Numbers of Exchangeable Hydrogens from LC-MS Data of Heavy Water Metabolically Labeled Samples.

Labeling with deuterium oxide (D2O) has emerged as one of the preferred approaches for measuring the synthesis of individual proteins in vivo. In these experiments, the synthesis rates of proteins are determined by modeling mass shifts in peptides during the labeling period. This modeling depends on a theoretical maximum enrichment determined by the number of labeling sites (NEH) of each amino acid in the peptide sequence. Currently, NEH is determined from one set of published values. However, it has been demonstrated that NEH can differ between species and potentially tissues. The goal of this work was to determine the number of NEH for each amino acid within a given experiment to capture the conditions unique to that experiment. We used four methods to compute the NEH values. To test these approaches, we used two publicly available data sets. In a de novo approach, we compute NEH values and the label enrichment from the abundances of three mass isotopomers. The other three methods use the complete isotope profiles and body water enrichment in deuterium as an input parameter. They determine the NEH values by (1) minimizing the residual sum of squares, (2) from the mole percent excess of labeling, and (3) the time course profile of the depletion of the relative isotope abundance of monoisotope. In the test samples, the method using residual sum of squares performed the best. The methods are implemented in a tool for determining the NEH for each amino acid within a given experiment to use in the determination of protein synthesis rates using D2O.

Association between summertime emergency department visits and maximum daily heat index in rural and non-rural areas of Virginia (2015-2022).

There is growing evidence that high ambient temperatures are associated with a range of adverse health outcomes. Further evidence suggests differences in rural versus non-rural populations' vulnerability to heat-related adverse health outcomes. The current project aims to 1) refine estimated associations between maximum daily heat index (HI) and emergency department (ED) visits in regions of Virginia, and 2) compare associations between maximum daily HI and ED visits in rural versus non-rural areas of Virginia and within those areas, for persons 65 years of age and older versus those younger than 65 years. Our study utilized 16,873,213 healthcare visits from Virginia facilities reporting to the Virginia Department of Health syndromic surveillance system between May and September 2015-2022. Federal Office of Rural Health Policy defined rural areas were assigned to patient home ZIP code. The estimated daily maximum HI at which ED visits begin to rise varies between 25 °C and 33 °C across climate zones and regions of Virginia. Across all regions, estimated ED visits attributable to days with maximum HI above 25.7 °C were higher in rural areas (3.7%, 95% CI: 3.5%, 3.9%) versus in non-rural areas (3.1%, 95% CIs: 3.0%, 3.2%). Patients aged 0-64 years had a higher estimated heat attributable fraction of ED visits (4.2%, 95% CI: 4.0%, 4.3%) than patients 65 years and older (3.1%, 95% CI: 2.9%, 3.4%). Rural patients older than 65 have a higher estimated fraction of heat attributable ED visits (2.7%, 95% CI: 2.2%, 3.1%) compared to non-rural patients 65 years and older (1.5%, 95% CI: 1.3%, 1.8%). State-level syndromic surveillance data can be used to optimize heat warning messaging based on expected changes in healthcare visits given a set of meteorological variables, and can be further refined based on climate, rurality and age.

Cutibacterium acnes invades submicron osteocyte lacuno-canalicular networks following implant-associated osteomyelitis.

Cutibacterium acnes, part of normal skin flora, is increasingly recognized as an opportunistic pathogen capable of causing chronic prosthetic joint infections (PJI) associated with total hip and knee arthroplasty. However, there is a paucity of literature examining the pathogenesis of C. acnes during PJI. To study this, we developed an implant-associated osteomyelitis murine model in which 8-10-week-old C57BL6 mice were subjected to transtibial implantation of titanium or stainless-steel L-shaped pins contaminated with C. acnes. Postsurgery, mice were killed on Days 14 and 28 for terminal assessments of (1) bacterial load in bone, implant, and internal organs (heart, spleen, kidney, and liver), (2) bone osteolysis (micro-CT), (3) abscess formation (histology), and (4) systematic electron microscopy (EM). In vitro scanning EM (SEM) confirmed that C. acnes can form biofilms on stainless-steel and titanium implants. In mice, C. acnes could persist for 28 days in the tibia. Also, we observed C. acnes dissemination to internal organs. C. acnes chronic osteomyelitis revealed markedly reduced bone osteolysis and abscess formation compared to Staphylococcus aureus infections. Importantly, transmission EM (TEM) investigation revealed the presence of C. acnes within canaliculi, demonstrating that C. acnes can invade the osteocyte lacuno-canalicular networks (OLCN) within bone. Our preliminary pilot study, for the first time, revealed that the OLCN in bone can be a reservoir for C. acnes and potentially provides a novel mechanism of why C. acnes chronic implant-associated bone infections are difficult to treat.

