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Measurement of IgG antibodies against group B streptococcus (GBS) capsular polysaccharide (CPS) by use of a standardized and internationally accepted multiplex immunoassay is important for the evaluation of candidate maternal GBS vaccines in order to compare results across studies. A standardized assay is also required if serocorrelates of protection against invasive GBS disease are to be established in infant sera for the six predominant GBS serotypes since it would permit the comparison of results across the six serotypes. We undertook an interlaboratory study across five laboratories that used standardized assay reagents and protocols with a panel of 44 human sera to measure IgG antibodies against GBS CPS serotypes Ia, Ib, II, III, IV, and V. The within-laboratory intermediate precision, which included factors like the lot of coated beads, laboratory analyst, and day, was generally below 20% relative standard deviation (RSD) for all six serotypes, across all five laboratories. The cross-laboratory reproducibility was < 25% RSD for all six serotypes, which demonstrated the consistency of results across the different laboratories. Additionally, anti-CPS IgG concentrations for the 44-member human serum panel were established. The results of this study showed assay robustness and that the resultant anti-CPS IgG concentrations were reproducible across laboratories for the six GBS CPS serotypes when the standardized assay was used.

Candida parapsilosis is a common human commensal and opportunistic fungal pathogen that is also found in non-human primates (NHPs). Here, we report the first draft sequence of C. parapsilosis NCYC 4418, a fecal isolate from an adult cynomolgus macaque.

Background: This analysis compared effects of the activin signaling inhibitor, sotatercept, across pulmonary arterial hypertension (PAH) subgroups stratified by baseline cardiac index (CI)., Methods: Pooled data from PULSAR (N=106; NCT03496207) and STELLAR (N=323; NCT04576988) were analyzed using two different CI thresholds, < and ≥ 2.0 L/min/m 2 or 2.5 L/min/m 2 . Median differences in change from baseline at week 24 were evaluated using Hodges-Lehmann (HL) estimator and mean differences by least squares (LS), with 95% confidence intervals and p-values; p=0.05 was significant. Categorial endpoints and time-to-clinical worsening were analyzed by Cochran-Mantel-Haenszel and Cox model (hazard ratio (HR), respectively, without multiplicity adjustment., Results: Of 429 participants, 51 and 378 had CI <2.0 L/min/m 2 and ≥ 2.0 L/min/m 2 , respectively, whereas 179 and 250 had CI <2.5 L/min/m 2 and ≥ 2.5 L/min/m 2 , respectively. Across all CI subgroups, sotatercept vs placebo significantly improved median 6-minute walk distance (range: 33.9 to 63.7 m: p<0.001), pulmonary vascular resistance (range: -202.8 to -395.4 dyn•s•cm -5 ; p≤0.002), and N-terminal pro-B-type natriuretic peptide (range: -317.3 to -1041.2 pg/mL; p<0.001). LS means showed reductions in pulmonary and right atrial pressures, decreased right ventricular size and enhanced tricuspid annular plane systolic excursion/ systolic pulmonary artery pressure in all subgroups. Sotatercept significantly delayed time to first occurrence of death or a worsening event in the subset of participants with CI ≥2.5 (HR 0.12; p<0.001), ≥2.0 (HR 0.13; p<0.001), and <2.5 (HR 0.21; p<0.001) L/min/m 2 . Improvements in World Health Organization functional class (all p<0.050) and European Society of Cardiology/European Respiratory Society risk score (all p<0.001) were seen within each subgroup., Conclusions: Efficacy and safety were consistent across baseline CI subgroups, supporting use of sotatercept in PAH patients irrespective of baseline cardiac hemodynamics., (Copyright © 2024. Published by Elsevier Inc.)

