COVID-19 vaccines are effective at preventing symptomatic and severe infection among healthcare workers: A clinical review.

Introduction: Health care workers (HCWs) have been at increased risk of infection during the SARS-CoV-2 pandemic and as essential workers have been prioritised for vaccination. Due to increased exposure HCW are considered a predictor of what might happen in the general population, particularly working age adults. This study aims to summarise effect of vaccination in this 'at risk' cohort. Methods: Ovid MEDLINE and Embase were searched, and 358 individual articles were identified. Of these 49 met the inclusion criteria for review and 14 were included in a meta-analysis. Results: Participants included were predominantly female and working age. Median time to infection was 51 days. Reported vaccine effectiveness against infection, symptomatic infection, and infection requiring hospitalisation were between 5 and 100 %, 34 and 100 %, and 65 and 100 % (respectively). No vaccinated HCW deaths were recorded in any study. Pooled estimates of protection against infection, symptomatic infection, and hospitalisation were, respectively, 84.7 % (95 % CI 72.6-91.5 %, p < 0.0001), 86.0 % (95 % CI 67.2 %-94.0 %; p < 0.0001), and 96.1 % (95 % CI 90.4 %-98.4 %). Waning protection against infection was reported by four studies, although protection against hospitalisation for severe infection persists for at least 6 months post vaccination. Conclusions: Vaccination against SARS-CoV2 in HCWs is protective against infection, symptomatic infection, and hospitalisation. Waning protection is reported but this awaits more mature studies to understand durability more clearly. This study is limited by varying non-pharmacological responses to COVID-19 between included studies, a predominantly female and working age population, and limited information on asymptomatic transmission or long COVID protection.

Characterization of lignin degrading enzyme PmdC, which catalyzes a key step in the synthesis of polymer precursor 2-pyrone-4,6-dicarboxylic acid (PDC).

Pyrone-2,4-dicarboxylic acid (PDC) is a valuable polymer precursor that can be derived from the microbial degradation of lignin. The key enzyme in the microbial production of PDC is CHMS dehydrogenase, which acts on the substrate 4-carboxy-2-hydroxymuconate-6-semialdehyde (CHMS). We present the crystal structure of CHMS dehydrogenase (PmdC from Comamonas testosteroni) bound to the cofactor NADP, shedding light on its three-dimensional architecture, and revealing residues responsible for binding NADP. Using a combination of structural homology, molecular docking, and quantum chemistry calculations we have predicted the binding site of CHMS. Key histidine residues in a conserved sequence are identified as crucial for binding the hydroxyl group of CHMS and facilitating dehydrogenation with NADP. Mutating these histidine residues results in a loss of enzyme activity, leading to a proposed model for the enzyme's mechanism. These findings are expected to help guide efforts in protein and metabolic engineering to enhance PDC yields in biological routes to polymer feedstock synthesis.

Direct Economic Burden of Cubital Tunnel Surgery in the United States: Total Payments and Components of Cost.

PURPOSE: Despite its widespread prevalence, the cost of cubital tunnel syndrome (CuTS) in the United States to patients and insurers is not well understood. The purpose of this study was to quantify the direct payments associated with operative treatment of CuTS. We hypothesized that CuTS represents a substantial cost to the payer in facility fees, surgeon fees and other expenses. METHODS: Utilizing the MarketScan database of insured patients (commercial and Medicaid), we identified a cohort of 41,777 patients aged 18-64 years with surgically treated CuTS from 2006 to 2018. We estimated the median 90-day payments from encounters associated with cubital tunnel release (CuTR) and/or ulnar nerve transposition surgery by summing all payments for claims within 90 days after the index surgery. Published estimates of the annual number of cubital tunnel surgeries were used to calculate the annual expenditure. RESULTS: Of 41,777 patients, the median (interquartile range [IQR]) values of total direct payments were $5,522 [$3,426, $9,541]. With an estimated 94,645 cases/year, this leads to an annual payment of more than $522 million. Index facility payments (median[IQR] $2,555 [$1,359, $4,708] were the highest, followed by index provider payments ($1,691 [$1,328, $2,217]). The median index surgeon payment (median[IQR] $905 [$707, $1,184]) represented just over half of the provider payments. Post-operative care had a median [IQR] payment of $377 ($424, $1,987). Limitations of claims databases prevented assessment of other indirect costs associated with cubital tunnel surgery. CONCLUSIONS: Payments for the surgical treatment of CuTS from the index surgery to 90 days post-operatively have an estimated median of $5,522 per patient, totaling $52 million annually. Index facility fees are responsible for more than 46% of payments, while index payments to surgeons represent approximately 16%. Defining this data is critical to understanding one component of the economic impact of CuTS. LEVEL OF EVIDENCE: Level IV.

