Formation of Paraldehyde (C6H12O3) in Interstellar Analog Ices of Acetaldehyde Exposed to Ionizing Radiation.

Acetaldehyde (CH3CHO) plays a crucial role in the synthesis of prebiotic molecules such as amino acids, sugars, and sugar-related compounds, and in the progress of chain reaction polymerization in deep space. Here, we report the first formation of the cyclic acetaldehyde trimer - paraldehyde (C6H12O3) - in low-temperature interstellar analog ices exposed to energetic irradiation as proxies of galactic cosmic rays (GCRs). Utilizing vacuum ultraviolet photoionization reflectron time-of-flight mass spectrometry and isotopic substitution experiments, paraldehyde was identified in the gas phase during the temperature-programmed desorption of the irradiated acetaldehyde ices based on the calculated adiabatic ionization energies and isomer-specific dissociative fragmentation patterns upon photoionization. As acetaldehyde is ubiquitous throughout the interstellar medium and has been tentatively identified in interstellar ices, paraldehyde could have formed in acetaldehyde-containing ices in a cold molecular cloud and is an excellent candidate for gas-phase observation in star-forming regions via radio telescopes. The identification of paraldehyde in the gas phase from the processed acetaldehyde ices advances our understanding of how complex organic molecules can be synthesized through polymerization reactions in extraterrestrial ices exposed to GCRs.

Self-Resistance Gene-Guided Discovery of the Molecular Basis for Biosynthesis of the Fatty Acid Synthase Inhibitor Cerulenin.

Cerulenin (1) is the first reported natural fatty acid synthase inhibitor and has been intensively researched for its antifungal, anticancer and anti-obesity properties. However, the molecular basis for its biosynthesis has remained a mystery for six decades. Here, we have identified the polyketide biosynthetic gene cluster (cer) responsible for the biosynthesis of 1 from two Sarocladium species using a self-resistance gene mining approach, which we validated via heterologous reconstitution of cer cluster in an Aspergillus nidulans host. Expression of various combinations of cer genes uncovered key pathway intermediates, electrocyclisation products derived from PKS-encoded polyenoic acids, and a suite of 13 new analogues of 1. This enabled us to establish a biosynthetic pathway to 1 that starts with a C12 polyketide precursor with both E and Z double bonds and involves a complex series of epoxidations, double bond shifts, E/Z isomerisation and epoxide reduction. Using in vitro assays, we further validated the roles of amidotransferase CerD in amidation, and oxidase CerF and reductase CerE in the final two-electron oxidation and enone reduction steps towards 1. These findings expand our understanding of complex tailoring modifications in highly reducing PKS pathways and pave the way for the engineered biosynthesis of cerulenin analogues.

Comparing Deprivation vs Vulnerability Index Performance Using Medicare Beneficiary Surgical Outcomes.

