Salivary toxicity from PSMA-targeted radiopharmaceuticals: What we have learned and where we are going.

Clinical trials of prostate-specific membrane antigen (PSMA) targeted radiopharmaceuticals have shown encouraging results. Some agents, like lutetium-177 [177Lu]Lu-PSMA-617 ([177Lu]Lu-PSMA-617), are already approved for late line treatment of metastatic castration-resistant prostate cancer (mCRPC). Projections are for continued growth of this treatment modality; [177Lu]Lu-PSMA-617 is being studied both in earlier stages of disease and in combination with other anti-cancer therapies. Further, the drug development pipeline is deep with variations of PSMA-targeting radionuclides, including higher energy alpha particles conjugated to PSMA-honing vectors. It is safe to assume that an increasing number of patients will be exposed to PSMA-targeted radiopharmaceuticals during the course of their cancer treatment. In this setting, it is important to better understand and mitigate the most commonly encountered toxicities. One particularly vexing side effect is xerostomia. In this review, we discuss the scope of the problem, inventories to better characterize and monitor this troublesome side effect, and approaches to preserve salivary function and effectively palliate symptoms. This article aims to serve as a useful reference for prescribers of PSMA-targeted radiopharmaceuticals, while also commenting on areas of missing data and opportunities for future research.

Amantadine interactions with phase separated lipid membranes.

Amantadine, a small amphilphic organic compound that consists of an adamantane backbone and an amino group, was first recognized as an antiviral in 1963 and received approval for prophylaxis against the type A influenza virus in 1976. Since then, it has also been used to treat Parkinson's disease-related dyskinesia and is being considered as a treatment for corona viruses. Since amantadine usually targets membrane-bound proteins, its interactions with the membrane are also thought to be important. Biological membranes are now widely understood to be laterally heterogeneous and certain proteins are known to preferentially co-localize within specific lipid domains. Does amantadine, therefore, preferentially localize in certain lipid composition domains? To address this question, we studied amantadine's interactions with phase separating membranes composed of cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), as well as single-phase DPhPC (1,2-diphytanoyl-sn-glycero-3-phos-phocholine) membranes. From Langmuir trough and differential scanning calorimetry (DSC) measurements, we determined, respectively, that amantadine preferentially binds to disordered lipids, such as POPC, and lowers the phase transition temperature of POPC/DSPC/cholesterol mixtures, implying that amantadine increases membrane disorder. Further, using droplet interface bilayers (DIBs), we observed that amantadine disrupts DPhPC membranes, consistent with its disordering properties. Finally, we carried out molecular dynamics (MD) simulations on POPC/DSPC/cholesterol membranes with varying amounts of amantadine. Consistent with experiment, MD simulations showed that amantadine prefers to associate with disordered POPC-rich domains, domain boundaries, and lipid glycerol backbones. Since different proteins co-localize with different lipid domains, our results have possible implications as to which classes of proteins may be better targets for amantadine.

Talus-derived reference coordinate system for 3D calcaneal assessment: A novel approach to improve morphological measurements.

In 3D-analysis of the calcaneus, a consistent coordinate system aligned with the original anatomical directions is crucial for pre- and postoperative analysis. This importance stems from the calcaneus's key role in weight-bearing and biomechanical alignment. However, defining a reliable coordinate system based solely on fractured or surgically reconstructed calcanei presents significant challenges. Given its anatomical prominence and consistent orientation, the talus offers a potential solution to this challenge. Our work explores the feasibility of talus-derived coordinate systems for 3D-modeling of the calcaneus across its various conditions. Four methods were tested on nonfractured, fractured and surgically reconstructed calcanei, utilizing Principal Component Analysis, anatomical landmarks, bounding box, and an atlas-based approach. The methods were compared with a self-defined calcaneus reference coordinate system. Additionally, the impact of deviation of the coordinate system on morphological measurements was investigated. Among methods for constructing nonfractured calcanei coordinate systems, the atlas-based method displayed the lowest Root Mean Square value in comparison with the reference coordinate system. For morphological measures like Böhler's Angle and the Critical angle of Gissane, the atlas talus-based system closely aligned with ground truth, yielding differences of 0.6° and 1.2°, respectively, compared to larger deviations seen in other talus-based coordinate systems. In conclusion, all tested methods were feasible for creating a talus derived coordinate system. A talus derived coordinate system showed potential, offering benefits for morphological measurements and clinical scenarios involving fractured and surgically reconstructed calcanei. Further research is recommended to assess the impact of these coordinate systems on surgical planning and outcomes.