Quantitative molecular imaging with PET can offer insights into physiologic and pathologic processes and is widely used for studying brain disorders. The NeuroEXPLORER is a recently developed dedicated brain PET system offering high spatial resolution and high sensitivity with an extended axial length. This study evaluated the quantitative precision and accuracy of the NeuroEXPLORER with phantom and human data for a variety of imaging conditions that are relevant to dynamic neuroimaging studies. Methods: Thirty-minute scans of an image quality (IQ) phantom and a 3-dimensional Hoffman brain phantom filled with [ 18 F]FDG were performed over 13 h, covering phantom activities of 1.3-177 MBq. Furthermore, a uniform cylindric phantom filled with 558 MBq of 11 C was scanned for 4 h. Quantitative accuracy was assessed using the contrast recovery coefficient (CRC), background variability, and background bias in the IQ phantom, the recovery coefficients (RCs) in the Hoffman phantom, and the bias in the uniform phantom. Results were compared at delayed time points, with different reconstruction parameters and frame lengths down to 1 s. Moreover, randomly subsampled frames of 2 imaging time points (0-2 min and 60-90 min) from a dynamic scan of a healthy volunteer with a 177-MBq injected dose of ( R )-4-(3-fluoro-5-(fluoro- 18 F)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidin-2-one ([ 18 F]SynVesT-1) were used to assess quantification of brain uptake and image-derived input function extraction. Results: Negligible effects were observed on CRC and background bias with 3-177 MBq in the IQ phantom, and bias was less than 5% with 1-558 MBq in the uniform phantom. RC variations were within ±1% with 2-169 MBq in the Hoffman phantom, showcasing the system's high spatial resolution and high sensitivity. Short-frame reconstructions of the 60- to 90-min healthy-volunteer scan showed a ±1% mean difference in quantification of brain uptake for frame lengths down to 30 s and demonstrated the feasibility of measuring image-derived input function with mean absolute differences below 10% for frame lengths down to 1 s. Conclusion: The NeuroEXPLORER, with its high detection sensitivity, maintains high precision and accuracy across a wide range of imaging conditions beyond those evaluated in standard performance tests. These results demonstrate its potential for quantitative neuroimaging applications., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

The protein gene product 9.5 (PGP9.5), also termed ubiquitin C-terminal hydrolase L1 (UCH-L1) is an important component of the ubiquitination/deubiquitination system and plays a role in axonal transport. To comprehensively determine PGP9.5 expression in neoplastic tissues, a tissue microarray containing 13,920 samples from 120 different tumor types and subtypes was analyzed by immunohistochemistry (IHC). PGP9.5 immunostaining was found in 109 of 120 tumor categories, 87 of which contained at least one strongly positive case. PGP9.5 positivity was most seen in neuronal and neuroendocrine neoplasms (50-100 %), germ cell neoplasms (28-84 %), sarcomas and carcinosarcomas (up to 91 %), and in mesotheliomas (58-83 %). In clear cell RCC (renal cell carcinomas), strong PGP9.5 staining was associated with high ISUP (International Society of Urological Pathology) grade (p<0.0001), advanced pT stage (p=0.0003), nodal (p=0.0242) and distant metastasis (p<0.0001) as well as with a short overall, tumor specific and recurrence free survival (p≤0.0007 each). In papillary RCC, strong PGP9.5 staining was associated with high ISUP grade (p=0.009) and reduced recurrence free survival (p=0.0221). In urothelial carcinoma of the urinary bladder, high PGP9.5 expression was associated with muscle-invasion (p<0.0001). PGP9.5 immunostaining was unrelated to histological parameters for tumor aggressiveness in 295 serous high-grade ovarian carcinomas, 174 endometrioid endometrium carcinomas, 292 papillary and 89 follicular thyroid carcinomas, 405 ductal adenocarcinomas of the pancreas and in 327 gastric adenocarcinomas. In summary, our data provide a comprehensive overview of PGP9.5 expression in cancer and demonstrate positive cases in a broad range of entities. PGP9.5 overexpression is linked to patient outcome in some tumor entities (i.e., clear cell RCC) but appears to be unrelated to clinically relevant tumor characteristics in many other frequent tumor entities., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The PGP9.5 antibody clone MSVA-905R was provided from MS Validated Antibodies GmbH (owned by a family member of GS). Conflict of interest The PGP9.5 antibody clone MSVA-905R was provided from MS Validated Antibodies GmbH (owned by a family member of GS)., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Concerns around concussion highlight the need for strategies to improve the implementation and translation of concussion guidelines in community sports. This study assessed players' utilisation and compliance with New Zealand Rugby's Concussion Management Pathway (CMP). This pragmatic, mixed methods study comprised of concussion injury surveillance and mapping of players' healthcare touchpoints through the CMP. Semi-structured interviews were conducted to understand stakeholders' experiences. Over the season, 27 different healthcare pathways were identified with 28% of players progressing through all phases of the CMP (ideal pathway). Of the 206 suspected concussions reported over the season, 70% were logged in the CMP phone App, and 89% of these had an associated valid baseline concussion assessment. Prior to returning to contact training, 64% of players obtained a medical clearance. One theme, 'belief in the value of pathway' was identified as a facilitator across all CMP components. Themes such as 'concussion knowledge and the nature of concussion'; 'communication between stakeholders and sufficient information on the process'; and 'strong relationships and clarity around responsibilities' were identified as facilitators across several pathway components. Other facilitators included 'ease and timing of general practitioner access'; 'the phone App as facilitator to logging'; and 'spotting for concussion as a team'. Additionally, the findings signify baseline testing as a potential pre-cursor to overall CMP compliance. Strategies that support the facilitators identified in this study may further enhance compliance., (© 2024 The Author(s). European Journal of Sport Science published by Wiley‐VCH GmbH on behalf of European College of Sport Science.)