Multi-source machine learning and spaceborne remote sensing data accurately predict three-dimensional soil moisture in an in-service uranium disposal cell.

One reason arid and semi-arid environments have been used to store waste is due to low groundwater recharge, presumably limiting the potential for meteoric water to mobilize and transport contaminants into groundwater. The U.S. Department of Energy Office of Legacy Management (LM) is evaluating selected uranium mill tailings disposal cell covers to be managed as evapotranspiration (ET) covers, where vegetation is used to naturally remove water from the cover profile via transpiration, further reducing deep percolation. An important parameter in monitoring the performance of ET covers is soil moisture (SM). If SM is too high, water may drain into tailings material, potentially transporting contaminants into groundwater; if SM is too low, radon flux may increase through the cover. However, monitoring SM via traditional instrumentation is invasive, expensive, and may fail to account for spatial heterogeneity, especially over vegetated disposal cells. Here we investigated the potential for non-invasive SM monitoring using radar remote sensing and other geospatial data to see if this approach could provide a practical, accurate, and spatially comprehensive tool to monitor SM. We used theoretical simulations to analyze the sensitivity of multi-frequency radar backscatter to SM at different depths of a field-scale (3 ha) drainage lysimeter embedded within an in-service LM disposal cell. We then evaluated a shallow and deep form of machine learning (ML) using Google Earth Engine to integrate multi-source observations and estimate the SM profile across six soil layers from depths of 0-2 m. The ML models were trained using in situ SM measurements from 2019 and validated using data from 2014 to 2018 and 2020-2021. Model predictors included backscatter observations from satellite synthetic aperture radar, vegetation, temperature products from optical infrared sensors, and accumulated, gridded rainfall data. The radar simulations confirmed that the lower frequencies (L- and P-band) and smaller incidence angles show better sensitivity to deeper soil layers and an overall larger SM dynamic range relative to the higher frequencies (C- and X-band). The ML models produced accurate SM estimates throughout the soil profile (r values from 0.75 to 0.94; RMSE = 0.003-0.017 cm3/cm3; bias = 0.00 cm3/cm3), with the simpler shallow-learning approach outperforming a selected deep-learning model. The ML models we developed provide an accurate, cost-effective tool for monitoring SM within ET covers that could be applied to other vegetated disposal cell covers, potentially including those with rock-armored covers.

Predicting Complications in Head and Neck Surgery: Comparing Calculators to Surgeons.

Objectives: Surgical outcomes determine national ranking, reputation, and funding, and are often assessed with objective surgical risk calculators (SRCs). Surgeons' assessments are not considered. This study aims to determine if surgeons or SRCs are more accurate in predicting outcomes. Methods: This prospective cohort study identified a surgeon's assessment on a patient's risk preoperatively. The patient's risk was also calculated using the SRC. Predictions were compared to patient outcomes and to each other to assess whether surgeons or the SRC were more accurate. Results: Of the 101 patients included, 37 (36.6%) experienced a complication of any kind and 18 (17.8%) experienced a serious complication. Smoking resulted in a 2.49 times higher overall complication rate (P = .04). Laryngectomy patients experienced the highest rate of complications (P = .02) compared to those undergoing free flap reconstruction [odds ratio (OR) 0.9] or any other surgery (OR 0.26). Both surgeons and the American College of Surgeons (ACS) tool performed poorly on the prediction of the outcome of any complication, with a receiver operating characteristic (ROC) area under the curve (AUC) of 0.51 [95% confidence interval (CI): 0.39-0.62] and 0.58 (95% CI: 0.47-0.70), respectively, which was not statistically significant (P = .34). For the prediction of the outcome of serious complication, the AUC for surgeons and the ACS tool were 0.55 (95% CI: 0.41-0.69) and 0.60 (95% CI: 0.46-0.74), respectively, which was not statistically significant (P = .58). Conclusions: Neither validated risk calculators nor surgeons are accurate in predicting perioperative risk. The only risk factor that contributes to improving predictions for complications is preoperative smoking, although age and type of surgery are also significant predictors. Risk calculators may therefore not be appropriate metrics for assessing hospital performance. These findings can help guide preoperative counseling and may help in the development of more accurate predictive tools as the healthcare field continues to incorporate artificial intelligence into surgical planning.