Structural evolution of pea-derived albumins during pH and heat treatment studied with light and X-ray scattering.

Pea albumins are found in the side stream during the isolation of pea proteins. They are soluble at acidic pH and have functional properties which differ from their globulin counterparts. In this study, we have investigated the aggregation and structural changes occurring to pea albumins under different environmental conditions, using a combination of size-exclusion chromatography coupled with multi-angle laser light scattering (SEC-MALS) and small-angle X-ray scattering (SAXS). Albumins were extracted from a dry fractionated pea protein concentrate by precipitating the globulin fraction at acidic pH. The albumins were then studied at different pH (3, 4, 4.5, 7, 7.5, and 8) values. The effect of heating at 90 °C for 1, 3, and 5 min on their structural changes was investigated using SAXS. In addition, size exclusion of the albumins showed 4 distinct populations, depending on pH and heating conditions, with two large aggregates peaks (∼250 kDa): a dimer peak (∼24 kDa) containing predominantly pea albumin 2 (PA2), and a monomer peak of a molar mass of about 12 kDa (PA1). X-ray scattering intensities as a function of q were modeled as polydisperse spheres, and their aggregation was followed as a function of heating time. Albumins was most stable at pH 3, showing no aggregation during heat treatment. While albumins at pH 7.5 and 8 showed aggregation after heating, solutions at pH 4, 4.5, and 7 already contained aggregates even before heating. This work provides new knowledge on the overall structural development of albumins under different environmental conditions, improving our ability to employ these as future ingredients in foods.

Pan-Cancer Interrogation of B7-H3 (CD276) as an Actionable Therapeutic Target across Human Malignancies.

B7-H3 (CD276) is a transmembrane glycoprotein of the B7 immune checkpoint superfamily that has emerged as a promising therapeutic target. To better understand the applicability of B7-H3-directed therapies, we analyzed 156,791 samples comprising 50 cancer types to interrogate the clinical, genomic, transcriptomic, and immunological correlates of B7-H3 mRNA expression. DNA (592-gene/whole-exome) and RNA (whole-transcriptome) sequencing was performed from samples submitted to Caris Life Sciences (Phoenix, AZ). B7-H3 high versus low expression was based on top and bottom quartiles for each cancer type. Patients' overall survival was determined from insurance claims data. Pathway analysis was performed using Gene Set Enrichment Analyses (GSEA). Immune cell fractions were inferred using quanTIseq. B7-H3 is expressed across several human malignancies including prostate, pancreatic, ovarian, and lung cancers. High B7-H3 expression is associated with differences in overall survival, possibly indicating a prognostic role of B7-H3 for some cancers. When examining molecular features across all cancer types, we did not identify recurrent associations between B7-H3 expression and genetic alterations in TP53, RB1, and KRAS. However, we find consistent enrichment of EMT, Wnt, TGF-beta, and Notch signaling pathways. Additionally, tumors with high B7-H3 expression are associated with greater proportions of M1 macrophages, but lower fractions of CD8+ T cells. We have begun to define the genomic, transcriptomic, clinical, and immunological features associated with B7-H3 expression in 50 cancer types. We report novel clinical and molecular features of B7-H3-high tumors which may inform how current B7-H3 therapeutics should be deployed and prioritized.

MOG Antibody-Associated Disease in the Setting of Metastatic Melanoma Complicated by Immune Checkpoint Inhibitor Use.

OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune demyelinating disease rarely associated with malignancy. We report the clinical, MRI, immunopathology, and treatment response in a person with MOGAD and melanoma. METHODS: This is a case report of a person with a multidisciplinary evaluation at a tertiary referral center. RESULTS: A 52-year-old man presented with progressive encephalomyelitis that led to identification of metastatic melanoma. Investigations revealed positive MOG-IgG at high titers in serum (1:1,000; normal, <1:20) and CSF (1:4,096; normal, <1:2). MRI demonstrated multifocal T2 lesions with enhancement in the brain and spine. Brain biopsy showed demyelination and inflammation. MOG immunostaining was not present in the tumor tissue. He initially improved with methylprednisolone, plasmapheresis, prolonged oral steroid taper, and cancer-directed treatment with BRAF and MEK 1/2 inhibitors, but then developed bilateral optic neuritis. IV immunoglobulin (IVIG) was initiated. Five months later, he developed metastases and immune checkpoint inhibitor (ICI) treatment was started, which precipitated optic neuritis and myelitis despite IVIG and prednisone. Tocilizumab, an interleukin-6 receptor blocker, was started with excellent and sustained clinical and radiologic response. DISCUSSION: This case revealed a presentation of MOGAD concurrent with melanoma without tumor MOG immunostaining. We highlight tocilizumab as a dual-purpose treatment of MOGAD and the neurologic immune-related adverse effect of ICI.

Timing of Complete Revascularization Stratified By Index Presentation During On- And Off-hours.

Recent trials suggested immediate complete revascularization (ICR) as a safe alternative to staged complete revascularization (SCR), but the impact of the respective percutaneous coronary intervention strategies between on- versus off-hours is unclear. On-hours was defined as an index revascularization performed between 8 AM and 6 PM, Monday to Friday, or else the procedure was defined as performed during off-hours. The primary endpoint consisted of a composite of all-cause mortality, myocardial infarction, unplanned ischemia driven revascularization and cerebrovascular events at 1 year follow-up. We used Cox regression models to relate randomized treatment with study endpoints. We evaluated multiplicative and additive interactions between on- vs. off-hours and randomized treatment. The BIOVASC trial enrolled 1097 and 428 patients during on- and off-hours respectively. Patients randomized during off-hours were more likely to present with ST-segment elevation myocardial infarction (66.4% vs. 29.5%, p < 0.001). The composite primary outcome occurred in 8.4% and 10.1% of patients randomized to ICR and SCR respectively during on-hours (HR 0.80, 95% CI 0.54 to 1.19). During off-hours the primary composite outcome occurred in 5.4% and 7.7% in ICR and SCR (0.69, 95% CI 0.32 to 1.46) with no evidence of a differential effect (interaction pmultiplicative = 0.70, padditive = 0.56). No differential effect was found between treatment allocation and on- versus off-hours in any of the secondary outcomes. In conclusion, no differential treatment effect was found when comparing immediate complete revascularization versus staged complete revascularization in patients presenting with acute coronary syndrome and multivessel disease during on- or off-hours.

Readability and quality assessment of online patient education materials for spinal and epidural anesthesia.

PURPOSE: Guidelines recommend that health-related information for patients should be written at or below the sixth-grade level. We sought to evaluate the readability level and quality of online patient education materials regarding epidural and spinal anesthesia. METHODS: We evaluated webpages with content written specifically regarding either spinal or epidural anesthesia, identified using 11 relevant search terms, with seven commonly used readability formulas: Flesh-Kincaid Grade Level (FKGL), Gunning Fox Index (GFI), Coleman-Liau Index (CLI), Automated Readability Index (ARI), Simple Measure of Gobbledygook (SMOG), Flesch Reading Ease (FRE), and New Dale-Chall (NDC). Two evaluators assessed the quality of the reading materials using the Brief DISCERN tool. RESULTS: We analyzed 261 webpages. The mean (standard deviation) readability scores were: FKGL = 8.8 (1.9), GFI = 11.2 (2.2), CLI = 10.3 (1.9), ARI = 8.1 (2.2), SMOG = 11.6 (1.6), FRE = 55.7 (10.8), and NDC = 5.4 (1.0). The mean grade level was higher than the recommended sixth-grade level when calculated with six of the seven readability formulas. The average Brief DISCERN score was 16.0. CONCLUSION: Readability levels of online patient education materials pertaining to epidural and spinal anesthesia are higher than recommended. When we evaluated the quality of the information using a validated tool, the materials were found to be just below the threshold of what is considered good quality. Authors of educational materials should provide not only readable but also good-quality information to enhance patient understanding.

