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Purpose: To investigate the influence of a new photochromic spectacle lens on glare discomfort (GD) and photostress recovery time (PRT) in normal healthy subjects. A subject-masked within-subject comparison was performed using the fully activated state of Transitions® Gen STM and clear control. Methods: 30 participants (M = 19.2 ± 1.3 years) were tested. GD was assessed both physically, by measuring palpebral fissure size, and subjectively, via a 5-point Likert scale. PRT was measured as the amount of time necessary to regain visual function after an intense (∼15 % bleach) 5-second exposure to a broadband (emulated sunlight) light stressor. Results: GD, measured both physically and subjectively was significantly reduced (p

Pulmonary arteriovenous malformations create continuous shunting of unoxygenated blood through the lungs into the systemic circulation. These malformations are asymptomatic if small, but cause serious symptoms as they grow in size. Treatment primarily consists of endovascular embolization; lobectomy is preserved for recurring or endovascularly untreatable cases. We describe a case of a 24-year-old man who was first treated with coil embolization 10 years previously, with complete symptom resolution. However, more recently he noted recurrent exercise intolerance, with shortness of breath and hypoxemia. After repeat re-embolization, a computed tomography scan noted some persistent flow. Given the patient's young age, we considered resection as a definite therapy. The patient underwent an uncomplicated robot-assisted right lower lobectomy. Afterward, his symptoms resolved completely. In selected cases, robotic lobectomy for pulmonary arteriovenous malformation is feasible and safe.

Large-bore aspiration thrombectomy is emerging as a promising alternative for thrombus removal in acute pulmonary embolism (PE). In this article, we report a successful case with the newly approved AlphaVac F1885 device in a 76-year-old patient presenting with an intermediate- to high-risk acute PE. Preoperative imaging demonstrated bilateral PE with a modified miller index of 30 and an right ventricle-to-left ventricle ratio of 2.1. Mechanical thrombectomy was performed under local anesthesia with mild sedation. The pulmonary artery pressures decreased from 85/27 to 46/13 immediately after thrombectomy. The postoperative course was notable for marked symptom improvement and repeat imaging showed a 63% decrease in clot burden with a decrease in right ventricle-to-left ventricle ratio to 1.3.

Summary: The lymphatic fluid is the conduit by which part of the tissue “omics” is transported to the draining lymph node for immunosurveillance. Following cannulation of the pre-nodal cervical and mesenteric afferent lymphatics, herein we investigate the lymph proteomic composition, uncovering that its composition varies according to the tissue of origin. Tissue specificity is also reflected in the dendritic cell-major histocompatibility complex class II-eluted immunopeptidome harvested from the cervical and mesenteric nodes. Following inflammatory disruption of the gut barrier, the lymph antigenic and inflammatory loads are analyzed in both mice and subjects with inflammatory bowel diseases. Gastrointestinal tissue damage reflects the lymph inflammatory and damage-associated molecular pattern signatures, microbiome-derived by-products, and immunomodulatory molecules, including metabolites of the gut-brain axis, mapped in the afferent mesenteric lymph. Our data point to the relevance of the lymphatic fluid to probe the tissue-specific antigenic and inflammatory load transported to the draining lymph node for immunosurveillance.

Background: Some studies have suggested the risk of wound complications may be higher using the direct anterior (DA) approach to total hip arthroplasty (THA). This study aimed to compare the risk of early postoperative wound complications between the DA and direct lateral (DL) approaches to THA and to determine patient risk factors that may contribute to this problem. Methods: All patients who underwent primary THA with a single surgeon over a 5-year period were retrospectively reviewed. All patients were treated with either the DA or DL approach. Data collected included patient demographics, surgical approach, and wound status. There was a minimum follow-up of 6 weeks to allow for an adequate assessment of surgical wound healing. Univariate and multivariate analyses were used to compare the 2 approaches. Results: Five hundred seventy-nine patients (77.6%) who underwent DA approach and 167 patients (22.4%) who underwent DL approach were included. Patients who underwent DL approach had a higher body mass index and a higher rate of diabetes than those treated with the DA approach. Forty patients (6.9%) in the DA cohort and 14 (8.4%) in the DL cohort experienced early wound complications, P = .523. After controlling for potential confounding variables, the surgical approach was not an independent risk factor for early postoperative wound complications. Conclusions: While there have been concerns regarding use of the DA approach in patients with higher body mass index and certain medical comorbidities, the results of this study suggest the choice of surgical approach may have minimal effect on the rate of early postoperative wound complications.

The study area is composed of mainly basement rocks, with problems of low yield of groundwater in most of the boreholes drilled. Therefore, this study was carried out to evaluate the hydraulic parameters of the basement aquifers using the vertical electrical sounding (VES), constant rate pumping test, and borehole logs. The mean value of aquifer resistivity and thickness are 408.4 Ωm and 20.2 m. The depth ranges from 20.9-88.0 m with a mean value of 55.5 m; showing appreciable groundwater potential mostly within the southern part. The value of transmissivity and hydraulic conductivity from the resistivity data ranges from 2.058-1761.033 m2/day and 0.205-138.664 m/day with a mean value of 152.251 m2/day and 8.841 m/day, respectively, indicating porous and permeable zones within the southern and northwestern part of the study area. The value of longitudinal conductance and transverse unit resistance ranges from 0.0034-4.2333 m-hom and 38.1-146439 Ωm2 with a mean value of 0.3250 m-hom and 9704.1 Ωm2; indicating poor to moderate protective capacity in almost the entire area except for the small portion within the southern part. The mean value of fracture contrast and the reflection coefficient are 0.743 and -0.333, showing that the southern part has more water-filled fractures. Conclusively, this study reveals, that the aquifer depth ranges from 60-90 m, the transmissivity and hydraulic conductivity demonstrate high porosity and permeability within the southern parts of the study area, and serve as a baseline for groundwater resource management policy in Nigeria.