Achieving Health Equity: Combatting the Disparities in American Access to Musculoskeletal Care : Disparities Exist in Every Aspect of Orthopaedic Care in the United States - Access to Outpatient Visits, Discretionary and Unplanned Surgical Care, and Postoperative Outcomes. What Can We Do?

PURPOSE OF REVIEW: Healthcare disparities influence multiple dimensions of orthopaedic care including access, burden and incidence of disease, and outcome in varying populations. These disparities impact healthcare at both the micro and macro scale of the healthcare experience from individual patient-physician relationships to reimbursement rates across the United States. This article provides a review of how healthcare disparities contribute to the landscape of orthopaedic care and specifically highlights how disparities affect outpatient visits, discretionary and unplanned surgical care, and postoperative outcomes. RECENT FINDINGS: Current research demonstrates the widespread presence of healthcare disparities in the field of orthopaedics and gives both objective and subjective evidence confirming disparities' measurable influence. The disparities most highlighted by our review include differences in orthopaedic care based on insurance type and race. Currently disparities in orthopaedic care are deeply connected to patient insurance status and race. In the outpatient setting insurance significantly impacts access to care, travel burden, and utilization of services. The emergent setting is similarly influenced with measurable differences in lack of access to acute care, rates of inappropriate triage, and timeliness of care based on insurance status and race. Additionally, the postoperative period is not immune to disparities with likelihood of follow up, experience of catastrophic medical expenses, and postoperative outcomes also being affected. Addressing these disparities is a pressing need and may include solutions like wider expansion and acceptance of publicly funded insurance and the development of readily available and easily measurable metrics for healthcare equity and quality in vulnerable populations.

Children's Health in London and Luton (CHILL) cohort: a 12-month natural experimental study of the effects of the Ultra Low Emission Zone on children's travel to school.

BACKGROUND: The Ultra-Low Emission Zone (ULEZ), introduced in Central London in April 2019, aims to enhance air quality and improve public health. The Children's Health in London and Luton (CHILL) study evaluates the impact of the ULEZ on children's health. This analysis focuses on the one-year impacts on the shift towards active travel to school. METHODS: CHILL is a prospective parallel cohort study of ethnically diverse children, aged 6-9 years attending 84 primary schools within or with catchment areas encompassing London's ULEZ (intervention) and Luton (non-intervention area). Baseline (2018/19) and one-year follow-up (2019/20) data were collected at school visits from 1992 (58%) children who reported their mode of travel to school 'today' (day of assessment). Multilevel logistic regressions were performed to analyse associations between the introduction of the ULEZ and the likelihood of switching from inactive to active travel modes, and vice-versa. Interactions between intervention group status and pre-specified effect modifiers were also explored. RESULTS: Among children who took inactive modes at baseline, 42% of children in London and 20% of children in Luton switched to active modes. For children taking active modes at baseline, 5% of children in London and 21% of children in Luton switched to inactive modes. Relative to the children in Luton, children in London were more likely to have switched from inactive to active modes (OR 3.64, 95% CI 1.21-10.92). Children in the intervention group were also less likely to switch from active to inactive modes (OR 0.11, 0.05-0.24). Moderator analyses showed that children living further from school were more likely to switch from inactive to active modes (OR 6.06,1.87-19.68) compared to those living closer (OR 1.43, 0.27-7.54). CONCLUSIONS: Implementation of clean air zones can increase uptake of active travel to school and was particularly associated with more sustainable and active travel in children living further from school.

Biofilm Formation is Durably Prevented on Pre-Fabricated Antibiotic Cement Spacers Compared to Cobalt Chrome and Polyethylene.