Importance: Health care researchers, professionals, payers, and policymakers are increasingly relying on publicly available composite indices of area-level socioeconomic deprivation to address health equity. Implications of index selection, however, are not well understood. Objective: To compare the performance of 2 frequently used deprivation indices using policy-relevant outcomes among Medicare beneficiaries undergoing 3 common surgical procedures. Design, Setting, and Participants: This cross-sectional study examined outcomes among Medicare beneficiaries (65 to 99 years old) undergoing 1 of 3 common surgical procedures (hip replacement, knee replacement, or coronary artery bypass grafting) between 2016 and 2019. Index discriminative performance was compared for beneficiaries residing in tracts with high- and low-deprivation levels (deciles) according to each index. Analyses were conducted between December 2022 and August 2023. Main Outcomes and Measures: Tract-level deprivation was operationalized using 2020 releases of the area deprivation index (ADI) and the social vulnerability index (SVI). Binary outcomes were unplanned surgery, 30-day readmissions, and 30-day mortality. Multivariable logistic regression models, stratified by each index, accounted for beneficiary and hospital characteristics. Results: A total of 2 433 603 Medicare beneficiaries (mean [SD] age, 73.8 [6.1] years; 1 412 968 female beneficiaries [58.1%]; 24 165 Asian [1.0%], 158 582 Black [6.5%], and 2 182 052 White [89.7%]) were included in analyses. According to both indices, beneficiaries residing in high-deprivation tracts had significantly greater adjusted odds of all outcomes for all procedures when compared with beneficiaries living in low-deprivation tracts. However, compared to ADI, SVI resulted in higher adjusted odds ratios (adjusted odds ratios, 1.17-1.31 for SVI vs 1.09-1.23 for ADI), significantly larger outcome rate differences (outcome rate difference, 0.07%-5.17% for SVI vs outcome rate difference, 0.05%-2.44% for ADI; 95% CIs excluded 0), and greater effect sizes (Cohen d, 0.076-0.546 for SVI vs 0.044-0.304 for ADI) for beneficiaries residing in high- vs low-deprivation tracts. Conclusions and Relevance: In this cross-sectional study of Medicare beneficiaries, SVI had significantly better discriminative performance-stratifying surgical outcomes over a wider range-than ADI for identifying and distinguishing between high- and low-deprivation tracts, as indexed by outcomes for common surgical procedures. Index selection requires careful consideration of index differences, index performance, and contextual factors surrounding use, especially when informing resource allocation and health care payment adjustment models to address health equity.

A Drosophila computational brain model reveals sensorimotor processing.

The recent assembly of the adult Drosophila melanogaster central brain connectome, containing more than 125,000 neurons and 50 million synaptic connections, provides a template for examining sensory processing throughout the brain1,2. Here we create a leaky integrate-and-fire computational model of the entire Drosophila brain, on the basis of neural connectivity and neurotransmitter identity3, to study circuit properties of feeding and grooming behaviours. We show that activation of sugar-sensing or water-sensing gustatory neurons in the computational model accurately predicts neurons that respond to tastes and are required for feeding initiation4. In addition, using the model to activate neurons in the feeding region of the Drosophila brain predicts those that elicit motor neuron firing5-a testable hypothesis that we validate by optogenetic activation and behavioural studies. Activating different classes of gustatory neurons in the model makes accurate predictions of how several taste modalities interact, providing circuit-level insight into aversive and appetitive taste processing. Additionally, we applied this model to mechanosensory circuits and found that computational activation of mechanosensory neurons predicts activation of a small set of neurons comprising the antennal grooming circuit, and accurately describes the circuit response upon activation of different mechanosensory subtypes6-10. Our results demonstrate that modelling brain circuits using only synapse-level connectivity and predicted neurotransmitter identity generates experimentally testable hypotheses and can describe complete sensorimotor transformations.

Breaking the barriers: Methodology of implementation of a non-mydriatic ocular fundus camera in an emergency department.

Despite evidence that non-mydriatic fundus cameras are beneficial in non-ophthalmic settings, they are only available in a minority of hospitals in the US. The lag from research-based evidence to change in clinical practice highlights the complexities of implementation of new technology and practice. We describe the steps used to implement successfully a non-mydriatic ocular fundus camera combined with optical coherence tomography (OCT) in a general emergency department (ED) using Kotter's 8-Step Change Model. We prospectively collected the number of trained personnel in the ED, the number of imaging studies obtained each week during the first year following implementation, and we documented major achievements each month, as well as outcome measures, barriers to implementation and possible solutions. Between 12 and 42 patients were imaged per week, resulting in a total of 1274 patients imaged demonstrating sustained usage of non-mydriatic fundus camera/OCT in the ED one year after implementation. The implementation process was contingent upon multidisciplinary collaboration, extensive communication, coordinated training of staff, and continuous motivation. The future will likely include the use of artificial intelligence deep learning systems for automated interpretation of ocular imaging as an immediate diagnostic aid for ED or other non-eye care providers.