RéSUMé: OBJECTIF: Les lignes directrices recommandent que les informations relatives à la santé destinées aux patient·es soient rédigées pour un niveau de sixième année ou en dessous. Nous avons cherché à évaluer le niveau de lisibilité et la qualité des matériels d'éducation disponibles en ligne pour les patient·es concernant l'anesthésie péridurale et la rachianesthésie. MéTHODE: Nous avons évalué les pages web dont le contenu était spécifiquement rédigé à propos de l'anesthésie rachidienne ou péridurale, identifiées à l'aide de 11 termes de recherche pertinents, avec sept formules de lisibilité couramment utilisées : Niveau scolaire Flesh-Kincaid (FKGL), Indice Gunning Fox (GFI), Indice Coleman-Liau (CLI), Indice de lisibilité automatisé (ARI), Mesure simple du charabia (SMOG), Facilité de lecture de Flesch (FRE) et New Dale-Chall (NDC). Deux personnes ont évalué la qualité du matériel de lecture à l'aide de l'outil Brief DISCERN. RéSULTATS: Nous avons analysé 261 pages web. Les scores de lisibilité moyens (écart type) étaient les suivants : FKGL = 8,8 (1,9), GFI = 11,2 (2,2), CLI = 10,3 (1,9), ARI = 8,1 (2,2), SMOG = 11,6 (1,6), FRE = 55,7 (10,8) et NDC = 5,4 (1,0). Le niveau de lecture moyen était plus élevé que le niveau recommandé de sixième année lorsqu'il a été calculé à l'aide de six des sept formules de lisibilité. Le score moyen de Brief DISCERN était de 16,0. CONCLUSION: Les niveaux de lisibilité des documents d'éducation en ligne relatifs à l'anesthésie péridurale et à la rachianesthésie destinés aux patient·es sont plus élevés que ceux recommandés. Lorsque nous avons évalué la qualité de l'information à l'aide d'un outil validé, nous avons constaté que les documents se situaient juste en dessous du seuil de ce qui est considéré comme de bonne qualité. Les personnes rédigeant du matériel éducatif doivent fournir des informations non seulement lisibles, mais aussi de bonne qualité afin d'améliorer la compréhension des patient·es.

Robotic transanal minimally invasive surgery (R-TAMIS): current evidence in the treatment of early rectal neoplasia.

INTRODUCTION: Robotic transanal minimally invasive surgery (R-TAMIS) was introduced in 2012 for the excision of benign rectal polyps and low grade rectal cancer. Ergonomic improvements over traditional laparoscopic TAMIS (L-TAMIS) include increased dexterity within a small operative field, with possibility of better surgical precision. We aim to collate the existing data surrounding the use of R-TAMIS to treat rectal neoplasms from cohort studies and larger case series, providing a foundation for future, large-scale, comparative studies. METHODS: Medline, EMBASE and Web of Science were searched as part of our review. Randomised controlled trials (RCTs), cohort studies or large case series (≥ 5 patients) investigating the use of R-TAMIS to resect rectal neoplasia (benign or malignant) were eligible for inclusion in our analysis. Quality assessment of included studies was performed via the Newcastle Ottawa Scale (NOS) risk of bias tool. Outcomes extracted included basic participant characteristics, operative details and histopathological/oncological outcomes. RESULTS: Eighteen studies on 317 participants were included in our analysis. The quality of studies was generally satisfactory. Overall complication rate from R-TAMIS was 9.7%. Clear margins (R0) were reported in 96.2% of patients. Local recurrence (benign or malignant) occurred in 2.2% of patients during the specified follow-up periods. CONCLUSION: Our review highlights the current evidence for R-TAMIS in the local excision of rectal lesions. While R-TAMIS appears to have complication, margin negativity and recurrence rates superior to those of published L-TAMIS series, comparative studies are needed.

Salmonid smolt caudal fin and liver transcriptome responses to low sulfur marine diesel and high sulfur fuel oil water accommodated fractions for assessing oil spill effects in marine environments.