BACKGROUND: A two-stage revision remains the standard for managing chronic periprosthetic joint infection (PJI). Despite multiple spacer options, whether a particular one better resists biofilm formation remains unclear. Prefabricated polymethylmethacrylate (PMMA) articulating spacers containing antibiotics and a proprietary pore structure were developed to increase antibiotic elution characterized by a rapid burst phase for the initial 1 to 2 days and an extended slow-release phase for > 28 days. This in vitro study determined whether biofilm formation is prevented during the initial rapid burst phase and/or the slow-release phase. METHODS: S. aureus-Xen36 was incubated in 1.5 ml of Luria-Bertani broth with PMMA discs with the proprietary pore structure either with or without gentamycin and vancomycin, or with 'Hoffman style' positive-control discs (ultra-high molecular weight polyethylene (UHMWPE) or cobalt-chrome). Non-adherent bacteria were removed by three Phosphate Buffered Saline rinses every 20 to 24 hours. Planktonic bacterial growth in the culture broth and biofilm formation on the discs were measured by Colony Forming Unit (CFU) counting and resazurin reduction assays. Experiments were repeated > 4 times. RESULTS: No detectable planktonic bacterial growth or biofilm formation occurred in cultures containing PMMA with antibiotics (≤ 15 CFUs/disc), whereas biofilms formed on PMMA without antibiotics, UHMWPE, and cobalt-chrome (1x107 to 4x108 CFUs/disc, P < 0.0001). Biofilm formation was confirmed by a 100-fold decrease in sensitivity to vancomycin. To determine whether the antibiotic slow-release phase is sufficient to block biofilm formation, PMMA discs with antibiotics were pre-eluted for 14 days with multiple saline changes prior to bacterial inoculation. After antibiotic elution, still no detectable biofilms formed on PMMA discs with antibiotics (≤ 15 CFUs/disc, P <0.0001). CONCLUSION: Antibiotic release during both the initial and slow-release phases prevented biofilm formation on PMMA with the proprietary pore structure. This may translate into improved infection eradication rates clinically.

Transcatheter Aortic Valve Implantation (TAVI) in Bicuspid Aortic Valve Disease: A Systematic Review.

Transcatheter aortic valve implantation (TAVI) is effective and safe, but its outcomes for patients with bicuspid aortic valve (BAV) disease are relatively unclear. A comprehensive search of PubMed, Medline, and Google Scholar till November 2023 yielded studies evaluating TAVI in BAV patients. Inclusion criteria were applied, and data were extracted on clinical and procedural outcomes, including echocardiographic measures and complications. Statistical analyses included descriptive statistics, subgroup analysis, and sensitivity analysis. From the 29 studies covering 8045 BAV patients, the mean age was found to be 72.5 ± 10.35 years with a male predominance of 56.4% ± 7.9%. TAVI was significantly beneficial, decreasing the mean aortic gradient from 46.9 to 10.4 mm Hg postprocedure and increasing aortic valve area, evidencing improved hemodynamics. A high procedural success rate of 93.3% was noted, predominantly through femoral access. However, complications included pacemaker need (12.6%), minor bleeding, and acute kidney injury. All-cause mortality escalated from 3.7% perioperatively to 16.8% after 1 year. Hazard ratios and P values highlighted significant outcomes: perioperative hazard ratio for mortality at 3.7% (P < 0.05), reduction in perioperative versus postoperative gradients (P < 0.001), and increase in postoperative aortic valve area (P < 0.001). The need for postdilatation was less than predilatation (P < 0.05), and significant differences were noted in device sizes (P < 0.05). TAVI in BAV patients showed good perioperative outcomes but with moderate complication rates. Notably, there was a significant rise in 1-year mortality, underscoring the importance of careful patient selection and strict postoperative care. More studies are necessary to determine long-term results and refine procedures for this group.

Development of CD33-Targeted Dual Drug-Loaded Nanoparticles for the Treatment of Pediatric Acute Myeloid Leukemia.

Paediatric acute myeloid leukemia (AML) is a heterogeneous hematological malignancy still heavily reliant on traditional chemotherapeutic approaches. Combination treatments have shown to be a superior approach, but their success is often hindered by side effects and different drugs' pharmacokinetics. Here, we investigated ABT-737 and Purvalanol A as a potential drug pairing for pediatric AML and described the development of CD33-targeted polymeric nanoparticles (NPs) to enable their simultaneous targeted codelivery. Separate drug encapsulation within poly(lactic-co-glycolic acid) (PLGA) NPs was optimized prior to coencapsulation of both drugs at a synergistic ratio in PEGylated PLGA NPs. The therapeutic effects of formulations were evaluated in a panel of pediatric AML cells, and dual drug-loaded NPs (dual NPs) demonstrated significantly enhanced apoptotic cell death. Moreover, conjugation to gemtuzumab resulted in improved NP binding and internalization in CD33-positive cells. Finally, CD33-targeted dual-loaded NPs showed enhanced cytotoxicity to CD33-positive AML cells via CD33-mediated targeted drug delivery.