NetSci: A Library for High Performance Biomolecular Simulation Network Analysis Computation.

We present the NetSci program-an open-source scientific software package designed for estimating mutual information (MI) between data sets using GPU acceleration and a k-nearest-neighbor algorithm. This approach significantly enhances calculation speed, achieving improvements of several orders of magnitude over traditional CPU-based methods, with data set size limits dictated only by available hardware. To validate NetSci, we accurately compute MI for an analytically verifiable two-dimensional Gaussian distribution and replicate the generalized correlation (GC) analysis previously conducted on the B1 domain of protein G. We also apply NetSci to molecular dynamics simulations of the Sarcoendoplasmic Reticulum Calcium-ATPase (SERCA) pump, exploring the allosteric mechanisms and pathways influenced by ATP and 2'-deoxy-ATP (dATP) binding. Our analysis reveals distinct allosteric effects induced by ATP compared to dATP, with predicted information pathways from the bound nucleotide to the calcium-binding domain differing based on the nucleotide involved. NetSci proves to be a valuable tool for estimating MI and GC in various data sets and is particularly effective for analyzing intraprotein communication and information transfer.

LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR.

Lysosomes have crucial roles in regulating eukaryotic metabolism and cell growth by acting as signalling platforms to sense and respond to changes in nutrient and energy availability1. LYCHOS (GPR155) is a lysosomal transmembrane protein that functions as a cholesterol sensor, facilitating the cholesterol-dependent activation of the master protein kinase mechanistic target of rapamycin complex 1 (mTORC1)2. However, the structural basis of LYCHOS assembly and activity remains unclear. Here we determine several high-resolution cryo-electron microscopy structures of human LYCHOS, revealing a homodimeric transmembrane assembly of a transporter-like domain fused to a G-protein-coupled receptor (GPCR) domain. The class B2-like GPCR domain is captured in the apo state and packs against the surface of the transporter-like domain, providing an unusual example of a GPCR as a domain in a larger transmembrane assembly. Cholesterol sensing is mediated by a conserved cholesterol-binding motif, positioned between the GPCR and transporter domains. We reveal that the LYCHOS transporter-like domain is an orthologue of the plant PIN-FORMED (PIN) auxin transporter family, and has greater structural similarity to plant auxin transporters than to known human transporters. Activity assays support a model in which the LYCHOS transporter and GPCR domains coordinate to sense cholesterol and regulate mTORC1 activation.

Validation of a 3D-Printed Silicone-Based Laryngeal Model for Resident Education.

OBJECTIVE: We sought to validate a laryngeal simulation model and subsequently demonstrate its efficacy in improving surgical technique. STUDY DESIGN: Pre-post interventional study. SETTING: Otolaryngology Program at a Tertiary Care Center. METHODS: A low-cost, high-fidelity laryngeal model was created using a 3-dimensional-printed cast and multilayered silicone to mimic vocal fold lesions. Participants (attendings and trainees) were first given a series of tasks including mucosal vocal fold lesion resection and microflap excision of a submucosal lesion. Trainees were then provided with an instructional video from a laryngologist and asked to repeat the same tasks on the model. Performance data was then assessed using validated surveys and blinded expert reviewers. RESULTS: Eighteen participants completed the simulation. All subjects agreed that the "simulation experience was useful" and 93% agreed "the simulator helped improve my ability to do microsurgical tasks." In the postinstruction self-evaluation, trainees reported a significant decrease in mental demand (95% confidence interval [CI]: 0.37-0.91; P = .038) and significant increase in subjective performance (95% CI: 1.51-51.89; P = .016) compared to the preinstruction self-evaluation. On the postinstruction attempt, there was a significant improvement in all domains of the adapted objective structured assessment of technical skills as measured by 3 blinded, expert reviewers. DISCUSSION: This study demonstrates the usefulness of a silicone larynx model and the value of instructional video in developing laryngeal microsurgical skills. Participants positively reviewed the laryngeal model and trainees saw both a subjective and objective improvement indicating tangible operative benefits from the use of this laryngeal simulation.