The environmental impact of oil spills is a critical concern, particularly pertaining to low sulfur marine diesel (LSMD) and high sulfur fuel oil (HSFO) that are commonly involved in coastal spills. Although transcriptomic biomonitoring of sentinel animals can be a powerful tool for assessing biological effects, conventional methods utilize lethal sampling to examine the liver. As a non-lethal alternative, we have previously shown salmonid caudal fin cyp1a1 is significantly responsive to LSMD-derived toxicants. The present study further investigated the transcriptomic biomonitoring potential of coho salmon smolt caudal fin in comparison to liver tissue in the context of LSMD and HSFO seawater accommodated fraction (seaWAF) exposure in cold-water marine environments. Assessing the toxicity of these seaWAFs involved quantifying polycyclic aromatic hydrocarbon (tPAH50) concentrations and generating gene expression profiles. Initial qPCR analyses revealed significant cyp1a1 response in both liver and caudal fin tissues of both genetic sexes to all seaWAF exposures. RNA-Seq analysis, focusing on the highest LSMD and HSFO seaWAF concentrations (28.4±1.8 and 645.08±146.3 µg/L tPAH50, respectively), revealed distinct tissue-specific and genetic sex-independent transcriptomic responses with an overall enrichment of oxidative stress, cell adhesion, and morphogenesis-related pathways. Remarkably, the caudal fin tissue exhibited transcriptomic response patterns comparable to liver tissue, particularly consistent differential expression of 33 gene transcripts in the liver (independent of sex and oil type) and 44 in the caudal fin. The present work underscores the viability of using the caudal fin as a non-lethal alternative to liver sampling for assessing and tracking oil spill exposure in marine environments.

Reverse repurposing: Potential utility of cancer drugs in nonmalignant illnesses.

Growth and immune process dysregulation can result in both cancer and nonmalignant disease (hereditary or acquired, with and without predisposition to malignancy). Moreover, perhaps unexpectedly, many nonmalignant illnesses harbor genomic alterations indistinguishable from druggable oncogenic drivers. Therefore, targeted compounds used successfully to treat cancer may have therapeutic potential for nonmalignant conditions harboring the same target. MEK, PI3K/AKT/mTOR, fibroblast growth factor receptor (FGFR), and NRG1/ERBB pathway genes have all been implicated in both cancer and noncancerous conditions, and several cognate antagonists, as well as Bruton's tyrosine kinase inhibitors, JAK inhibitors, and CD20-directed antibodies, have established or theoretical therapeutic potential to bridge cancer and benign diseases. Intriguingly, pharmacologically tractable cancer drivers characterize a wide spectrum of disorders without malignant potential, including but not limited to Alzheimer's disease and a variety of other neurodegenerative conditions, rheumatoid arthritis, achondroplastic dwarfism, and endometriosis. Expanded repositioning of oncology agents in order to benefit benign but serious medical illnesses is warranted.

Cobalamin decyanation by the membrane transporter BtuM.

BtuM is a bacterial cobalamin transporter that binds the transported substrate in the base-off state, with a cysteine residue providing the α-axial coordination of the central cobalt ion via a sulfur-cobalt bond. Binding leads to decyanation of cobalamin variants with a cyano group as the ß-axial ligand. Here, we report the crystal structures of untagged BtuM bound to two variants of cobalamin, hydroxycobalamin and cyanocobalamin, and unveil the native residue responsible for the ß-axial coordination, His28. This coordination had previously been obscured by non-native histidines of His-tagged BtuM. A model in which BtuM initially binds cobinamide reversibly with low affinity (KD = 4.0 µM), followed by the formation of a covalent bond (rate constant of 0.163 s-1), fits the kinetics data of substrate binding and decyanation of the cobalamin precursor cobinamide by BtuM. The covalent binding mode suggests a mechanism not used by any other transport protein.

Prehospital crushed versus integral prasugrel loading dose in STEMI patients with a large myocardial area.