Machine learning for automating subjective clinical assessment of gait impairment in people with acquired brain injury - a comparison of an image extraction and classification system to expert scoring.

BACKGROUND: Walking impairment is a common disability post acquired brain injury (ABI), with visually evident arm movement abnormality identified as negatively impacting a multitude of psychological factors. The International Classification of Functioning, Disability and Health (ICF) qualifiers scale has been used to subjectively assess arm movement abnormality, showing strong intra-rater and test-retest reliability, however, only moderate inter-rater reliability. This impacts clinical utility, limiting its use as a measurement tool. To both automate the analysis and overcome these errors, the primary aim of this study was to evaluate the ability of a novel two-level machine learning model to assess arm movement abnormality during walking in people with ABI. METHODS: Frontal plane gait videos were used to train four networks with 50%, 75%, 90%, and 100% of participants (ABI: n = 42, healthy controls: n = 34) to automatically identify anatomical landmarks using DeepLabCut™ and calculate two-dimensional kinematic joint angles. Assessment scores from three experienced neurorehabilitation clinicians were used with these joint angles to train random forest networks with nested cross-validation to predict assessor scores for all videos. Agreement between unseen participant (i.e. test group participants that were not used to train the model) predictions and each individual assessor's scores were compared using quadratic weighted kappa. One sample t-tests (to determine over/underprediction against clinician ratings) and one-way ANOVA (to determine differences between networks) were applied to the four networks. RESULTS: The machine learning predictions have similar agreement to experienced human assessors, with no statistically significant (p < 0.05) difference for any match contingency. There was no statistically significant difference between the predictions from the four networks (F = 0.119; p = 0.949). The four networks did however under-predict scores with small effect sizes (p range = 0.007 to 0.040; Cohen's d range = 0.156 to 0.217). CONCLUSIONS: This study demonstrated that machine learning can perform similarly to experienced clinicians when subjectively assessing arm movement abnormality in people with ABI. The relatively small sample size may have resulted in under-prediction of some scores, albeit with small effect sizes. Studies with larger sample sizes that objectively and automatically assess dynamic movement in both local and telerehabilitation assessments, for example using smartphones and edge-based machine learning, to reduce measurement error and healthcare access inequality are needed.

Colossal Core/Shell CdSe/CdS Quantum Dot Emitters.

Single-photon sources are essential for advancing quantum technologies with scalable integration being a crucial requirement. To date, deterministic positioning of single-photon sources in large-scale photonic structures remains a challenge. In this context, colloidal quantum dots (QDs), particularly core/shell configurations, are attractive due to their solution processability. However, traditional QDs are typically small, about 3 to 6 nm, which restricts their deterministic placement and utility in large-scale photonic devices, particularly within optical cavities. The largest existing core/shell QDs are a family of giant CdSe/CdS QDs, with total diameters ranging from about 20 to 50 nm. Pushing beyond this size limit, we introduce a synthesis strategy for colossal CdSe/CdS QDs, with sizes ranging from 30 to 100 nm, using a stepwise high-temperature continuous injection method. Electron microscopy reveals a consistent hexagonal diamond morphology composed of 12 semipolar {101̅1} facets and one polar (0001) facet. We also identify conditions where shell growth is disrupted, leading to defects, islands, and mechanical instability, which suggest synthetic requirements for growing crystalline particles beyond 100 nm. The stepwise growth of thick CdS shells on CdSe cores enables the synthesis of emissive QDs with long photoluminescence lifetimes of a few microseconds and suppressed blinking at room temperature. Notably, QDs with 80 and 100 CdS monolayers exhibit high single-photon emission purity with second-order photon correlation g(2)(0) values below 0.2.