Background: Post-exertional malaise (PEM) is considered a characteristic feature of chronic multi-symptom illnesses (CMI) like Gulf War illness (GWI); however, its pathophysiology remains understudied. Previous investigations in other CMI populations (i.e., Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) have reported associations between PEM and expression of genes coding for adrenergic, metabolic, and immune function. Objectives: To investigate whether PEM is meditated by gene expression in Veterans with GWI. Methods: Veterans with GWI (n = 37) and healthy control Gulf War Veterans (n = 25) provided blood samples before and after 30-min of cycling at 70% of age-predicted heart rate reserve. Relative quantification of gene expression, symptom measurements, and select cardiopulmonary parameters were compared between groups at pre-, 30 minpost-, and 24 hpost-exercise using a doubly multivariate repeated measures analysis of variance (RM-MANOVA). Mediation analyses were used to test indirect effects of changes in gene expression on symptom responses (i.e., PEM) to the standardized exercise challenge. Results: Veterans with GWI experienced large symptom exacerbations following exercise compared to controls (Cohen's d: 1.65; p

Objective: To evaluate the prognostic significance of detectable circulating cell-free DNA (cfDNA) BRAF V600E/K mutations in patients with advanced melanoma enrolled in a clinical trial without BRAF-targeted therapy. Patients and Methods: BRAF V600E/K mutation status was determined on archived tissue and pretreatment stored plasma from 149 patients with unresectable stage IV melanoma who were enrolled between May 5, 2010 and May 2, 2014 in the North Central Cancer Treatment Group/Alliance N0879 randomized phase 2 clinical trial. Results were reported as presence or absence of cfDNA BRAF V600E/K detection of assay vs tissue. Progression-free survival (PFS) and overall survival (OS) were assessed for patients with and without detectable BRAF mutation. Results: In total, 63 of 149 (42.3%) patients had BRAF V600E/K results for tissue and blood, and 20 of 63 (31.7%) patients had tissue-diagnosed mutant BRAF. Of these, 11 of 20 (55.0%) patients had detectable plasma cfDNA BRAF. Among patients with tissue-mutant BRAF V600E/K, PFS and OS were shorter for those with corresponding cfDNA mutations (PFS, 5.8 vs 12.0 months; P=.051; OS, 9.2 vs 27.1 months; P=.054). Our assay demonstrated sensitivity of 55% (95% CI, 0.322 to 0.768), specificity of 97.7% (95% CI, 0.932 to 1.000), positive predictive value of 91.7% (95% CI, 0.760 to 1.000), and negative predictive value of 82.4% (95% CI, 0.719 to 0.928). Conclusion: In advanced melanoma, detectable cfDNA BRAF V600E/K mutation is present in about half the patients with stage IV with BRAF-mutant melanoma tumor tissue and appears to confer a poorer prognosis when detectable. Given the poorer prognosis, cfDNA can be used to risk-stratify patients with metastatic melanoma in practice or clinical trials.Trial Registration: clinicaltrials.gov Identifier: NCT00976573

Objective: To assess underrepresented undergraduate and postbaccalaureate learners’ perceptions of (1) the medical field, (2) barriers that might prevent individuals from pursuing professional medical careers, and (3) resources that assist in overcoming these barriers. Participants and Methods: A qualitative study with focus groups was designed to achieve the objective. Participants were recruited from a community initiative to provide early exploration of the medical field to disadvantaged and minority individuals. Thirty-five individuals voluntarily participated in semistructured interviews. Audio from the interviews was analyzed using a qualitative descriptive approach and thematic analysis. This study was conducted from October 20, 2018, to April 6, 2019. Results: Participants identified multiple characteristics related to the health care work environment and desirable attributes of health care personnel. The following barriers were identified: financial burden, lacking knowledge of the path to becoming a medical professional, inadequate social support, and lacking the metrics of a competitive candidate. Resources identified by participants to overcome barriers included professional networks and programmatic considerations. Conclusion: The study participants discussed negative and positive aspects of the health care environment, such as implicit and explicit biases and attributes that promote or sustain success. Participants expounded on financial, academic, social, and personal factors as barriers to success. In regard to resources that were believed to be helpful to mitigate barriers and promote success, participants commented on activities that simulate a professional medical environment, include networking with medical personnel, support well-being, and provide exposure to structured information on the process of obtaining professional medical training.

Summary: lncRAP2 is a conserved cytoplasmic lncRNA enriched in adipose tissue and required for adipogenesis. Using purification and in vivo interactome analyses, we show that lncRAP2 forms complexes with proteins that stabilize mRNAs and modulate translation, among them Igf2bp2. Surveying transcriptome-wide Igf2bp2 client mRNAs in white adipocytes reveals selective binding to mRNAs encoding adipogenic regulators and energy expenditure effectors, including adiponectin. These same target proteins are downregulated when either Igf2bp2 or lncRAP2 is downregulated, hindering adipocyte lipolysis. Proteomics and ribosome profiling show this occurs predominantly through mRNA accumulation, as lncRAP2-Igf2bp2 complex binding does not impact translation efficiency. Phenome-wide association studies reveal specific associations of genetic variants within both lncRAP2 and Igf2bp2 with body mass and type 2 diabetes, and both lncRAP2 and Igf2bp2 are suppressed in adipose depots of obese and diabetic individuals. Thus, the lncRAP2-Igf2bp2 complex potentiates adipose development and energy expenditure and is associated with susceptibility to obesity-linked diabetes.