BACKGROUND: The effect of administering a crushed prasugrel loading dose is uncertain in patients presenting with a large myocardial infarction and ST-segment elevation myocardial infarction (STEMI). AIMS: The aim of this study was to investigate if patients with a large myocardial infarction may benefit from prehospital administration of a crushed prasugrel loading dose. METHODS: Patients from the CompareCrush trial with an available ambulance electrocardiography (ECG) were included in the study. An independent core laboratory confirmed a prehospital large myocardial area. We compared pre- and postprocedural angiographic markers, including Thrombolysis in Myocardial Infarction (TIMI) 3 flow in the infarct-related artery, high thrombus burden, and myocardial blush grade 3, in STEMI patients with and without a prehospital large myocardial area. RESULTS: Ambulance ECG was available for 532 patients, of whom 331 patients were identified with a prehospital large myocardial area at risk. Crushed prasugrel significantly improved postprocedural TIMI 3 flow rates in STEMI patients with a prehospital large myocardial area at risk (92% vs 79%, odds ratio [OR] 3.00, 95% confidence interval [CI]: 1.50-6.00) but not in STEMI patients without a prehospital large myocardial area at risk (91% vs 95%, OR 0.47, 95% CI: 0.14-1.57; pinteraction=0.009). CONCLUSIONS: Administration of crushed prasugrel may improve postprocedural TIMI 3 flow in STEMI patients with signs of a large myocardial area at risk on the ambulance ECG. The practice of crushing tablets of prasugrel loading dose might, therefore, represent a safe, fast and cost-effective strategy to improve myocardial reperfusion in this high-risk STEMI subgroup undergoing primary percutaneous coronary intervention.

Patterns of stressful life events and polygenic scores for five mental disorders and neuroticism among adults with depression.

The dominant ('general') version of the diathesis-stress theory of depression views stressors and genetic vulnerability as independent risks. In the Australian Genetics of Depression Study (N = 14,146; 75% female), we tested whether polygenic scores (PGS) for major depression, bipolar disorder, schizophrenia, anxiety, ADHD, and neuroticism were associated with reported exposure to 32 childhood, past-year, lifetime, and accumulated stressful life events (SLEs). In false discovery rate-corrected models, the clearest PGS-SLE relationships were for the ADHD- and depression-PGSs, and to a lesser extent, the anxiety- and schizophrenia-PGSs. We describe the associations for childhood and accumulated SLEs, and the 2-3 strongest past-year/lifetime SLE associations. Higher ADHD-PGS was associated with all childhood SLEs (emotional abuse, emotional neglect, physical neglect; ORs = 1.09-1.14; p's < 1.3 × 10-5), more accumulated SLEs, and reported exposure to sudden violent death (OR = 1.23; p = 3.6 × 10-5), legal troubles (OR = 1.15; p = 0.003), and sudden accidental death (OR = 1.14; p = 0.006). Higher depression-PGS was associated with all childhood SLEs (ORs = 1.07-1.12; p's < 0.013), more accumulated SLEs, and severe human suffering (OR = 1.17; p = 0.003), assault with a weapon (OR = 1.12; p = 0.003), and living in unpleasant surroundings (OR = 1.11; p = 0.001). Higher anxiety-PGS was associated with childhood emotional abuse (OR = 1.08; p = 1.6 × 10-4), more accumulated SLEs, and serious accident (OR = 1.23; p = 0.004), physical assault (OR = 1.08; p = 2.2 × 10-4), and transportation accident (OR = 1.07; p = 0.001). Higher schizophrenia-PGS was associated with all childhood SLEs (ORs = 1.12-1.19; p's < 9.3-8), more accumulated SLEs, and severe human suffering (OR = 1.16; p = 0.003). Higher neuroticism-PGS was associated with living in unpleasant surroundings (OR = 1.09; p = 0.007) and major financial troubles (OR = 1.06; p = 0.014). A reversed pattern was seen for the bipolar-PGS, with lower odds of reported physical assault (OR = 0.95; p = 0.014), major financial troubles (OR = 0.93; p = 0.004), and living in unpleasant surroundings (OR = 0.92; p = 0.007). Genetic risk for several mental disorders influences reported exposure to SLEs among adults with moderately severe, recurrent depression. Our findings emphasise that stressors and diatheses are inter-dependent and challenge diagnosis and subtyping (e.g., reactive/endogenous) based on life events.