Telestroke Training: Considerations for Expansion of Vascular Neurology Program Requirements.

Telemedicine for stroke (Telestroke) has been a key component to efficient, widespread acute stroke care for many years. The expansion of reimbursement through the Furthering Access to Stroke Telemedicine Act and rapid deployment of telemedicine resources during the COVID-19 public health emergency have further expanded remote care, with practitioners of varying educational backgrounds, and experience providing acute stroke care via telemedicine (Telestroke). Some Telestroke practitioners have not had fellowship-level vascular neurology training and many are without training specific to virtual modalities. While many vascular neurology fellowship programs incorporate Telestroke training into the curriculum, components of this curriculum are not consistent, extent of involvement is variable, and not all fellows receive hands-on training in remote care. Furthermore, the extent of training and evaluation of Telestroke in American Board of Psychiatry and Neurology training requirements and Accreditation Council for Graduate Medical Education assessments for vascular neurology fellowship are not standardized. We suggest that Telestroke be formally incorporated into vascular neurology fellowship curricula and provide considerations for key components of this training and metrics for evaluation.

Acetabular labral entrapment following spontaneous nonconcentric reduction of posterior hip dislocation in a child.

Traumatic pediatric hip dislocations are uncommon and can occur following minor trauma. This injury may be overlooked, as pediatric hip dislocations can reduce spontaneously prior to medical attention. In this scenario, the presenting hip radiographs may provide evidence of a prior transient hip dislocation episode by demonstrating signs of a nonconcentric hip reduction, and prompt further evaluation with advanced imaging. We present a rare case of a traumatic posterior hip dislocation with spontaneous nonconcentric reduction in a child. CT and MRI revealed a block in concentric reduction by the avulsed and entrapped posterior acetabular labrum and contiguous epiphyseal fragment. This case highlights the imaging characteristics of this rare injury, and the importance of early diagnosis to guide surgical management.

Homelessness and Type 2 Diabetes: A Qualitative Study of Facilitators and Barriers to Self-Management and Medication Adherence.

PURPOSE: In this study, we explore the barriers and facilitators to diabetes medication adherence and self-management for people with type 2 diabetes who have experienced homelessness. METHODS: We conducted five focus groups and two interviews with 26 participants. Our multi-disciplinary analysis team utilized principles of grounded theory and conducted thematic analysis with an inductive, iterative process to identify central themes. RESULTS: The majority of participants identified as Black/African American and over half stayed in shelters or had no steady place to stay at enrollment. Three key themes emerged regarding medication adherence and diabetes self-management for people who have experienced homelessness: personal autonomy and security, predictability and stability, and supportive, knowledgeable relationships (both social and medical). We define personal autonomy and security as individual agency and choice when making decisions related to one's health and well-being as well as protection from risk or harm to one's physical or psychological well-being, belongings, or means of income. Predictability and stability take place through the development of a system of connections and routines built over time where individuals can reliably adopt and maintain diabetes self-management activities. Supportive, knowledgeable relationships include medical and social relationships that offer encouragement, information, and hands-on care promoting diabetes self-management and connection to clinical care and resources. Participants also highlighted a "domino effect" where a cascade of events negatively and consequently impacted their health and well-being. We describe the interactions of these themes, the intersection of structural vulnerability and individual social risks, and resulting impacts on medication adherence and diabetes self-management. CONCLUSIONS: Our findings highlight the structural vulnerabilities impacting people experiencing homelessness and identify inflection points of opportunity at structural and individual levels to strengthen diabetes medication adherence and self-management. This understanding can inform policy change and future tailored diabetes interventions.

Integrating Social Determinants of Health in Machine Learning-Driven Decision Support for Diabetes Case Management: Protocol for a Sequential Mixed Methods Study.