Neurologic Clinical, Electrophysiologic, and Pathologic Characteristics of Primary vs Secondary Neurolymphomatosis.

BACKGROUND AND OBJECTIVES: Neurolymphomatosis (NL) is characterized by lymphomatous infiltration of the peripheral nervous system presenting as the initial manifestation of a lymphoma (primary NL [PNL]) or in relapse of a known lymphoma (secondary NL [SNL]). This report details and compares the neurologic clinicopathologic characteristics of these 2 groups. METHODS: This retrospective study was performed on patients diagnosed with pathologically confirmed NL in nerve between January 1, 1992, and June 31, 2020. Patient clinical characteristics, neurologic examination, imaging studies, EMG, and nerve biopsy data were collected, analyzed, and compared between PNL and SNL. RESULTS: A total of 58 patients were identified (34 PNL and 24 SNL). Time from neurologic symptom onset to diagnosis was longer in PNL at 18.5 months compared with 5.5 months in SNL (p = 0.01). Neurologic symptoms were similar in both patient groups and included primarily sensory loss (98%), severe pain (76%), and asymmetric weakness (76%). A wide spectrum of EMG-confirmed different neuropathy patterns were observed, but patients with SNL had increased numbers of mononeuropathies (n = 8) compared with PNL (n = 1, p = 0.01). MRI studies detected NL more frequently (86%) compared with fluorodeoxyglucose (FDG)-PET CT imaging studies (60%) (p = 0.007). Nerve biopsies revealed B-cell lymphoma (PNL n = 32, SNL n = 22), followed by T-cell lymphoma (PNL n = 2, SNL n = 2), with increased demyelination in both groups and increased axonal degeneration (p = 0.01) and multifocal myelinated fiber loss (p = 0.04) significant in SNL vs PNL. Identifying SNL resulted in patient treatment modifications but a worse prognosis compared with PNL (p = 0.025). DISCUSSION: While PNL and SNL are both primarily painful and asymmetric neuropathies with axonal and demyelinating features on EMG and nerve biopsy, SNL presents somewhat differently than PNL with fulminant, asymmetric often mononeuropathies better detected on MRI than FDG-PET/CT. The focal pattern of SNL is likely a result of residual cancer cells that evaded initial chemotherapy, which does not cross the blood-nerve barrier, and these cells can later recur and result in fulminant disease. Although still resulting in a poorer prognosis, identifying SNL is important because this changed treatment and management in every SNL case.

Origins of enhanced oxygen reduction activity of transition metal nitrides.

Transition metal nitride (TMN-) based materials have recently emerged as promising non-precious-metal-containing electrocatalysts for the oxygen reduction reaction (ORR) in alkaline media. However, the lack of fundamental understanding of the oxide surface has limited insights into structure-(re)activity relationships and rational catalyst design. Here we demonstrate how a well-defined TMN can dictate/control the as-formed oxide surface and the resulting ORR electrocatalytic activity. Structural characterization of MnN nanocuboids revealed that an electrocatalytically active Mn3O4 shell grew epitaxially on the MnN core, with an expansive strain along the [010] direction to the surface Mn3O4. The strained Mn3O4 shell on the MnN core exhibited an intrinsic activity that was over 300% higher than that of pure Mn3O4. A combined electrochemical and computational investigation indicated/suggested that the enhancement probably originates from a more hydroxylated oxide surface resulting from the expansive strain. This work establishes a clear and definitive atomistic picture of the nitride/oxide interface and provides a comprehensive mechanistic understanding of the structure-reactivity relationship in TMNs, critical for other catalytic interfaces for different electrochemical processes.

Taphonomic impact of vertebrate scavengers on degradation and dispersal of remains, southeastern British Columbia.

