaria and chronic urticaria flares (both with and without mast cell-mediated angioedema), but their benefits and harms are unclear. OBJECTIVE: To evaluate the efficacy and safety of treating acute urticaria or chronic urticaria flares with versus without systemic corticosteroids. METHODS: We searched the MEDLINE, EMBASE, CENTRAL, CNKI, VIP, Wanfang, and CBM databases from inception to July 8, 2023, for randomized controlled trials of treating urticaria with versus without systemic corticosteroids. Paired reviewers independently screened records, extracted data, and appraised risk of bias with the Cochrane 2.0 tool. We performed random-effects meta-analyses of urticaria activity, itch severity, and adverse events. We assessed certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach. RESULTS: We identified 12 randomized trials enrolling 944 patients. For patients with low or moderate probability (17.5%-64%) to improve with antihistamines alone, add-on systemic corticosteroids likely improve urticaria activity by a 14% to 15% absolute difference (odds ratio [OR], 2.17, 95% confidence interval [CI]: 1.43-3.31; number needed to treat [NNT], 7; moderate certainty). Among patients with a high chance (95.8%) for urticaria to improve with antihistamines alone, add-on systemic corticosteroids likely improved urticaria activity by a 2.2% absolute difference (NNT, 45; moderate certainty). Corticosteroids may improve itch severity (OR, 2.44; 95% CI: 0.87-6.83; risk difference, 9%; NNT, 11; low certainty). Systemic corticosteroids also likely increase adverse events (OR, 2.76; 95% CI: 1.00-7.62; risk difference, 15%; number needed to harm, 9; moderate certainty). CONCLUSIONS: Systemic corticosteroids for acute urticaria or chronic urticaria exacerbations likely improve urticaria, depending on antihistamine responsiveness, but also likely increase adverse effects in approximately 15% more.

Cosmetic injectables in skin of color: A review of uses, safety, and effectiveness of neuromodulators and dermal fillers.

BACKGROUND: Skin of color (SOC) individuals represent a growing market for cosmetic injectables and can have different aesthetic goals and responses to treatment. OBJECTIVE: A review of the uses, safety, and effectiveness of injectable neuromodulators and dermal fillers in SOC individuals. METHODS AND MATERIALS: A search of the PubMed/MEDLINE database was conducted from August 1960 to December 2020. Studies that were included either had a focus on SOC (>20% SOC study participants) or dedicated article content commenting on the safety and/or efficacy of injectables in SOC participants. RESULTS: Of the 503 publications identified, a total of 88 articles were selected for this review. Differences in aging and cultural factors can influence aesthetic goals amongst SOC populations. Available data suggests that botulinum toxin (BTX) and dermal fillers are safe and effective in SOC populations, with the largest amount of data existing for Asian populations. There remains a paucity of research on Black and Latinx populations. CONCLUSION: BTX and dermal fillers are generally effective and well tolerated in SOC populations, particularly Asian populations for which the greatest amount of data exists. More high quality, randomized controlled trials in Black and Latinx populations are warranted.

Autophagy inhibition suppresses hormone production and cell growth in pituitary tumor cells: A potential approach to pituitary tumors.

Pituitary tumors (PTs) represent about 10% of all intracranial tumors, and most are benign. However, some PTs exhibit continued growth despite multimodal therapies. Although temozolomide (TMZ), an alkylating chemotherapeutic agent, is a first-line medical treatment for aggressive PTs, some PTs are resistant to TMZ. Existing literature indicated the involvement of autophagy in cell growth in several types of tumors, including PTs, and autophagy inhibitors have anti-tumor effects. In this study, the expression of several autophagy-inducible genes, including Atg3, Beclin1, Map1lc3A, Map1lc3b, Ulk1, Wipi2, and Tfe3 in two PT cell lines, the mouse corticotroph AtT-20 cells and the rat mammosomatotroph GH4 cells were identified. Down regulation of Tfe3, a master switch of basal autophagy, using RNA interference, suppressed cell proliferation in AtT-20 cells, suggesting basal autophagy contributes to the maintenance of cellular functions in PT cells. Expectedly, treatment with bafilomycin A1, an autophagy inhibitor, suppressed cell proliferation, increased the cleavage of PARP1, and reduced ACTH production in AtT-20 cells. Treatment with two additional autophagy inhibitors, chloroquine (CQ) and monensin, demonstrated similar effects on cell proliferation, apoptosis, and ACTH production in AtT-20 cells. Also, treatment with CQ suppressed cell proliferation and growth hormone production in GH4 cells. Moreover, the combination of CQ and TMZ had an additive effect on the inhibition of cell proliferation in AtT-20 and GH4 cells. The additive effect of anti-cancer drugs such as CQ alone or in combination with TMZ may represent a novel therapeutic approach for PTs, in particular tumors with resistance to TMZ.

Patterns of Access to Radiology Reports and Images Through a Patient Portal.