The Role of Glutamate and Blood-Brain Barrier Disruption as a Mechanistic Link between Epilepsy and Depression.

Epilepsy is associated with substantial neuropsychiatric impairments that persist long after the onset of the condition, significantly impacting quality of life. The goal of this review was to uncover how the pathological consequences of epilepsy, such as excessive glutamate release and a disrupted blood-brain barrier (BBB), contribute to the emergence of neuropsychiatric disorders. We hypothesize that epilepsy induces a dysfunctional BBB through hyperexcitation, which then further amplifies post-ictal glutamate levels and, thus, triggers neurodegenerative and neuropsychiatric processes. This review identifies the determinants of glutamate concentration levels in the brain and explores potential therapeutic interventions that restore BBB integrity. Our focus on therapeutic BBB restoration is guided by the premise that it may improve glutamate regulation, consequently mitigating the neurotoxicity that contributes to the onset of neuropsychiatric symptoms.

Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson's disease in vivo.

Abnormal alpha-synuclein (αSyn) and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim to visualize αSyn inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. The fluorescent pyrimidoindole derivative THK-565 probe was characterized by means of recombinant fibrils and brains from 10- to 11-month-old M83 mice. Concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging were subsequently performed in vivo. Structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 T as well as scanning transmission x-ray microscopy (STXM) were performed to characterize the iron deposits in the perfused brains. Immunofluorescence and Prussian blue staining were further performed on brain slices to validate the detection of αSyn inclusions and iron deposition. THK-565 showed increased fluorescence upon binding to recombinant αSyn fibrils and αSyn inclusions in post-mortem brain slices from patients with PD and M83 mice. Administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 min post-intravenous injection by wide-field fluorescence compared to nontransgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe3+ form, as evinced by the STXM results. In conclusion, we demonstrated in vivo mapping of αSyn by means of noninvasive epifluorescence and vMSOT imaging and validated the results by targeting the THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo.

Modulation of sleep/wake patterns by gephyrin phosphorylation status.

Sleep/wake cycles intricately shape physiological activities including cognitive brain functions, yet the precise molecular orchestrators of sleep remain elusive. Notably, the clinical impact of benzodiazepine drugs underscores the pivotal role of GABAergic neurotransmission in sleep regulation. However, the specific contributions of distinct GABAA receptor subtypes and their principal scaffolding protein, gephyrin, in sleep dynamics remain unclear. The evolving role of synaptic phospho-proteome alterations at excitatory and inhibitory synapses suggests a potential avenue for modulating gephyrin and, consequently, GABAARs for sleep through on-demand kinase recruitment. Our study unveils the distinctive roles of two prevalent GABAA receptor subtypes, α1- and α2-GABAARs, in influencing sleep duration and electrical sleep activity. Notably, the absence of α1-GABAARs emerges as central in sleep regulation, manifesting significant alterations in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep during dark or active phases, accompanied by altered electroencephalogram (EEG) patterns across various frequencies. Gephyrin proteomics analysis reveals sleep/wake-dependent interactions with a repertoire of known and novel kinases. Crucially, we identify the regulation of gephyrin interaction with ERK1/2, and phosphorylations at serines 268 and 270 are dictated by sleep/wake cycles. Employing AAV-eGFP-gephyrin or its phospho-null variant (S268A/S270A), we disrupt sleep either globally or locally to demonstrate gephyrin phosphorylation as a sleep regulator. In summary, our findings support the local cortical sleep hypothesis and we unveil a molecular mechanism operating at GABAergic synapses, providing critical insights into the intricate regulation of sleep.

Ligand Equilibrium Influences Photoluminescence Blinking in CsPbBr3: A Change Point Analysis of Widefield Imaging Data.