Understanding the pattern of species extinction risk is key to biodiversity conservation. Previous studies showed extinction risk correlates strongly with taxon species richness. However, there is no consistent conclusion to this hypothesis, and patterns differ among different taxonomic groups. Here, we collated lists of vascular plant and terrestrial vertebrate species information on their threatened status in Yunnan Province and performed the first systematical analysis to test the relationship between the proportion of threatened or extinct species and species richness at the family-level of the two above taxa in Yunnan Province, China. We found that extinction risk was not randomly distributed among families and the estimated extinction risk was higher among closer phylogenetic families than expected by chance. Moreover, there were significant negative correlations between extinction risk and family size in vascular plants and terrestrial vertebrates. Our results suggest that family size is a good predictor of extinction risk and extinction risk is related to evolutionary history at family-level among vascular plants and terrestrial vertebrates in Yunnan.

Emerging antimicrobial drug resistance is increasing the complexity involved in treating critical conditions such as bacterial induced sepsis. Methods for diagnosing specific drug resistance tend to be rapid or sensitive, but not both. Detection methods like sequence-specific single-molecule analysis could address this concern if they could be adapted to work on smaller targets similar to those produced in traditional clinical situations. In this work we demonstrate that a 120 bp double stranded polynucleotide with an overhanging single stranded 25 bp probe sequence can be created by immobilizing DNA with a biotin/streptavidin magnetic bead system, labeling with SYBR Gold, and rinsing the excess away while the probe retains multiple fluorophores. These probes with multiple fluorophores can then be used to label a bacterial plasmid target in a sequence-specific manner. These probes enabled the detection of 1 pM plasmid samples containing a portion of an antibiotic resistance gene sequence. This system shows the possibility of improving capture and fluorescence labeling of small nucleic acid fragments, generating lower limits of detection for clinically relevant samples while maintaining rapid processing times.

Summary: Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. Pharmacological inhibition of glycolysis and insulin growth factor (IGF) signaling reduce proliferation and tumorigenesis preferentially in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating an increased use of the glycolysis pathway for enhanced biomass needs via enhancer reprogramming, thus presenting an opportunity for therapeutic intervention through glycolysis or IGF pathway inhibitors.

Summary: Kingdonia uniflora, an alpine herb, has an extremely narrow distribution and represents a model for studying evolutionary mechanisms of species that have adapted to undisturbed environments for evolutionarily long periods of time. We assembled a 1,004.7-Mb draft genome (encoding 43,301 genes) of K. uniflora and found significant overrepresentation in gene families associated with DNA repair, underrepresentation in gene families associated with stress response, and loss of most plastid ndh genes. During the evolutionary process, the overrepresentation of gene families involved in DNA repair could help asexual K. uniflora reduce the accumulation of deleterious mutations, while reducing genetic diversity, which is important in responding to environment fluctuations. The underrepresentation of gene families related to stress response and functional loss of ndh genes could be due to lack or loss of ability to respond to environmental changes caused by long-term adaptation to a relatively stable ecological environment.

The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways. Importantly, such acetylation changes were also observed between benign nevi and malignant melanoma human tissues. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Through these results, we define functionally relevant chromatin states associated with melanoma progression.

Summary: NMDA receptors (NMDARs) play subunit-specific roles in synaptic function and are implicated in neuropsychiatric and neurodegenerative disorders. However, the in vivo consequences and therapeutic potential of pharmacologically enhancing NMDAR function via allosteric modulation are largely unknown. We examine the in vivo effects of GNE-0723, a positive allosteric modulator of GluN2A-subunit-containing NMDARs, on brain network and cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer’s disease (AD). GNE-0723 use dependently potentiates synaptic NMDA receptor currents and reduces brain oscillation power with a predominant effect on low-frequency (12–20 Hz) oscillations. Interestingly, DS and AD mouse models display aberrant low-frequency oscillatory power that is tightly correlated with network hypersynchrony. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in DS and AD mouse models. GluN2A-subunit-containing NMDAR enhancers may have therapeutic benefits in brain disorders with network hypersynchrony and cognitive impairments. : Hanson et al. examine the therapeutic effects of enhancing GluN2A-subunit-containing NMDAR function in Dravet syndrome and Alzheimer’s disease mice. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in both disease models. GluN2A NMDAR enhancers may benefit brain disorders with network hypersynchrony and cognitive impairments. Keywords: J20, epilepsy, learning, memory, APP, Nav1.1, SCN1A, interneuron, EEG, MK-801

Introduction & Aim. The role of age as a predictor of mortality after transjugular intra hepatic portosystemic shunt (TIPS) is controversial. Age has been found to be an important predictor of post-TIPS mortality in some, but not all, studies and is not a component of the MELD score. The purpose of this study was to compare the 90-day survival of subjects with cirrhosis age ≥ 70 years with younger subjects undergoing TIPS.Material and methods. A database of adult with cirrhosis undergoing TIPS from 2003-2011 was analyzed. The primary endpoint was survival 90-days post-TIPS. Survival was analyzed by the Kaplan-Meier method and proportional hazard modeling.Results. 539 subjects met study criteria. 474 (88%) were between the ages of 24-69 and 65 (12%) were age 70-89 years. The groups were similar with respect to the indication for TIPS, mean MELD score and distribution of MELD score. Survival 90-days post-TIPS was 60% in the older cohort compared with 85% in the younger cohort (p < 0.001). Proportional hazards modeling controlled for comorbidities identified age ≥ 70 and MELD score as predictors of early post-TIPS survival. The hazard ratio associated with age increased monotonically, became significant at age ≥ 70 years (HR 3.22; 95% CI 1.81-5.74; p < 0.001) and exceeded the effect of MELD on survival.Conclusions. Age ≥ 70 was associated with reduced survival within 90 days following TIPS. The findings from this study indicate that age is a relevant consideration in assessing the early mortality risk of TIPS.