Vertebrate scavengers represent important taphonomic agents that can act on a body, particularly when in an outdoor environment. Understanding the effects of these agents will direct how and where to search for human remains and influence the likelihood of discovery in a particular region. The current study aimed to identify the taphonomic impact of scavenger guilds in the peri-urban and rural regions of southeastern British Columbia. Vertebrate scavenger activity on pig carcasses was recorded remotely using trail cameras and analyzed to determine temporal scavenging profiles. Both the peri-urban and rural environments produced comparable scavenger guilds, namely: turkey vultures, American crows/northern ravens (classified as "corvids"), American black bears, and coyotes. Although the two locations had different study lengths due to variable degrees of scavenging, for the period that was common to both locations (summer to early fall), the black bear was the most frequent scavenger followed by coyote. However, the dispersal of remains by the mammalian scavengers was distinctly different between sites. Only 12%-33% of skeletal elements were recovered at the rural sites compared to 80%-90% recovered at the peri-urban sites, even though the latter sites had a longer study timeframe. The extended timeframe of the peri-urban sites confirmed that certain scavengers (e.g., turkey vultures and black bears) are only seasonally active in this region. These findings demonstrate the variability of scavenger behavior and the need to assign caution and local ecological knowledge when predicting scavenger trends. Such taphonomic information is relevant for human remains searches in regions with comparable scavenger guilds.

Distinct trajectories of neuropsychiatric symptoms in the 12 months following traumatic brain injury (TBI): a TRACK-TBI study.

BACKGROUND: Neuropsychiatric symptoms are common after traumatic brain injury (TBI) and often resolve within 3 months post-injury. However, the degree to which individual patients follow this course is unknown. We characterized trajectories of neuropsychiatric symptoms over 12 months post-TBI. We hypothesized that a substantial proportion of individuals would display trajectories distinct from the group-average course, with some exhibiting less favorable courses. METHODS: Participants were level 1 trauma center patients with TBI (n = 1943), orthopedic trauma controls (n = 257), and non-injured friend controls (n = 300). Trajectories of six symptom dimensions (Depression, Anxiety, Fear, Sleep, Physical, and Pain) were identified using growth mixture modeling from 2 weeks to 12 months post-injury. RESULTS: Depression, Anxiety, Fear, and Physical symptoms displayed three trajectories: Stable-Low (86.2-88.6%), Worsening (5.6-10.9%), and Improving (2.6-6.4%). Among symptomatic trajectories (Worsening, Improving), lower-severity TBI was associated with higher prevalence of elevated symptoms at 2 weeks that steadily resolved over 12 months compared to all other groups, whereas higher-severity TBI was associated with higher prevalence of symptoms that gradually worsened from 3-12 months. Sleep and Pain displayed more variable recovery courses, and the most common trajectory entailed an average level of problems that remained stable over time (Stable-Average; 46.7-82.6%). Symptomatic Sleep and Pain trajectories (Stable-Average, Improving) were more common in traumatically injured groups. CONCLUSIONS: Findings illustrate the nature and rates of distinct neuropsychiatric symptom trajectories and their relationship to traumatic injuries. Providers may use these results as a referent for gauging typical v. atypical recovery in the first 12 months post-injury.

Peptide Bundlemer Networks or Lattices: Controlling Cross-Linking and Self-Assembly Using Protein-like Display of Chemistry.

Coiled-coil 'bundlemer' peptides were selectively modified with allyloxycarbonyl (alloc)-protected lysine, a non-natural amino acid containing an alkene on its side chain. The specific display of this alkene from the coiled-coil surface with protein-like specificity enabled this residue to be used as a covalent linkage for creating peptide networks with controllable properties or as a physical linkage for the self-assembly of bundlemers into unexpected, intricate lattices driven by the hydrophobic nature of the side chain. For network formation, peptides were modified with both alloc-protected lysine and cysteine amino acids for solution assembly into solvent-swollen films and subsequent covalent cross-linking via thiol-ene photo click reactions. The degree of network cross-linking, as determined by rheometry, was finely tuned by varying the specific spatial display of reactive groups on the bundlemer building block particles, transitioning between intrabundle and interbundle cross-linking. The designed display of alloc groups from the center of the bundlemer building block also prompted particle self-assembly into an unexpected intricate lattice with a porous morphology. The lattices were studied in a variety of solution conditions using transmission electron microscopy, cryotransmission electron microscopy, and small-angle X-ray scattering. The approximate particle arrangement in the lattice was determined by using coarse-grained modeling and machine learning optimization techniques along with experimental methods. The proposed truss-like face-centered cubic packing of the alloc-functionalized bundlemers agrees well with the experimental results.

Genetic Testing History in Adults with Autism Spectrum Disorder.