Photoluminescence intermittency remains one of the biggest challenges in realizing perovskite quantum dots (QDs) as scalable single photon emitters. We compare CsPbBr3 QDs capped with different ligands, lecithin, and a combination of oleic acid and oleylamine, to elucidate the role of surface chemistry on photoluminescence intermittency. We employ widefield photoluminescence microscopy to sample the blinking behavior of hundreds of QDs. Using change point analysis, we achieve the robust classification of blinking trajectories, and we analyze representative distributions from large numbers of QDs (Nlecithin = 1308, Noleic acid/oleylamine = 1317). We find that lecithin suppresses blinking in CsPbBr3 QDs compared with oleic acid/oleylamine. Under common experimental conditions, lecithin-capped QDs are 7.5 times more likely to be nonblinking and spend 2.5 times longer in their most emissive state, despite both QDs having nearly identical solution photoluminescence quantum yields. We measure photoluminescence as a function of dilution and show that the differences between lecithin and oleic acid/oleylamine capping emerge at low concentrations during preparation for single particle experiments. From experiment and first-principles calculations, we attribute the differences in lecithin and oleic acid/oleylamine performance to differences in their ligand binding equilibria. Consistent with our experimental data, density functional theory calculations suggest a stronger binding affinity of lecithin to the QD surface compared to oleic acid/oleylamine, implying a reduced likelihood of ligand desorption during dilution. These results suggest that using more tightly binding ligands is a necessity for surface passivation and, consequently, blinking reduction in perovskite QDs used for single particle and quantum light experiments.

Clinical and genetic risk factors for progressive fibrosis in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Fibrosis-4 (FIB4) is a recommended noninvasive test to assess hepatic fibrosis among patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we used FIB4 trajectory over time (ie, "slope" of FIB4) as a surrogate marker of liver fibrosis progression and examined if FIB4 slope is associated with clinical and genetic factors among individuals with clinically defined MASLD within the Million Veteran Program Cohort. METHODS: In this retrospective cohort study, FIB4 slopes were estimated through linear regression for participants with clinically defined MASLD and FIB4 <2.67 at baseline. FIB4 slope was correlated with demographic parameters and clinical outcomes using logistic regression and Cox proportional hazard models. FIB4 slope as a quantitative phenotype was used in a genome-wide association analysis in ancestry-specific analysis and multiancestry meta-analysis using METAL. RESULTS: FIB4 slopes, generated from 98,361 subjects with MASLD (16,045 African, 74,320 European, and 7996 Hispanic), showed significant associations with sex, ancestry, and cardiometabolic risk factors (p < 0.05). FIB4 slopes also correlated strongly with hepatic outcomes and were independently associated with time to cirrhosis. Five genetic loci showed genome-wide significant associations (p < 5 × 10-8) with FIB4 slope among European ancestry subjects, including 2 known (PNPLA3 and TM6SF2) and 3 novel loci (TERT 5.1 × 10-11; LINC01088, 3.9 × 10-8; and MRC1, 2.9 × 10-9). CONCLUSIONS: Linear trajectories of FIB4 correlated significantly with time to progression to cirrhosis, with liver-related outcomes among individuals with MASLD and with known and novel genetic loci. FIB4 slope may be useful as a surrogate measure of fibrosis progression.

Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals or no treatment in England: a retrospective cohort study.