Peritalar fracture dislocations typically involve the talar neck and are classified according to Hawkins. To our knowledge, peritalar fracture dislocation involving the talar body has not been formally reported. In this article, we describe a case of peritalar fracture dislocation of the talar body. Keywords: Peritalar dislocation, Talus fracture, Talar body fracture dislocation, Medial subtalar dislocation

Adipocyte differentiation is orchestrated by the ligand-activated nuclear receptor PPARγ. Endogenous ligands comprise oxidized derivatives of arachidonic acid and structurally similar PUFAs. Although expression of PPARγ peaks in mature adipocytes, ligands are produced primarily at the onset of differentiation. Concomitant with agonist production, murine fibroblasts undergo two rounds of mitosis referred to as mitotic clonal expansion. Here we show that mouse embryonic fibroblasts deficient in either of two cell cycle inhibitors, the transcription factor p53 or its target gene encoding the cyclin-dependent kinase inhibitor p21, exhibit increased adipogenic potential. The antiadipogenic effect of p53 relied on its transcriptional activity and p21 expression but was circumvented by administration of an exogenous PPARγ agonist suggesting a linkage between cell cycling and PPARγ ligand production. Indeed, cell cycle inhibitory compounds decreased PPARγ ligand production in differentiating 3T3-L1 preadipocytes. Furthermore, these inhibitors abolished the release of arachidonic acid induced by the hormonal cocktail initiating adipogenesis. Collectively, our results suggest that murine fibroblasts require clonal expansion for PPARγ ligand production at the onset of adipocyte differentiation.

The mitochondrial lipids from avocado fruit, cauliflower buds, and potato tubers, and the lipids of chloroplasts isolated from avocado fruit and from cauliflower leaves were identified and the concentrations were determined. The lipid composition was compared with that of beef heart mitochondria. Phospholipids constituted 50–56% of total lipids in plant mitochondria while this fraction made up 90% of the lipids in beef heart mitochondria. In both cases the chief phospholipids were phosphatidylcholine and phosphatidylethanolamine. A characteristic feature of plant mitochondria was the presence of monogalactosyl- and digalactosyldiglyceride and of sulfolipid. Potato mitochondria differed from the particles of other species investigated by their higher content of galactolipids, sterol glycosides, and carotenoids and lower content of phospholipids and of total lipids in the lipid–protein complex.The galactolipid content was markedly higher in chloroplasts from all sources than in mitochondria. The spectrum of lipids in the phospholipid fraction differed more strikingly between chloroplasts of the leaf and the mitochondria of the bud of cauliflower than between the two organelles of the avocado mesocarp. The fatty acid distribution of individual lipids and of classes of lipids was also more similar in the two organelles of the fruit tissue than in the cauliflower material.

This work reports on laser-processed silicon surfaces' morphological and wetting characteristics. The silicon surfaces were initially exposed to pulsed laser radiation in the femtosecond regime. The laser emitted in its fundamental wavelength (λ = 1030 nm), and the processing was carried out in air at atmospheric pressure. The surfaces were then subjected to electrochemical modification to create micro and nano porosity. The experimental conditions allowed the creation of various hybrid systems based on laser radiation and subsequent electrochemical treatment (using HF-DMSO). This procedure altered the surface wetting behavior from hydrophilic to hydrophobic due to the distinct surface morphology without needing a specific coating.

Summary: Heat pumps are essential for decarbonizing heating, as shown by numerous studies. Their adoption depends significantly on economic attractiveness. Using Great Britain (GB) as a case study, this paper examines the total cost of ownership (TCO) for heat pumps versus gas boilers. TCO is calculated using official energy statistics, field trial data, and residential energy prices, alongside scenario analyses on business as usual, shifting levies from electricity bills to general taxation or to gas bills. Findings reveal that heat pumps provide cost savings for units performing at an above-average efficiency under standard tariffs but yield significant savings with smart tariffs. Results indicate that a carbon tax on gas, matching electricity permit prices, has limited impact. However, shifting levies from electricity to general taxation significantly enhances TCO compared to gas heating, with even greater incentives when levies are shifted to gas heating.

Multifocal nodular hepatic steatosis (MFNHS) is a rare benign clinical entity mimicking metastatic disease. This study is designed to describe the imaging and histopathologic findings and clinical course of patients with MFNHS. In this retrospective study during 2005 and 2023, 10 patients with an imaging and pathologic diagnosis of MFNHS were included. The imaging and histopathology findings were reviewed in each case. The follow-up images were reviewed to assess the clinical course of the disease. The mean age was 50.0 ± 10.5 years, and the male-to-female ratio was 4:6. Three patients had a past medical history of cancer. All patients were found to have lesions suspicious of malignancy on either ultrasound (US) or computed tomography (CT) requiring further workup. Six patients underwent magnetic resonance imaging (MRI), and 4 patients underwent an image-guided biopsy which resulted in hepatic steatosis. During the follow-up period, the majority of patients (71.5%) remained unchanged or improved, while 2 patients (28.5%) progressed. MRI is a reliable modality in detecting and characterizing MFNHS and should be considered to further assess multiple hepatic lesions in cases where the clinical suspicion is not high for metastasis.