Objective: There is concern that current surgical residents are suboptimally prepared for autonomous practice. This qualitative study aimed to clarify perceptions of competency, autonomy and surgical training goals by Canadian cardiac surgery programs and trainees., Design: This was a qualitative study using semistructured interviews. These were audio recorded and transcribed verbatim. We used thematic analysis and content analysis to deductively analyze interview transcripts. From this, we identified major themes describing competency, autonomy, and goals of surgical training., Setting: All interviews were conducted online over Zoom., Participants: We interviewed 16 individuals (7 trainees and 9 program directors) from 10 Canadian cardiac surgery training programs., Results: Both trainees and staff agreed that the goal of surgical residency is to produce competent, not autonomous, surgeons. When defining competency, both faculty and trainees identified the importance of technical skills and nontechnical skills, such as surgical decision-making. Both groups believed autonomy and competency to be different, wherein autonomy assumes competency and is distinguished by the ability to make decisions independently. Importantly, 81% (n=13) believed that nontechnical skills were more important for independent practice than technical skills. Only 57% (n=4) of trainees and 33% (n=3) of staff surgeons felt that the current RCPSC competencies were reasonable to achieve during residency training., Conclusion: We have identified several important discrepancies in the perceptions of competency, autonomy, and surgical training goals. The RCPSC (Royal College of Physicians and Surgeons of Canada) stated goal of producing trainees who are ready for independent practice is discordant with the perspective of Canadian cardiac surgery programs. Many staff and trainees do not feel that the currently espoused competencies are feasible to achieve by graduation. The results of our study will allow us to identify the barriers during training to produce trainees ready for independent practice., (Copyright © 2024 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Breast cancer is the most common cancer in women, and incidence rates are rising, it is thought in part, due to increasing levels of obesity. Endocrine therapy (ET) remains the cornerstone of systemic therapy for early and advanced oestrogen receptor-positive (ER + ) breast cancer, but despite treatment advances, it is becoming more evident that obesity and insulin resistance are associated with worse outcomes. Here, we describe the current understanding of the relationship between both obesity and diabetes and the prevalence and outcomes for ER+ breast cancer. We also discuss the mechanisms associated with resistance to ET and the relationship to treatment toxicity., Competing Interests: Competing interests: SL—Honoraria: Eisai, Prosigna, Roche, Pfizer, Novartis, Sanofi. Advisory: Shionogi, Sanofi, GLG Consulting: Rejuversen, Oxford Biodynamics. Research grant funding: CRUK, NIHR, Against Breast Cancer, Pathios Therapeutics. Travel/Accommodation/ Expenses: Pfizer, Roche, Synthon, Piqur Therapeutics. Stock holding: Mitox Therapeutics. Previous employment: Pfizer. My institution has received funding for clinical trials for which I am chief investigator or principal investigator from: Cancer Research UK, Boehringer Ingelheim, Piqur Therapeutics, AstraZeneca, Carrick Therapeutics, Sanofi, Merck KGaA, Synthon, Roche, Exscientia, BioInvent, RS Oncology. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Context.—: Steroidogenic acute regulatory (StAR) protein is a mitochondrial transport protein with a critical regulatory role for steroid hormone production. The tissue distribution of StAR expression is limited to few human normal tissues., Objective.—: To assess the diagnostic and prognostic value of StAR immunohistochemistry analysis., Design.—: A tissue microarray containing 19 202 samples from 152 different tumor types and subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry., Result.—: StAR immunostaining occurred in 198 (1.2%) of the 17 135 analyzable tumors. StAR expression was observed in 27 of 152 tumor categories, 9 of which included at least 1 strongly positive case. The highest rate of StAR positivity occurred in Leydig cell tumors of the testis and the ovary (100%), steroid cell tumors of the ovary (100%), adrenocortical carcinomas (93%) and adenomas (87%), Sertoli-Leydig cell tumors (67%) and granulosa cell tumors of the ovary (56%), as well as seminomas (7%). Nineteen other tumor entities showed-a usually weak-StAR positivity in less than 6% of cases. A comparison with preexisting Melan-A (a melanocyte antigen) data revealed that StAR was more often positive in adrenocortical neoplasms and in Leydig cell tumors while StAR (but not Melan-A) was negative in Sertoli cell tumors., Conclusions.—: Our data provide a comprehensive overview on the patterns of StAR immunostaining in human tumors and suggest a diagnostic utility of StAR immunohistochemistry for supporting a diagnosis of Leydig cell tumors or of normal or neoplastic adrenocortical tissue., Competing Interests: The rabbit recombinant StAR antibody, clone MSVA-740R, was provided from MS Validated Antibodies GmbH (owned by a family member of Sauter). The other authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