OBJECTIVE: To describe characteristics and acute clinical outcomes for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated patients at highest risk per National Health Service (NHS) criteria. METHODS: Retrospective study of non-hospitalized patients between 1 December 2021 and 31 May 2022, using data from the Discover-NOW dataset (North-West London). Included patients were aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated but expected to be eligible for early treatment per NHS highest-risk criteria. COVID-19-related and all-cause hospitalizations were reported for 28 days from COVID-19 diagnosis (index). Subgroup analyses were conducted in patients with advanced renal disease, those aged 18-64 and ≥65 years, and by period of Omicron BA.1, BA.2 and BA.5 (post-hoc exploratory) predominance. RESULTS: Overall, 1503 treated and 4044 eligible high-risk untreated patients were included. A high proportion of patients on sotrovimab had advanced renal disease (29.3%), ≥3 high-risk comorbidities (47.6%) and were aged ≥65 years (36.9%). Five of 696 (0.7%) patients on sotrovimab, <5/337 (0.3-1.2%) on nirmatrelvir/ritonavir, 10/470 (2.1%) on molnupiravir and 114/4044 (2.8%) untreated patients were hospitalized with COVID-19. Similar results were observed across all subgroups. The proportion of patients dying within 28 days of the index period was similarly low across all cohorts (<2%). CONCLUSION: Patients receiving sotrovimab appeared to show evidence of multiple high-risk comorbidities. Low hospitalization rates were observed for all treated cohorts across subgroups and periods of predominant variants of concern. These results require confirmation with comparative effectiveness analyses adjusting for differences in underlying patient characteristics.

Strategic use of resources to enhance colorectal cancer screening for patients with diabetes (SURE: CRC4D) in federally qualified health centers: a protocol for hybrid type ii effectiveness-implementation trial.

BACKGROUND: Persons with diabetes have 27% elevated risk of developing colorectal cancer (CRC) and are disproportionately from priority health disparities populations. Federally qualified health centers (FQHCs) struggle to implement CRC screening programs for average risk patients. Strategies to effectively prioritize and optimize CRC screening for patients with diabetes in the primary care safety-net are needed. METHODS: Guided by the Exploration, Preparation, Implementation and Sustainment Framework, we conducted a stakeholder-engaged process to identify multi-level change objectives for implementing optimized CRC screening for patients with diabetes in FQHCs. To identify change objectives, an implementation planning group of stakeholders from FQHCs, safety-net screening programs, and policy implementers were assembled and met over a 7-month period. Depth interviews (n = 18-20) with key implementation actors were conducted to identify and refine the materials, methods and strategies needed to support an implementation plan across different FQHC contexts. The planning group endorsed the following multi-component implementation strategies: identifying clinic champions, development/distribution of patient educational materials, developing and implementing quality monitoring systems, and convening clinical meetings. To support clinic champions during the initial implementation phase, two learning collaboratives and bi-weekly virtual facilitation will be provided. In single group, hybrid type 2 effectiveness-implementation trial, we will implement and evaluate these strategies in a in six safety net clinics (n = 30 patients with diabetes per site). The primary clinical outcomes are: (1) clinic-level colonoscopy uptake and (2) overall CRC screening rates for patients with diabetes assessed at baseline and 12-months post-implementation. Implementation outcomes include provider and staff fidelity to the implementation plan, patient acceptability, and feasibility will be assessed at baseline and 12-months post-implementation. DISCUSSION: Study findings are poised to inform development of evidence-based implementation strategies to be tested for scalability and sustainability in a future hybrid 2 effectiveness-implementation clinical trial. The research protocol can be adapted as a model to investigate the development of targeted cancer prevention strategies in additional chronically ill priority populations. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (NCT05785780) on March 27, 2023 (last updated October 21, 2023).

Mendelian randomization analyses clarify the effects of height on cardiovascular diseases.

An inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested causal association. However, the extent to which the effect estimated by MR can be explained by cardiovascular, anthropometric, lung function, and lifestyle-related risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized a well-powered set of genetic instruments for human stature, comprising >1,800 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height (~6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 0.02). However, multivariable analyses demonstrated independent effects of height on other cardiovascular traits beyond CAD, consistent with epidemiologic associations and univariable MR experiments. In contrast with published reports, we observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest the impact of height on CAD risk beyond previously established cardiovascular risk factors is minimal and not explained by lung function measures.

Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.

Effect of biological sex and short-term high-fat diet on cellular proliferation, ribosomal biogenesis, and targeted protein abundance in murine articular cartilage.