The recent growth in renewable energy development in the United States has been accompanied by a simultaneous surge in renewable energy siting ordinances. These zoning laws play a critical role in dictating the placement of wind and solar resources that are critical for achieving low-carbon energy futures. In this context, efficient access to and management of siting ordinance data becomes imperative. The National Renewable Energy Laboratory (NREL) recently introduced a public wind and solar siting database to fill this need. This paper presents a method for harnessing Large Language Models (LLMs) to automate the extraction of these siting ordinances from legal documents, enabling this database to maintain accurate up-to-date information in the rapidly changing energy policy landscape. A novel contribution of this research is the integration of a decision tree framework with LLMs. Our results show that this approach is 85 to 90 % accurate with outputs that can be used directly in downstream quantitative modeling. We discuss opportunities to use this work to support similar large-scale policy research in the energy sector. By unlocking new efficiencies in the extraction and analysis of legal documents using LLMs, this study enables a path forward for automated large-scale energy policy research.

Background: Radicular pain is the most predominant symptom among adults with Lyme neuroborreliosis (LNB) but the duration preceding and following diagnosis remains unknown. We aimed to investigate whether patients with LNB have increased obtainment of analgesics before and after diagnosis and for how long. Methods: We performed a nationwide, population-based, matched cohort study (2009–2021). all Danish residents with LNB (positive Borrelia burgdorferi intrathecal antibody index test and cerebrospinal fluid pleocytosis) were included. To form a comparison cohort, individuals from the general population were randomly extracted and matched 10:1 to patients with LNB on age and sex. Outcomes were obtainment of simple analgesics, antiepileptics, tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, tramadol, and other opioids. We calculated monthly and six-monthly proportions of individuals with obtainment of analgesics and absolute risk differences. Results: 1,056 patients with LNB and 10,560 comparison cohort members were included. An increased proportion of patients with LNB obtained analgesics from 3 months before study inclusion, especially simple analgesics, tramadol, and other opioids. Within the 0–1-month period after study inclusion, patients with LNB most frequently obtained simple analgesics (15 %), antiepileptics (11 %), and tramadol (10 %). Thereafter, obtainment of analgesics declined within a few months. A slightly larger proportion of patients with LNB obtained antiepileptics up to 2.5 years after diagnosis. Conclusions: Up to 3 months preceding diagnosis, LNB was preceded by increased obtainment of analgesics, which suggests diagnostic delay. Importantly, most patients with LNB did not obtain analgesics after the immediate disease course, although obtainment remained more frequent up to 2.5 years after.

Background: The current limit on NO2 concentrations of 40 μg/m3, set by the European Union, has been regularly exceeded in Munich, Germany. This limit will likely be reduced towards the WHO recommended target of 10 μg/m3. Against this backdrop, the city implemented a selective diesel vehicle ban within the existing low-emission zone in February 2023, targeting Euro 4 and older diesel vehicles. Our study investigated the effect of Munich’s selective diesel vehicle ban on NO2 concentrations, focusing on the half-year period following its implementation. Methods: Our study utilized a synthetic control approach (primary analysis) and a controlled interrupted time series approach (secondary analysis). These quasi-experimental methodologies create a ‘counterfactual’ no-intervention scenario, enabling comparison between observed and counterfactual scenarios to estimate an intervention effect. We employed historical controls, using routine data from multiple monitoring stations located within and outside the low-emission zone for 2014 to 2022, and considered possible confounders. Results: NO2 concentrations within Munich’s low-emission zone showed overall declining trends from August 2014 to July 2023. Effects of the selective diesel vehicle ban were small and wide confidence intervals indicate large uncertainty in the magnitude and direction of the effect. At Landshuter Allee, the average intervention effect was −2.67 μg/m3 (95 %-CI = [-12.72; 7.38]), at Stachus it was −2.74 μg/m3 (95 %-CI = [-9.91; 4.42]), and at Lothstrasse it was −1.03 μg/m3 (95 %-CI = [-7.75; 5.69]). The secondary analysis confirmed these findings, reinforcing uncertainty about the effect of the intervention. Conclusion: Our study suggests that Munich’s selective diesel vehicle ban had a limited effect on lowering NO2 concentrations. Possible explanations include the ban’s focus on Euro 4 and older diesel vehicles, many exemptions to the selective ban, and unclear enforcement. This highlights that comprehensive approaches and ongoing, well-designed monitoring and evaluation are crucial for addressing urban air pollution and protecting public health.