Background & Objectives Many genes have been identified in autism spectrum disorder (ASD). Yet little is known about how many adults with ASD receive recommended genetic testing and their outcomes. We investigated the percentage of adults with ASD who received genetic testing using recommended methods in our ASD specialty clinic and the percentage with positive findings. Methods Potentially eligible adults were identified through search of our health system data repository and ASD diagnoses confirmed using review of relevant medical records by consensus of psychiatrists specializing in ASD. Patients were included (N=630) who had at least one visit with a qualifying clinician between 5/1/2010 and 12/15/2020 and demographic data available. Data were collected through manual retrospective review of the electronic health record. Results Only 41% of the adults with ASD (261/630) had a history of genetic testing documented in the medical record. Genetic testing was declined by patients or families for 11% (72) of records and not recorded in 47% (297). Mean (SD; range) age for the 261 adults with testing documented was 28.5 (5.3; 22-58) years. Sixty-seven (26%) were identified as female, 14 (6%) as Asian, 8 (3%) as Black or African American, 226 (89%) as White, 6 (2%) as other race, and 2 (1%) as Hispanic. 189 (73%) had intellectual disability. Ninety-one percent (236) had the genetic testing method recorded. Only 54% (95% CI: 46%, 61%) of patients had testing using a recommended method (chromosomal array, autism/intellectual disability sequencing panel, or exome sequencing). Few adults had received testing with sequencing technologies. A genetic cause of ASD was found in 28% (95% CI: 19%, 39%) of the 121 adults with results from ASD-related genetic testing recorded. Discussion Genetic testing can offer clinical and research insights. Yet it is underutilized in this population of adults with ASD. Nearly half of the adults in our sample lacked documentation of genetic testing. Thus, the percentage of adults with confirmed ASD who had any recommended genetic testing may be even lower than reported. Adults with ASD may benefit from having their genetic testing history reviewed in the clinic and the latest genetic testing performed.

Leveraging Generative AI to Accelerate Biocuration of Medical Actions for Rare Disease.

BACKGROUND: Structured representations of clinical data can support computational analysis of individuals and cohorts, and ontologies representing disease entities and phenotypic abnormalities are now commonly used for translational research. The Medical Action Ontology (MAxO) provides a computational representation of treatments and other actions taken for the clinical management of patients. Currently, manual biocuration is used to assign MAxO terms to rare diseases, enabling clinical management of rare diseases to be described computationally for use in clinical decision support and mechanism discovery. However, it is challenging to scale manual curation to comprehensively capture information about medical actions for the more than 10,000 rare diseases. METHODS: We present AutoMAxO, a semi-automated workflow that leverages Large Language Models (LLMs) to streamline MAxO biocuration for rare diseases. AutoMAxO first uses LLMs to retrieve candidate curations from abstracts of relevant publications. Next, the candidate curations are matched to ontology terms from MAxO, Human Phenotype Ontology (HPO), and MONDO disease ontology via a combination of LLMs and post-processing techniques. Finally, the matched terms are presented in a structured form to a human curator for approval. RESULTS: We used this approach to process 4,918 unique medical abstracts and identified annotations for 21 rare genetic diseases, we extracted 18,631 candidate disease-treatment curations, 538 of which were confirmed and transferred to the MAxO annotation dataset. CONCLUSION: The results of this project underscore the potential of generative AI to accelerate precision medicine by enabling a robust and comprehensive curation of the primary literature to represent information about diseases and procedures in a structured fashion. Although we focused on MAxO in this project, similar approaches could be taken for other biomedical curation tasks.

Genetics of posttraumatic stress disorder and cardiovascular conditions using Life's Essential 8, Electronic Health Records, and Heart Imaging.