Objective: To identify factors contributing to sex-differences in OA risk by evaluating the short-term effect of high-fat (HF) diet on sex-specific changes in cartilage cell proliferation, ribosomal biogenesis, and targeted extra-cellular and cellular protein abundance. Materials and methods: Knee cartilage was harvested to the subchondral bone from 20-week-old female and male C57BL/6J mice fed a low-fat or HF diet for 4 weeks and labeled with deuterium oxide for 1, 3, 5, 7, 15, or 21 days. Deuterium enrichment was quantified in isolated DNA and RNA to measure cell proliferation and ribosomal biogenesis, respectively. Protein concentration was measured using targeted high resolution accurate mass spectrometry. Results: HF diet increased the maximal deuterium incorporation into DNA from approximately 40 to 50%, albeit at a slower rate. These findings, which were magnified in female versus male mice, indicate a greater number of proliferating cells with longer half-lives under HF diet conditions. HF diet caused distinct sex-dependent effects on deuterium incorporation into RNA, increasing the fraction of ribosomes undergoing biogenesis in male mice and doubling the rate of ribosome biogenesis in female mice. HF diet altered cartilage protein abundance similarly in both sexes, except for matrilin-3, which was more abundant in HF versus LF conditions in female mice only. Overall, HF diet treatment had a stronger effect than sex on cartilage protein abundance, with most changes involving extracellular matrix and matrix-associated proteins. Conclusions: Short-term HF diet broadly altered cartilage matrix protein abundance, while sex-dependent effects primarily involved differences in cell proliferation and ribosomal biogenesis.

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein.

PURPOSE: There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils. METHODS: SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aß)42, K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies. RESULTS: We optimized the protocol for the immobilization of Aß42, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aß in arcAß mice, and AT-8/AT-100-positivity in pR5 mice. CONCLUSION: SPR measurements of small molecules binding to Aß42, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.

Expanded Polytetrafluoroethylene Mesh in Chest-wall Reconstruction: A 27-year Experience.

OBJECTIVES: To evaluate the success of expanded polytetrafluoroethylene (ePTFE) mesh in chest-wall reconstruction. METHODS: We retrospectively reviewed patients who underwent ePTFE (Gore-Tex®) chest-wall reconstruction. The main outcome was a mesh-related event, defined as a mesh-related reoperation (e.g., mesh infection requiring debridement with/without explant, tumor recurrence with explant) and/or structural dehiscence/mesh loosening with/without a hernia. Demographics and surgical outcomes were reported. RESULTS: 246 reconstructions met inclusion (1994-2021). Fifty-five (22.4%) reconstructions had mesh-related events within a median of 1.08 years (IQR 0.08, 4.53) postoperatively; those without had a stable chest for a median of 3.9 years (IQR, 1.59, 8.23, p<0.001). Forty-one (16.6%) of meshes became infected, requiring reoperation. Eighty-eight percent (36/41) were completely explanted; 8.3% (3/36) required additional mesh placement. Predictors of mesh-related events were prior chest-wall radiation (OR=9.73, CI 3.47 to 30.10, p<0.001), higher BMI (OR 1.08, CI 1.01 to 1.16, p=0.019), and larger defects (OR 1.48, CI 1.02 to 2.17, p=0.042). The risk of mesh-related events with obesity was higher with prior chest-wall radiation. CONCLUSIONS: Most (78%) patients with an ePTFE mesh had a stable reconstruction after a median of 4 years. Obesity, larger defects, and prior chest-wall radiation were associated with a higher risk of a mesh-related event mostly due to mesh infections. Seventeen percent of reconstructions had reoperation for mesh infection; 88% were completely explanted. Only 8% required replacement mesh, suggesting that experienced surgeons can safely manage them without replacement. Future studies should compare various meshes for high-risk patients to help guide the optimal mesh selection.

A real-time prognostic model for venous thromboembolic events among hospitalized adults.