Purpose: To gain an understanding of data labeling requirements to train deep learning models for measurement of geographic atrophy (GA) with fundus autofluorescence (FAF) images. Design: Evaluation of artificial intelligence (AI) algorithms. Subjects: The Age-Related Eye Disease Study 2 (AREDS2) images were used for training and cross-validation, and GA clinical trial images were used for testing. Methods: Training data consisted of 2 sets of FAF images; 1 with area measurements only and no indication of GA location (Weakly labeled) and the second with GA segmentation masks (Strongly labeled). Main Outcome Measures: Bland–Altman plots and scatter plots were used to compare GA area measurement between ground truth and AI measurements. The Dice coefficient was used to compare accuracy of segmentation of the Strong model. Results: In the cross-validation AREDS2 data set (n = 601), the mean (standard deviation [SD]) area of GA measured by human grader, Weakly labeled AI model, and Strongly labeled AI model was 6.65 (6.3) mm2, 6.83 (6.29) mm2, and 6.58 (6.24) mm2, respectively. The mean difference between ground truth and AI was 0.18 mm2 (95% confidence interval, [CI], −7.57 to 7.92) for the Weakly labeled model and −0.07 mm2 (95% CI, −1.61 to 1.47) for the Strongly labeled model. With GlaxoSmithKline testing data (n = 156), the mean (SD) GA area was 9.79 (5.6) mm2, 8.82 (4.61) mm2, and 9.55 (5.66) mm2 for human grader, Strongly labeled AI model, and Weakly labeled AI model, respectively. The mean difference between ground truth and AI for the 2 models was −0.97 mm2 (95% CI, −4.36 to 2.41) and −0.24 mm2 (95% CI, −4.98 to 4.49), respectively. The Dice coefficient was 0.99 for intergrader agreement, 0.89 for the cross-validation data, and 0.92 for the testing data. Conclusions: Deep learning models can achieve reasonable accuracy even with Weakly labeled data. Training methods that integrate large volumes of Weakly labeled images with small number of Strongly labeled images offer a promising solution to overcome the burden of cost and time for data labeling. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

We report the generation of a gene-edited human induced pluripotent stem cell (iPSC) line from an Alzheimer’s disease patient-derived iPSC line harbouring the PSEN1 H163R mutation. This line demonstrates pluripotent stem cell morphology, expression of pluripotency markers, and maintains a normal karyotype.