This study examined whether autistic people with siblings score higher on measures of empathy than those without siblings. Cohorts of autistic children (n = 939; mean age = 7.35 years (SD = 2.15)) and autistic adults (n = 736; mean age = 37 years (SD = 12.39)) from the Cambridge Autism Research Database (CARD) were each divided into two groups: with or without siblings. Empathy was measured using the children version of the Empathy Quotient (EQ) (parent-report) for children. For adults, the EQ (self-report version) and the Reading the Mind in the Eyes Test (RMET) were used. Contrary to the hypothesis, autistic children without siblings scored higher on EQ than those with siblings (t (283.70)  = 4.20, p < .001; d = 0.50). In adults, there was no difference between autistic adults with and without siblings on both measures, but there was an interaction effect between sex and group on the RMET (f (1732)  = 4.10, p = 0.04): whilst autistic males without siblings on average scored lower than females, autistic males with siblings on average performed similarly to females. Future research should investigate the possible effect of siblings on autistic males' empathy performance in a larger cohort of autistic individuals. Children's empathic abilities may be underestimated by their parents when they have siblings due to a contrast effect., (© 2023. The Author(s).)

Objective: To provide detailed guidance on the administration of systemic bevacizumab in patients with recurrent respiratory papillomatosis (RRP) based on a detailed review of the scientific literature and a consensus of experts with real-world clinical experience., Methods: A bevacizumab consensus working group (N = 10) was composed of adult and pediatric otolaryngologists, adult and pediatric oncologists, and a representative from the RRP Foundation (RRPF), all with experience administering systemic bevacizumab in patients with RRP. After extensive review of the medical literature, a modified Delphi method-based survey series was utilized to establish consensus on the following key areas: clinical and patient characteristics ideal for treatment candidacy, patient perspective in treatment decisions, treatment access, initial dosing, monitoring, guidelines for tapering and discontinuation, and reintensifying therapy., Results: Seventy-nine statements were identified across nine critical domains, and 45 reached consensus [clinical benefits of bevacizumab (3), patient and disease characteristics for treatment consideration (7), contraindications for treatment (3), shared decision-making (incorporating the patient perspective) (5), treatment access (3), initial dosing and administration (8), monitoring (7), tapering and discontinuation (6), and reintensification (3)]., Conclusion: This consensus statement provides the necessary guidance for clinicians to initiate systemic administration of bevacizumab and represents a potential paradigm shift toward nonsurgical treatment options for patients with RRP., Level of Evidence: 5 Laryngoscope, 134:5041-5046, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