Background: Hospital-acquired venous thromboembolism (HA-VTE) is a leading cause of morbidity and mortality among hospitalized adults. Guidelines recommend use of a risk-prediction model to estimate HA-VTE risk for individual patients. Extant models do not perform well for broad patient populations and are not conducive to automation in clinical practice. Objectives: To develop an automated, real-time prognostic model for venous thromboembolism during hospitalization among all adult inpatients using readily available data from the electronic health record. Methods: The derivation cohort included inpatient hospitalizations ("encounters") for patients ≥16 years old at Vanderbilt University Medical Center between 2018 and 2020 (n = 132,330). HA-VTE events were identified using International Classification of Diseases, 10th Revision, codes. The prognostic model was developed using least absolute shrinkage and selection operator regression. Temporal external validation was performed in a validation cohort of encounters between 2021 and 2022 (n = 62,546). Prediction performance was assessed by discrimination accuracy (C statistic) and calibration (integrated calibration index). Results: There were 1187 HA-VTEs in the derivation cohort (9.0 per 1000 encounters) and 864 in the validation cohort (13.8 per 1000 encounters). The prognostic model included 25 variables, with placement of a central line among the most important predictors. Prediction performance of the model was excellent (C statistic, 0.891; 95% CI, 0.882-0.900; integrated calibration index, 0.001). The model performed similarly well across subgroups of patients defined by age, sex, race, and type of admission. Conclusion: This fully automated prognostic model uses readily available data from the electronic health record, exhibits superior prediction performance compared with existing models, and generates granular risk stratification in the form of a predicted probability of HA-VTE for each patient.

[Cholestasis, delirium and pulmonary nocardiosis in a man with systemic lupus erythematosus of late onset]. / Colestasis, delirium y nocardiosis pulmonar en un varón con lupus eritematoso sistémico de inicio tardío.

A case is presented of a 64-year-old male patient who was admitted because of delirium, jaundice, a pattern of cholestasis in the liver profile and a right lung mass in the context of a constitutional syndrome and weight loss in the last eight months. The lung mass was punctured and the culture of the obtained material developed white colonies, identified by mass spectrometry (MALDI-TOF) as Nocardia cyriacigeorgica. Regarding the clinical diagnosis, it was considered as systemic lupus erythematosus (SLE), on the basis of fulfilling 8 criteria according to SLICC 2012 group, and 24 points according to EULAR/ACR 2019. The liver biopsy showed a mixt cellular infiltrate in portal spaces, with absence of interphase hepatitis and presence of peripheral ductular reaction. These findings were interpreted as liver compromise relate to SLE. Delirium was also considered as a neurological manifestation related to SLE on the basis of ruling out other causes. After being treated with antibiotics and documenting a reduction in the size of the lung mass he received cyclophosphamide in intravenous pulses, achieving normalization of his liver profile and his state of consciousness, and a progressively weight recovering. A year after he was in good health. The report of this case is justified because of the rare presenting form of late onset SLE, as well as the concomitant pulmonary nocardiosis in the absence of previous immunosuppressant treatment.

Se presenta el caso de un varón de 64 años que fue internado por delirium asociado a ictericia con patrón de colestasis en el hepatograma, y una masa en el pulmón derecho en el contexto de pérdida de peso y síndrome constitucional de 8 meses de evolución. Se realizó punción de la masa pulmonar cuyo cultivo desarrolló colonias blanquecinas identificadas como Nocardia cyriacigeorgica por espectrometría de masas (MALDI-TOF MS). Se llegó al diagnóstico de lupus eritematosos sistémico (LES) por presentar 8 de los criterios de acuerdo con el grupo SLICC 2012 y 24 puntos de acuerdo a los criterios EULAR/ACR 2019. La biopsia hepática mostró leve y variable infiltrado inflamatorio mixto en espacios porta, con ausencia de hepatitis de interfase y presencia de reacción ductular periférica. Se interpretaron estos hallazgos como vinculados a hepatopatía por LES. El delirium fue interpretado como afectación neurológica por LES en base al descarte de otras enfermedades. Recibió tratamiento antibiótico y tras constatarse reducción del tamaño de la masa pulmonar se administraron pulsos de ciclofosfamida intravenosa. Evolucionó favorablemente, con normalización del hepatograma y el estado de conciencia, y recuperación del peso en forma progresiva. Al año se lo encontró en buen estado de salud. Justifica el reporte del caso la rara forma de presentación del LES de comienzo tardío, así como la nocardiosis pulmonar concomitante sin tratamiento inmunosupresor previo.