Size-resolved aerosol at a Coastal Great Lakes Site: Impacts of new particle formation and lake spray.

The quantification of aerosol size distributions is crucial for understanding the climate and health impacts of aerosols, validating models, and identifying aerosol sources. This work provides one of the first continuous measurements of aerosol size distribution from 1.02 to 8671 nm near the shore of Lake Michigan. The data were collected during the Lake Michigan Ozone Study (LMOS 2017), a comprehensive air quality measurement campaign in May and June 2017. The time-resolved (2-min) size distribution are reported herein alongside meteorology, remotely sensed data, gravimetric filters, and gas-phase variables. Mean concentrations of key aerosol parameters include PM2.5 (6.4 µg m-3), number from 1 to 3 nm (1.80x104 cm-3) and number greater than 3 nm (8x103 cm-3). During the field campaign, approximately half of days showed daytime ultrafine burst events, characterized by particle growth from sub 10 nm to 25-100 nm. A specific investigation of ultrafine lake spray aerosol was conducted due to enhanced ultrafine particles in onshore flows coupled with sustained wave breaking conditions during the campaign. Upon closer examination, the relationships between the size distribution, wind direction, wind speed, and wave height did not qualitatively support ultrafine particle production from lake spray aerosol; statistical analysis of particle number and wind speed also failed to show a relationship. The alternative hypothesis of enhanced ultrafine particles in onshore flow originating mainly from new particle formation activity is supported by multiple lines of evidence.

Chronotype and subjective sleep quality predict white matter integrity in young people with emerging mental disorders.

Protecting brain health is a goal of early intervention. We explored whether sleep quality or chronotype could predict white matter (WM) integrity in emerging mental disorders. Young people (N = 364) accessing early-intervention clinics underwent assessments for chronotype, subjective sleep quality, and diffusion tensor imaging. Using machine learning, we examined whether chronotype or sleep quality (alongside diagnostic and demographic factors) could predict four measures of WM integrity: fractional anisotropy (FA), and radial, axial, and mean diffusivities (RD, AD and MD). We prioritised tracts that showed a univariate association with sleep quality or chronotype and considered predictors identified by ≥80% of machine learning (ML) models as 'important'. The most important predictors of WM integrity were demographics (age, sex and education) and diagnosis (depressive and bipolar disorders). Subjective sleep quality only predicted FA in the perihippocampal cingulum tract, whereas chronotype had limited predictive importance for WM integrity. To further examine links with mood disorders, we conducted a subgroup analysis. In youth with depressive and bipolar disorders, chronotype emerged as an important (often top-ranking) feature, predicting FA in the cingulum (cingulate gyrus), AD in the anterior corona radiata and genu of the corpus callosum, and RD in the corona radiata, anterior corona radiata, and genu of corpus callosum. Subjective quality was not important in this subgroup analysis. In summary, chronotype predicted altered WM integrity in the corona radiata and corpus callosum, whereas subjective sleep quality had a less significant role, suggesting that circadian factors may play a more prominent role in WM integrity in emerging mood disorders.

Laparoscopic totally extraperitoneal hernia repair in patients with a history of previous abdominopelvic surgery.

A retrospective cohort study of patients undergoing laparoscopic inguinal hernia repair compared short- and long-term outcomes between individuals with or without history of previous abdominopelvic surgery, aiming to determine the feasibility of totally extraperitoneal (TEP) repair within this population. All patients who underwent elective TEP inguinal hernia repair by one consultant surgeon across three London hospitals from January 2017 to May 2023 were retrospectively analysed to assess perioperative outcomes. Two hundred sixty-two patients were identified, of whom two hundred forty-three (93%) underwent laparoscopic TEP repair. The most frequent complications were haematoma (6.2%) and seroma (4.1%). Recurrence occurred in four cases (1.6% of operations, 1.1% of hernias). One hundred eighty-four patients (76%) underwent day-case surgery. There were no mesh infections or explanations, vascular or visceral injuries, port-site hernias, damage to testicle, or persisting numbness. There were no requirements for blood transfusion, returns to theatre, or readmissions within 30 days. There was one conversion to open and one death within 60 days of surgery. Eighty-three (34%) had a history of previous AP surgery. There was no significant difference in perioperative outcomes between the AP and non-AP arms. This finding carried true for subgroup analysis of 44 patients whose AP surgical history did not include previous inguinal hernia repair and for those undergoing repair of recurrent hernia. In expert hands, laparoscopic TEP repair is associated with excellent outcomes and low rates of long-term complications, and thus should be considered as standard for patients regardless of a history of AP surgery.