Background: The objective of this review is to evaluate the associations between short-term exposure to radiofrequency electromagnetic fields (RF-EMF) and cognitive performance in human experimental studies. Methods: Online databases (PubMed, Embase, Scopus, Web of Science and EMF-Portal) were searched for studies that evaluated effects of exposure to RF-EMF on seven domains of cognitive performance in human experimental studies. The assessment of study quality was based on the Risk of Bias (RoB) tool developed by the Office of Health Assessment and Translation (OHAT). Random effects meta-analyses of Hedges’s g were conducted separately for accuracy- and speed-related performance measures of various cognitive domains, for which data from at least two studies were available. Finally, the certainty of evidence for each identified outcome was assessed according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: 57,543 records were identified and 76 studies (80 reports) met the inclusion criteria. The included 76 studies with 3846 participants, consisting of humans of different age, sex and health status from 19 countries, were conducted between 1989 and 2021. Quantitative data from 50 studies (52 reports) with 2433 participants were included into the meta-analyses. These studies were performed in 15 countries between 2001 and 2021. The majority of the included studies used head exposure with GSM 900 uplink.None of the meta-analyses observed a statistically significant effect of RF-EMF exposure compared to sham on cognitive performance as measured by the confidence interval surrounding the Hedges’s g or the significance of the z-statistic.For the domain Orientation and Attention, subclass Attention – Attentional Capacity RF-EMF exposure results in little to no difference in accuracy (Hedges’s g 0.024, 95 % CI [−0.10; 0.15], I2 = 28 %, 473 participants).For the domain Orientation and Attention, subclass Attention – Concentration / Focused Attention RF-EMF exposure results in little to no difference in speed (Hedges’s g 0.005, 95 % CI [−0.17; 0.18], I2 = 7 %, 132 participants) and probably results in little to no difference in accuracy; it does not reduce accuracy (Hedges’s g 0.097, 95 % CI [−0.05; 0.24], I2 = 0 %, 217 participants).For the domain Orientation and Attention, subclass Attention – Vigilance RF-EMF exposure probably results in little to no difference in speed and does not reduce speed (Hedges’s g 0.118, 95 % CI [−0.04; 0.28], I2 = 41 %, 247 participants) and results in little to no difference in accuracy (Hedges’s g 0.042, 95 % CI, [−0.09; 0.18], I2 = 0 %, 199 participants).For the domain Orientation and Attention, subclass Attention – Selective Attention RF-EMF exposure probably results in little to no difference in speed and does not reduce speed (Hedges’s g 0.080, 95 % CI [−0.09; 0.25], I2 = 63 %, 452 participants); it may result in little to no difference in accuracy, but it probably does not reduce accuracy (Hedges’s g 0.178, 95 % CI [−0.02; 0.38], I2 = 68 %, 480 participants).For the domain Orientation and Attention, subclass Attention – Divided Attention RF-EMF exposure results in little to no difference in speed (Hedges’s g −0.010, 95 % CI [−0.14; 0.12], I2 = 5 %, 307 participants) and may result in little to no difference in accuracy (Hedges’s g −0.089, 95 % CI [−0.35; 0.18], I2 = 53 %, 167 participants).For the domain Orientation and Attention, subclass Processing Speed − Simple Reaction Time Task RF-EMF exposure results in little to no difference in speed (Hedges’s g 0.069, 95 % CI [−0.02; +0.16], I2 = 29 %, 820 participants).For the domain Orientation and Attention, subclass Processing Speed – 2-Choice Reaction Time Task RF-EMF exposure results in little to no difference in speed (Hedges’s g −0.023, 95 % CI [−0.13; 0.08], I2 = 0 %, 401 participants), and may result in little to no difference in accuracy (Hedges’s g −0.063, 95 % CI [−0.38; 0.25], I2 = 63 %, 117 participants).For the domain Orientation and Attention, subclass Processing Speed – >2-Choice Reaction Time Task RF-EMF exposure results in little to no difference in speed (Hedges’s g −0.054, 95 % CI [−0.14; 0.03], I2 = 0 %, 544 participants) and probably results in little to no difference in accuracy (Hedges’s g −0.129, 95 % CI [−0.30; 0.04], I2 = 0 %, 131 participants).For the domain Orientation and Attention, subclass Processing Speed – Other Tasks RF-EMF exposure probably results in little to no difference in speed and does not reduce speed (Hedges’s g 0.067, 95 % CI [−0.12; 0.26], I2 = 38 %, 249 participants); it results in little to no difference in accuracy (Hedges’s g 0.036, 95 % CI [−0.08; 0.15], I2 = 0 %, 354 participants).For the domain Orientation and Attention, subclass Working Memory – n-back Task (0–3-back) we found Hedges’s g ranging from −0.090, 95 % CI [−0.18; 0.01] to 0.060, 95 % CI [−0.06; 0.18], all I2 = 0 %, 237 to 474 participants, and conclude that RF-EMF exposure results in little to no difference in both speed and accuracy.For the domain Orientation and Attention, subclass Working Memory – Mental Tracking RF-EMF exposure results in little to no difference in accuracy (Hedges’s g −0.047, 95 % [CI −0.15; 0.05], I2 = 0 %, 438 participants).For the domain Perception, subclass Visual and Auditory Perception RF-EMF exposure may result in little to no difference in speed (Hedges’s g −0.015, 95 % CI [−0.23; 0.195], I2 = 0 %, 84 participants) and probably results in little to no difference in accuracy (Hedges’s g 0.035, 95 % CI [−0.13; 0.199], I2 = 0 %, 137 participants).For the domain Memory, subclass Verbal and Visual Memory RF-EMF exposure probably results in little to no difference in speed and does not reduce speed (Hedges’s g 0.042, 95 % CI [−0.15; 0.23], I2 = 0 %, 102 participants); it may result in little to no difference in accuracy (Hedges’s g −0.087, 95 % CI [−0.38; 0.20], I2 = 85 %, 625 participants).For the domain Verbal Functions and Language Skills, subclass Verbal Expression, a meta-analysis was not possible because one of the two included studies did not provide numerical values. Results of both studies did not indicate statistically significant effects of RF-EMF exposure on both speed and accuracy.For the domain Construction and Motor Performance, subclass Motor Skills RF-EMF exposure may reduce speed, but the evidence is very uncertain (Hedges’s g −0.919, 95 % CI [−3.09; 1.26], I2 = 96 %, 42 participants); it probably results in little to no difference in accuracy and does not reduce accuracy (Hedges’s g 0.228, 95 % CI [−0.01; 0.46], I2 = 0 %, 109 participants).For the domain Concept Formation and Reasoning, subclass Reasoning RF-EMF exposure results in little to no difference in speed (Hedges’s g 0.010, 95 % CI [−0.11; 0.13], I2 = 0 %, 263 participants) and probably results in little to no difference in accuracy and does not reduce accuracy (Hedges’s g 0.051, 95 % CI [−0.14; 0.25], I2 = 0 %, 100 participants).For the domain Concept Formation and Reasoning, subclass Mathematical Procedures RF-EMF exposure results in little to no difference in speed (Hedges’s g 0.033, 95 % CI [−0.12; 0.18], I2 = 0 %, 168 participants) and may result in little to no difference in accuracy but probably does not reduce accuracy (Hedges’s g 0.232, 95 % CI [−0.12; +0.59], I2 = 86 %, 253 participants).For the domain Executive Functions there were no studies. Discussion: Overall, the results from all domains and subclasses across their speed- and accuracy-related outcome measures according to GRADE provide high to low certainty of evidence that short-term RF-EMF exposure does not reduce cognitive performance in human experimental studies. For 16 out of 35 subdomains some uncertainty remains, because of limitations in the study quality, inconsistency in the results or imprecision of the combined effect size estimate. Future research should focus on construction and motor performance, elderly, and consideration of both sexes. Other: This review was partially funded by the WHO radioprotection programme.The protocol for this review was registered in Prospero reg. no. CRD42021236168 and published in Environment International (Pophof et al. 2021).

The WHO’s initiative to eliminate cervical cancer by 2030 does not address the increasing incidence of vulvar, anal, and oropharyngeal cancers linked to high-risk HPV. Currently, the prevention of these three cancers faces various obstacles, such as a lack of specialized screening programs, well-defined management guidelines, and widespread public awareness. Without any interventions, the incidence of these three cancers will likely rise in the upcoming years, increasingly affecting younger individuals. We recommend expanding the WHO’s initiative to include vulvar, anal, and oropharyngeal cancers. This involves developing screening and management protocols similar to those for cervical cancer, implementing gender-neutral HPV vaccination programs, establishing clear referral pathways to specialized centers, promoting public awareness, and providing education to healthcare providers and high-risk individuals.