The nuclear envelope (NE) separates translation and transcription and is the location of multiple functions, including chromatin organization and nucleocytoplasmic transport. The molecular basis for many of these functions have diverged between eukaryotic lineages. Trypanosoma brucei , a member of the early branching eukaryotic lineage Discoba, highlights many of these, including a distinct lamina and kinetochore composition. Here, we describe a cohort of proteins interacting with both the lamina and NPC, which we term l amina- a ssociated p roteins (LAPs). LAPs represent a diverse group of proteins, including two candidate NPC-anchoring pore membrane proteins (POMs) with architecture conserved with S. cerevisiae and H. sapiens , and additional peripheral components of the NPC. While many of the LAPs are Kinetoplastid specific, we also identified broadly conserved proteins, indicating an amalgam of divergence and conservation within the trypanosome NE proteome, highlighting the diversity of nuclear biology across the eukaryotes, increasing our understanding of eukaryotic and NPC evolution.

The unique properties of the lanthanide (Ln) elements make them critical components of modern technologies, such as lasers, anti-corrosive films and catalysts. Thus, there is significant interest in establishing structure-property relationships for Ln-containing materials to advance these technologies. Extended X-ray absorption fine structure (EXAFS) is an excellent technique for this task considering its ability to determine the average local structure around the Ln atoms for both crystalline and amorphous materials. However, the limited availability of EXAFS reference spectra of the Ln oxides and challenges in the EXAFS analysis have hindered the application of this technique to these elements. The challenges include the limited k -range available for the analysis due to the superposition of L -edges on the EXAFS, multielectron excitations (MEEs) creating erroneous peaks in the EXAFS and the presence of inequivalent absorption sites. Herein, we removed MEEs to model the local atomic environment more accurately for light Ln oxides. Further, we investigated the use of cubic and non-cubic lattice expansion to minimize the fitting parameters needed and connect the fitting parameters to physically meaningful crystal parameters. The cubic expansion reduced the number of fitting parameters but resulted in a statistically worse fit. The non-cubic expansion resulted in a similar quality fit and showed non-isotropic expansion in the crystal lattice of Nd 2 O 3 . In total, the EXAFS spectra and the fits for the entire set of Ln oxides (excluding promethium) are included. The knowledge developed here can assist in the structural determination of a wide variety of Ln compounds and can further studies on their structure-property relationships., Competing Interests: The authors specify no conflicts of interest., (© Adam Smerigan et al. 2024.)

Abstract: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

White matter hyperintensities (WMH) increase with age, with marked interindividual variation. There is a need for normative data by age and sex, to improve individualized WMH burden assessment. In this study, we pooled cross-sectional data from 15 population-based cohorts (14,876 nondemented individuals, age 18-97 years), through the Meta VCI Map consortium. Whole brain and tract-specific MRI-assessed WMH volumes were calculated in MNI-152 space. We used quantile regression to create centile curves of WMH volume versus age, stratified by sex. Total WMH volume and interindividual variance increased exponentially with age for both sexes, with females showing higher WMH volumes. WMH volume increase with aging was not uniform across the white matter, but instead followed one of three different patterns depending on location. Age- and sex-specific normative data for total and regional WMH volumes were created. Our study provides detailed information on the normal distribution of total and regional WMH volumes across adulthood. The normative data enable a quantitative approach to interpreting total and regional WMH volumes in clinical practice and research settings., Competing Interests: Disclosure Statement PSS has served on the Advisory Committees of Biogen Australia and Roche Australia in 2020–2022. NC serves on DSMBs for AstraZeneca. All other authors report no declarations of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