BACKGROUND: The use of both clinical factors and social determinants of health (SDoH) in referral decision-making for case management may improve optimal use of resources and reduce outcome disparities among patients with diabetes. OBJECTIVE: This study proposes the development of a data-driven decision-support system incorporating interactions between clinical factors and SDoH into an algorithm for prioritizing who receives case management services. The paper presents a design for prediction validation and preimplementation assessment that uses a mixed methods approach to guide the implementation of the system. METHODS: Our study setting is a large, tertiary care academic medical center in the Deep South of the United States, where SDoH contribute to disparities in diabetes-specific hospitalizations and emergency department (ED) visits. This project will develop an interpretable artificial intelligence model for a population with diabetes using SDoH and clinical data to identify which posthospitalization cases have a higher likelihood of subsequent ED use. The electronic health record data collected for the study include demographics, SDoH, comorbidities, hospitalization-related factors, laboratory test results, and medication use to predict posthospitalization ED visits. Subsequently, a mixed methods approach will be used to validate prediction outcomes and develop an implementation strategy from insights into patient outcomes from case managers, clinicians, and quality and patient safety experts. RESULTS: As of December 2023, we had abstracted data on 174,871 inpatient encounters between January 2018 and September 2023, involving 89,355 unique inpatients meeting inclusion criteria. Both clinical and SDoH data items were included for these patient encounters. In total, 85% of the inpatient visits (N=148,640) will be used for training (learning from the data) and the remaining 26,231 inpatient visits will be used for mixed-methods validation (testing). CONCLUSIONS: By integrating a critical suite of SDoH with clinical data related to diabetes, the proposed data-driven risk stratification model can enable individualized risk estimation and inform health professionals (eg, case managers) about the risk of patients' upcoming ED use. The prediction outcome could potentially automate case management referrals, helping to better prioritize services. By taking a mixed methods approach, we aim to align the model with the hospital's specific quality and patient safety considerations for the quality of patient care and the optimization of case management resource allocation. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/56049.

Contemporary Approach to The Diagnosis and Classification of Myelodysplastic Neoplasms/Syndromes- Recommendations from The International Consortium for MDS (icMDS).

Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of biologically distinct entities characterized by variable degrees of ineffective hematopoiesis. Recently, two classification systems (the 5th edition of the WHO Classification and the International Consensus Classification) further sub-characterized MDS into morphologic and genetically defined groups. Accurate diagnosis and subclassification of MDS require a multistep systemic approach. The International Consortium for MDS (icMDS) summarizes a contemporary, practical, and multimodal approach to MDS diagnosis and classification.

Genome-wide meta-analysis of ascertainment and symptom structures of major depression in case-enriched and community cohorts.

BACKGROUND: Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and etiological subtypes. There are several challenges to integrating symptom data from genetically informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data. METHODS: We conducted genome-wide association studies of major depressive symptoms in three cohorts that were enriched for participants with a diagnosis of depression (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts who were not recruited on the basis of diagnosis (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors. RESULTS: The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for the skip-structure in community cohorts (use of Depression and Anhedonia as gating symptoms). CONCLUSION: The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analyzing genetic association data.

Posterior Glenoid Bone Grafting in the Setting of Excessive Glenoid Retroversion Does Not Provide Adequate Stability in a Cadaveric Posterior Instability Model.