BACKGROUND: Patients with post-traumatic stress disorder (PTSD) experience higher risk of adverse cardiovascular (CV) outcomes. This study explores shared loci, and genes between PTSD and CV conditions from three major domains: CV diagnoses from electronic health records (CV-EHR), cardiac and aortic imaging, and CV health behaviors defined in Life's Essential 8 (LE8). METHODS: We used genome-wide association study (GWAS) of PTSD (N=1,222,882), 246 CV diagnoses based on EHR data from Million Veteran Program (MVP; N=458,061), UK Biobank (UKBB; N=420,531), 82 cardiac and aortic imaging traits (N=26,893), and GWAS of traits defined in the LE8 (N = 282,271 ∼ 1,320,016). Shared loci between PTSD and CV conditions were identified using local genetic correlations (rg), and colocalization (shared causal variants). Overlapping genes between PTSD and CV conditions were identified from genetically regulated proteome expression in brain and blood tissues, and subsequently tested to identify functional pathways and gene-drug targets. Epidemiological replication of EHR-CV diagnoses was performed in AllofUS cohort (AoU; N=249,906). RESULTS: Among the 76 PTSD-susceptibility risk loci, 33 loci exhibited local rg with 45 CV-EHR traits (|rg|≥0.4), four loci with eight heart imaging traits(|rg|≥0.5), and 44 loci with LE8 factors (|rg|≥0.36) in MVP. Among significantly correlated loci, we found shared causal variants (colocalization probability > 80%) between PTSD and 17 CV-EHR (in MVP) at 11 loci in MVP, that also replicated in UKBB and/or other cohorts. Of the 17 traits, the observational analysis in the AoU showed PTSD was associated with 13 CV-EHR traits after accounting for socioeconomic factors and depression diagnosis. PTSD colocalized with eight heart imaging traits on 2 loci and with LE8 factors on 31 loci. Leveraging blood and brain proteome expression, we found 33 and 122 genes, respectively, shared between PTSD and CVD. Blood proteome genes were related to neuronal and immune processes, while the brain proteome genes converged on metabolic and calcium-modulating pathways (FDR p <0.05). Drug repurposing analysis highlighted DRD2, NOS1, GFAP, and POR as common targets of psychiatric and CV drugs. CONCLUSION: PTSD-CV comorbidities exhibit shared risk loci, and genes involved in tissue-specific regulatory mechanisms.

Early Inflammation and Interferon Signaling Direct Enhanced Intestinal Crypt Regeneration after Proton FLASH Radiotherapy.

Ultra-high dose rate ("FLASH") radiotherapy (>40-60 Gy/s) is a promising new radiation modality currently in human clinical trials. Previous studies showed that FLASH proton radiotherapy (FR) improves toxicity of normal tissues compared to standard proton radiotherapy (SR) without compromising anti-tumor effects. Understanding this normal tissue sparing effect may offer insight into how toxicities from cancer therapy can be improved. Here, we show that compared to SR, FR resulted in improved acute weight recovery and survival in mice after whole-abdomen irradiation. Improved morbidity and mortality after FR were associated with greater proliferation of damage-induced epithelial progenitor cells followed by improved tissue regeneration. FR led to the accelerated differentiation of revival stem cells (revSCs), a rare damage-induced stem cell required for intestinal regeneration, and to qualitative and quantitative changes in activity of signaling pathways important for revSC differentiation and epithelial regeneration. Specifically, FR resulted in greater infiltration of macrophages producing TGF-ß, a cytokine important for revSC induction, that was coupled to augmented TGF-ß signaling in revSCs. In pericryptal fibroblasts, FR resulted in greater type I IFN (IFN-I) signaling, which directly stimulates production of FGF growth factors supporting revSC proliferation. Accordingly, the ability of FR to improve epithelial regeneration and morbidity was dependent on IFN-I signaling. In the context of SR, however, IFN-I had a detrimental effect and promoted toxicity. Thus, a tissue-level signaling network coordinated by differences in IFN-I signaling and involving stromal cells, immune cells, and revSCs underlies the ability of FLASH to improve normal tissue toxicity without compromising anti-tumor efficacy.

Disseminated Gonococcal Infection Presenting as Isolated Septic Arthritis: A Case Report and Review of Literature.

Neisseria gonorrhoeae is a gram-negative diplococcus that passes from one person to another through sexual contact. On rare occasions, Neisseria gonorrhoeae may spread from the primary mucosal site to distant parts of the body and present with signs of systemic illness; this is commonly known as disseminated gonococcal infection (DGI). We present a case report of an 18-year-old patient who was diagnosed with septic arthritis of the right third metacarpophalangeal (MCP) joint without mucosal involvement or systemic symptoms and who was found to have gonococcal bacteremia. This case highlights the importance of clinician awareness of the many extragenital manifestations of DGI and a high index of suspicion in the setting of septic arthritis and high-risk sexual practices. Diagnosing DGI early and providing prompt treatment may prevent complications of sepsis, joint destruction, and a prolonged hospital stay.