Lingo: an automated, web-based deep phenotyping platform for language ability.

Background: Language and the ability to communicate effectively are key factors in mental health and well-being. Despite this critical importance, research on language is limited by the lack of a scalable phenotyping toolkit. Methods: Here, we describe and showcase Lingo - a flexible online battery of language and nonverbal reasoning skills based on seven widely used tasks (COWAT, picture narration, vocal rhythm entrainment, rapid automatized naming, following directions, sentence repetition, and nonverbal reasoning). The current version of Lingo takes approximately 30 minutes to complete, is entirely open source, and allows for a wide variety of performance metrics to be extracted. We asked > 1,300 individuals from multiple samples to complete Lingo, then investigated the validity and utility of the resulting data. Results: We conducted an exploratory factor analysis across 14 features derived from the seven assessments, identifying five factors. Four of the five factors showed acceptable test-retest reliability (Pearson's R > 0.7). Factor 2 showed the highest reliability (Pearson's R = 0.95) and loaded primarily on sentence repetition task performance. We validated Lingo with objective measures of language ability by comparing performance to gold-standard assessments: CELF-5 and the VABS-3. Factor 2 was significantly associated with the CELF-5 "core language ability" scale (Pearson's R = 0.77, p-value < 0.05) and the VABS-3 "communication" scale (Pearson's R = 0.74, p-value < 0.05). Factor 2 was positively associated with phenotypic and genetic measures of socieconomic status. Interestingly, we found the parents of children with language impairments had lower Factor 2 scores (p-value < 0.01). Finally, we found Lingo factor scores were significantly predictive of numerous psychiatric and neurodevelopmental conditions. Conclusions: Together, these analyses support Lingo as a powerful platform for scalable deep phenotyping of language and other cognitive abilities. Additionally, exploratory analyses provide supporting evidence for the heritability of language ability and the complex relationship between mental health and language.

Immediate or staged complete revascularisation in patients presenting with acute coronary syndrome by number of diseased vessels: a substudy of the BIOVASC randomised trial.

BACKGROUND: In patients presenting with acute coronary syndrome (ACS), the number of diseased vessels may affect the efficacy of a complete revascularisation strategy. AIMS: The authors sought to evaluate the safety and efficacy of immediate complete revascularisation (ICR) and staged complete revascularisation (SCR) in patients presenting with ACS stratified by the number of diseased vessels. METHODS: In this prespecified analysis of the BIOVASC trial, ICR was compared with SCR in patients with two-vessel disease (2VD) or three-vessel disease (3VD). The primary endpoint was a composite of all-cause mortality, myocardial infarction (MI), any unplanned ischaemia-driven revascularisation or cerebrovascular events at 1 year after the index procedure. Comparisons were performed using Cox regression. RESULTS: A total of 1,525 patients were enrolled in the BIOVASC trial, of whom 1,177 presented with 2VD and 265 with 3VD. In the 2VD group, 613 patients were assigned to ICR and 564 to SCR. In the 3VD group, 117 patients were assigned to ICR and 148 to SCR. ICR and SCR led to similar results in both the 2VD (hazard ratio [HR] 0.76, 95% confidence interval [CI]: 0.50-1.13; p=0.18) and 3VD groups (HR 0.79, 95% CI: 0.39-1.59; p=0.51) (pinteraction=0.91) in terms of the primary endpoint. ICR was associated with a lower rate of MI in patients with 3VD (HR 0.21, 95% CI: 0.046-0.93; p=0.04) (pinteraction=0.30). CONCLUSIONS: ICR might be an option in patients presenting with extensive 3VD and might be associated with a lower rate of myocardial infarction compared with SCR.