BACKGROUND: Excessive glenoid retroversion is a known risk factor for posterior shoulder instability and failure after soft tissue stabilization procedures. Whether excessive glenoid retroversion is a risk factor for failure after posterior glenoid bone grafting is unknown. PURPOSE: To evaluate the biomechanical effectiveness of posterior iliac crest bone grafting (ICBG) for posterior shoulder instability with increasing glenoid retroversion. STUDY DESIGN: Controlled laboratory study. METHODS: Six fresh-frozen cadaveric shoulders had a posterior glenoid osteotomy allowing the glenoid retroversion to be set at 0°, 10°, and 20°. At these 3 preset angles, 4 conditions were simulated consecutively on the same specimen: (1) intact glenohumeral joint, (2) posterior Bankart lesion, (3) 20% posterior glenoid bone defect, and (4) posterior ICBG. Stability was evaluated in the jerk position (60° of glenohumeral anteflexion, 60° of internal rotation) by measuring (A) posterior humeral head (HH) translation (in mm) and (B) peak translational force (in N) necessary for translation of the HH over 25% of glenoid width. RESULTS: At 0° of retroversion, the ICBG restored posterior HH translation and peak translational force to values comparable with those of the intact condition (P = .649 and P = .979, respectively). At 10° of retroversion, the ICBG restored the peak translational force to a value comparable with that of the intact condition (22.3 vs 24.7 N, respectively; P = .418) but showed a significant difference in posterior HH translation in comparison to the intact condition (4.5 vs 2.0 mm, respectively; P = .026). There was a significant increase in posterior HH translation and significant decrease in peak translational force with the ICBG at 20° of glenoid retroversion compared with the intact condition (posterior HH translation: 7.9 vs 2.0 mm, respectively; P < .006; peak translational force: 15.3 vs 24.7 N, respectively; P = .014). CONCLUSION: In this cadaveric study, posterior ICBG was able to restore stability to a level comparable to that of the native condition at 0° and to some extent at 10° of retroversion. However, posterior ICBG was not able to provide adequate stability at 20° of glenoid retroversion. CLINICAL RELEVANCE: Posterior glenoid bone grafting with ICBG should be used with caution when performed in isolation in the setting of posterior instability associated with glenoid bone loss and combined glenoid retroversion of >10°.

Early external fixation of tibial plateau fractures is associated with an increased risk of compartment syndrome.

INTRODUCTION: Tibial plateau fractures are often associated with high-energy trauma necessitating external fixation as a means of temporization. There is evidence that pin placement and fracture distraction may result in transient increases in compartment pressures, and the optimal timing of external fixator placement is unknown. This study sought to determine the effect of early versus late external fixator placement on the risk of compartment syndrome after a tibial plateau fracture. METHODS: The Trauma Quality Improvement Program was retrospectively queried between 2015 and 2019 for adult patients with a tibial plateau fracture who underwent external fixator placement. Patients with concomitant tibial shaft and/or distal femur fractures, requiring lower extremity fasciotomy before external fixation, or external fixation >7 days after admission were excluded. The primary study outcome was inpatient compartment syndrome. Secondary outcomes were inpatient acute respiratory failure/unplanned intubation, surgical site infection, and venous thromboembolism (VTE). A time threshold of delayed external fixation was identified at which the odds of compartment syndrome no longer significantly decreased with increasing time using a Markov Chain Monte Carlo simulation of a restricted cubic spline model. The odds of each outcome were compared between patients who underwent early versus delayed external fixation on or after the time threshold, adjusting for potential confounding by patients, injury, and hospital characteristics. Significance was defined as p < 0.05. RESULTS: A threshold for delayed external fixation was identified at 28.8 h from admission. Of the 3,185 eligible patients, 2,656 (83.4 %) were classified as early external fixation and 529 (16.6 %) were classified as delayed external fixation. Delayed external fixation was associated with lower adjusted odds (aOR) of compartment syndrome (aOR: 0.31, 95 % Confidence Interval (CI): 0.13-0.74, p = 0.008) and higher aOR of acute respiratory failure/unplanned intubation (aOR: 2.13, 95 % CI: 1.13-4.0.2, p = 0.019), however no significant differences in adjusted odds of surgical site infection or VTE were observed. CONCLUSION: Patients with tibial plateau fractures who underwent closed reduction and external fixation within 28.8 h of admission were associated with greater odds of compartment syndrome than those undergoing external fixation after this time threshold.