Access to radiology reports and images through a patient portal offers several advantages. The purpose of this study was to characterize patient's interactions with their radiology results. This was a retrospective study that evaluated radiography, ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography, exams performed between July 2020 and June 2021 for patients aged 12 and older. Exam information, access logs of radiology reports and images, and patient demographics were obtained from the electronic health record and image viewing software. Descriptive statistics were computed. The study included 1,685,239 exams. A total of 54.1% of reports were viewed. MRI and PET reports were viewed with the greatest frequency (70.2% and 67.6%, respectively); 25.5% of exam images were viewed, with the greatest frequency for MRI (40.1%). Exams were shared a total of 17,095 times and downloaded 8409 times; 64% of reports were viewed for patients aged 18-39 and 34% for patients aged 80 and greater. The rate of reports viewed was greater for patients with English as their preferred language (57.1%) compared to other languages (33.3%). Among those viewed, 56.5% of reports and 48.2% of images were viewed multiple times; 72.8% of images were viewed on smartphones, 25.8% on desktop computers, and 1.4% on tablets. Patients utilize a portal to view reports and view and share images. Continued efforts are warranted to promote the use of portals and create patient-friendly imaging results to help empower patients.

Identifying general reaction conditions by bandit optimization.

Reaction conditions that are generally applicable to a wide variety of substrates are highly desired, especially in the pharmaceutical and chemical industries1-6. Although many approaches are available to evaluate the general applicability of developed conditions, a universal approach to efficiently discover these conditions during optimizations is rare. Here we report the design, implementation and application of reinforcement learning bandit optimization models7-10 to identify generally applicable conditions by efficient condition sampling and evaluation of experimental feedback. Performance benchmarking on existing datasets statistically showed high accuracies for identifying general conditions, with up to 31% improvement over baselines that mimic state-of-the-art optimization approaches. A palladium-catalysed imidazole C-H arylation reaction, an aniline amide coupling reaction and a phenol alkylation reaction were investigated experimentally to evaluate use cases and functionalities of the bandit optimization model in practice. In all three cases, the reaction conditions that were most generally applicable yet not well studied for the respective reaction were identified after surveying less than 15% of the expert-designed reaction space.

Maternal and Fetal Radiation-Induced Cancer Risk From Computed Tomography Pulmonary Angiography During Pregnancy: A Retrospective Cohort Study Across a Multihospital Integrated Health Care Network.

OBJECTIVE: Computed tomography pulmonary angiogram (CTPA) is important to evaluate suspected pulmonary embolism in pregnancy but has maternal/fetal radiation risks. The objective of this study was to estimate maternal and fetal radiation-induced cancer risk from CTPA during pregnancy. METHODS: Simulation modeling via the National Cancer Institute's Radiation Risk Assessment Tool was used to estimate excess cancer risks from 17 organ doses from CTPA during pregnancy, with doses determined by a radiation dose indexing monitoring system. Organ doses were obtained from a radiation dose indexing monitoring system. Maternal and fetal cancer risks per 100,000 were calculated for male and female fetuses and several maternal ages. RESULTS: The 534 CTPA examinations had top 3 maternal organ doses to the breast, lung, and stomach of 17.34, 15.53, and 9.43 mSv, respectively, with a mean uterine dose of 0.21 mSv. The total maternal excess risks of developing cancer per 100,000 were 181, 151, 121, 107, 94.5, 84, and 74.4, respectively, for a 20-, 25-, 30-, 35-, 40-, 45-, and 50-year-old woman undergoing CTPA, compared with baseline cancer risks of 41,408 for 20-year-old patients. The total fetal excess risks of developing cancer per 100,000 were 12.3 and 7.3 for female and male fetuses, respectively, when compared with baseline cancer risks of 41,227 and 48,291. DISCUSSION: Excess risk of developing cancer from CTPA was small relative to baseline cancer risk for pregnant patients and fetuses, decreased for pregnant patients with increasing maternal age, and was greater for female fetuses than male fetuses.

Mimicking Protein Kinase C Phosphorylation Inhibits Arc/Arg3.1 Palmitoylation and Its Interaction with Nucleic Acids.

Activity-regulated cytoskeleton-associated protein (Arc) plays essential roles in diverse forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity. In addition, it assembles into virus-like particles that may deliver mRNAs and/or other cargo between neurons and neighboring cells. Considering this broad range of activities, it is not surprising that Arc is subject to regulation by multiple types of post-translational modification, including phosphorylation, palmitoylation, SUMOylation, ubiquitylation, and acetylation. Here we explore the potential regulatory role of Arc phosphorylation by protein kinase C (PKC), which occurs on serines 84 and 90 within an α-helical segment in the N-terminal domain. To mimic the effect of PKC phosphorylation, we mutated the two serines to negatively charged glutamic acid. A consequence of introducing these phosphomimetic mutations is the almost complete inhibition of Arc palmitoylation, which occurs on nearby cysteines and contributes to synaptic weakening. The mutations also inhibit the binding of nucleic acids and destabilize high-order Arc oligomers. Thus, PKC phosphorylation of Arc may limit the full expression of LTD and may suppress the interneuronal transport of mRNAs.