Background: Lyme borreliosis is a tick-borne disease caused by the bacterium Borrelia burgdorferi (Bb) sensu lato complex. Previous studies have suggested an association between Lyme borreliosis and heart failure, which have been suggested to be a possible manifestation of Lyme carditis. We aimed to investigate the risk of heart failure among individuals tested for serum Bb antibodies, and serum Bb seropositive individuals. Methods: We performed a matched nationwide cohort study (Denmark, 1993–2020) and included 52,200 Bb seropositive individuals, and two age- and sex-matched comparison cohorts: 1) 104,400 Bb seronegative comparison cohort members, and 2) 261,000 population controls. We investigated the risk associated with 1) being tested for serum Bb antibodies, and 2) being Bb seropositive. Outcomes were: 1) a composite of heart failure, cardiomyopathy, and/or myocarditis diagnosis, and 2) redemption of cardiovascular medicine used for treatment of heart failure. We calculated short-term odds ratios (aOR) (within 1 month) and long-term hazard rates (aHR) (after 1 month) adjusted for age, sex, diabetes, pre-existing heart failure, and kidney disease. Results: Compared with the population controls, individuals tested for Bb antibodies, regardless of the test result, had increased short-term risk of heart failure, cardiomyopathy, and myocarditis (aOR 8.3, 95 %CI: 6.7–10.2), and both increased short- and long-term risk of redemption of cardiovascular medicine (aOR 4.3, 95 %CI: 3.8–4.8, aHR 1.13, 95 % CI: 1.11–1.15). The Bb seropositive individuals had no increased short- or long-term risk of any outcome compared with Bb seronegative comparison cohort members. Conclusions: In conclusion, Bb antibody tests seemed to be performed in the diagnostic work-up of heart failure, but Bb seropositivity was not associated with heart failure.

Age-related endothelial dysfunction is a pivotal factor in the development of cardiovascular diseases, stemming, at least in part, from mitochondrial dysfunction and a consequential increase in oxidative stress. These alterations are central to the decline in vascular health seen with aging, underscoring the urgent need for interventions capable of restoring endothelial function for preventing cardiovascular diseases. Dietary interventions, notably time-restricted feeding (TRF), have been identified for their anti-aging effects on mitochondria, offering protection against age-associated declines in skeletal muscle and other organs. Motivated by these findings, our study aimed to investigate whether TRF could similarly exert protective effects on endothelial health in the vasculature, enhancing mitochondrial function and reducing oxidative stress. To explore this, 12-month-old C57BL/6 mice were placed on a TRF diet, with food access limited to a 6-h window daily for 12 months. For comparison, we included groups of young mice and age-matched controls with unrestricted feeding. We evaluated the impact of TRF on endothelial function by measuring acetylcholine-induced vasorelaxation of the aorta. Mitochondrial health was assessed using fluororespirometry, and vascular reactive oxygen species (ROS) production was quantified with the redox-sensitive dye dihydroethidium. We also quantified 4-hydroxynonenal (4-HNE) levels, a stable marker of lipid peroxidation, in the aorta using ELISA. Our findings demonstrated that aged mice on a standard diet exhibited significant impairments in aortic endothelial relaxation and mitochondrial function, associated with elevated vascular oxidative stress. Remarkably, the TRF regimen led to substantial improvements in these parameters, indicating enhanced endothelial vasorelaxation, better mitochondrial function, and reduced oxidative stress in the aortas of aged mice. This investigation establishes a vital foundation, paving the way for subsequent clinical research aimed at exploring the cardiovascular protective benefits of intermittent fasting.

Summary: Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, exclusive to Nairoviridae, is a target of protective antibodies and is a key antigen in preclinical vaccine candidates. Here, we isolate 188 GP38-specific antibodies from human survivors of infection. Competition experiments show that these antibodies bind across 5 distinct antigenic sites, encompassing 11 overlapping regions. Additionally, we show structures of GP38 bound with 9 of these antibodies targeting different antigenic sites. Although these GP38-specific antibodies are non-neutralizing, several display protective efficacy equal to or better than murine antibody 13G8 in two highly stringent rodent models of infection. Together, these data expand our understanding regarding this important viral protein and may inform the development of broadly effective CCHFV antibody therapeutics.

Phyllodes tumors of the breast are rare fibroepithelial neoplasms that account for less than 1% of all breast tumors. They tend to affect middle-aged women, who present with a rapidly growing, palpable mass. Here we present a case of a 34-year-old female surrogate mother without any reported personal or family history of breast cancer who presented with a rapidly growing left breast mass, pathologically proven to be a phyllodes tumor. The patient was a G7P7 surrogate mother who received estrogen and progesterone injections for her twin surrogate pregnancy starting 4 months before embryo implantation, after which, she discovered a large palpable mass in the left breast at approximately week 7 gestational age. At the initial presentation, the patient was at week 23 gestational age. She underwent C-section delivery of the twins at this time and obtained further work-up of the mass. She had a core needle biopsy which yielded a benign fibroepithelial tumor. Due to the size of her breast mass and atypical morphology, including extension to the nipple, and skin ulceration, the patient subsequently underwent left mastectomy. At the time of mastectomy, which was 8 months after the initial work-up, the mass had grown to measure approximately 12 × 10 cm on physical examination and took up most of her left breast. It was completely resected and was pathologically determined to be a borderline phyllodes tumor. Only a few cases have been reported about the development of phyllodes tumor during pregnancy in the literature, and we believe this is the first case report of phyllodes tumor related to a surrogate pregnancy. Although the relationship between exogenous hormones and fibroepithelial tumors is not well understood, the case poses the clinical question if screening mammograms should be offered to patients undergoing exogenous hormonal therapy, regardless of age to establish a baseline and monitor for the development (if any) or growth of these tumors.

We report a case of a vascular leiomyoma arising from the superficial femoral artery presenting as a non-painful thigh mass in a 55-year-old woman. Leiomyomas typically arise from the uterus and gastrointestinal tract, and rarely arise from vessels. We present this case to emphasize that although extremity leiomyomas are rare, they should be considered if there is a soft tissue mass abutting a vessel. Radiologists should be familiar with the imaging features associated with vascular leiomyomas.