PAX6 immunohistochemistry (IHC) was proposed as a tool to identify a pancreatic origin of neuroendocrine neoplasms (NENs). To evaluate the diagnostic utility of PAX6 IHC, a tissue microarray containing 19,214 samples from 150 tumor types was analyzed. Data on progesterone receptor (PR) and glutamate decarboxylase 2 (GAD2) expression were available from previous studies. PAX6 staining occurred in 2.6% of 17,224 analyzable tumors and 60 tumor categories showed PAX6 positivity in at least one case. The highest rates of PAX6 positivity occurred in pancreatic (42.9-70.8%) and other NENs (up to 50.0%), testicular tumors (up to 58.3%), basal cell carcinomas of the skin (51.9%), squamous cell carcinomas of different organs (1.5-11.8%), and in gynecological tumors (up to 30%). For detection of pancreatic origin of NENs, sensitivity was highest for PAX6 (68.7%) followed by GAD2 (62.6%) and PR (52.5%) while specificity was highest for GAD2 (95.2%), followed by PR (91.3%), and PAX6 (91.1%). Of the analyzed combinations, the highest sensitivity (53.8%) and specificity (100%) was found for PAX6/GAD2, although combinations of PAX6/PR (49.5%/99.3%), PR/GAD2 (40.7%/98.9%), and PAX6/PR/GAD2 (40.6%/100%) did also result in high specificity. Only 14% of the 118 NENs with negativity for all three antibodies were of pancreatic origin. It is concluded that PAX6 IHC is useful to identify a pancreatic origin in case of NEN metastases of unknown origin. The combination with GAD2 and PR further increase the diagnostic performance of PAX6 and results in a >98% specificity in case of positivity for at least 2 of these markers., Competing Interests: Declaration of competing interest The mouse monoclonal PAX6 antibody, clone MSVA-706M was provided from MS Validated Antibodies GmbH, Hamburg, Germany (owned by a family member of GS)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The primary objective was to assess incidence and severity of acute laryngeal injury (ALgI) following intubation at time of tracheostomy using a proposed grading scale. The secondary objective was to evaluate what factors influence the rate of decannulation., Methods: Single institution cohort study with review of prospectively maintained database including patients from October 2021 to October 2022 who underwent tracheostomy for prolonged intubation/critical illness. Severity of ALgI was graded as mild, moderate, or severe based on intraoperative endoscopic findings (laryngeal mucosal ulceration and/or granulation tissue). Rates of tracheostomy decannulation were collected as the secondary outcome measure., Results: Twenty-eight patients met criteria for inclusion. About 60.7% (n = 17) patients were female. Average age was 59.0 ± 13.2 years old. Average body mass index was 32.3 ± 14.0 kg/m 2 . The most common endotracheal tube size was 7.5 (range = 6.0-8.0) inner diameter (ID) for men and 7.0 (range = 5.5-8.0) ID for women. Average Charlson Comorbidity Index (CCI) was 4.8 ± 2.4. Length of intubation was 15.7 ± 6.5 days (range = 5-30). Direct laryngoscopy at the time of tracheostomy demonstrated ALgI in 92.8% (n = 26) of patients. This was graded as mild (25.0%, n = 7), moderate (42.9%, n = 12), or severe (25.0%, n = 7). Severe ALgI was correlated with a reduced rate of tracheostomy decannulation compared to no/mild/moderate ALgI (28.5% vs 81.2%, P  = .04)., Conclusions: ALgI is highly prevalent in patients undergoing tracheostomy for prolonged intubation. Severe injury is associated with reduced rates of decannulation. Direct laryngoscopy at time of tracheostomy is warranted to diagnose ALgI and guide interventions. Determining the extent of laryngeal injury is prognostic and could help tailor follow-up and management strategies., Level of Evidence: 4., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

X-ray computed tomography (CT) in PET/CT is commonly operated with a single energy, resulting in a limitation of lacking tissue composition information. Dual-energy (DE) spectral CT enables material decomposition by using two different x-ray energies and may be combined with PET for improved multimodality imaging, but would either require hardware upgrade or increase radiation dose due to the added second x-ray CT scan. Recently proposed PET-enabled DECT method allows dual-energy spectral imaging using a conventional PET/CT scanner without the need for a second x-ray CT scan. A gamma-ray CT (gCT) image at 511 keV can be generated from the existing time-of-flight PET data with the maximum-likelihood attenuation and activity (MLAA) approach and is then combined with the low-energy x-ray CT image to form dual-energy spectral imaging. To improve the image quality of gCT, a kernel MLAA method was further proposed by incorporating x-ray CT as a priori information. The concept of this PET-enabled DECT has been validated using simulation studies, but not yet with 3D real data. In this work, we developed a general open-source implementation for gCT reconstruction from PET data and use this implementation for the first real data validation with both a physical phantom study and a human subject study on a uEXPLORER total-body PET/CT system. These results have demonstrated the feasibility of this method for spectral imaging and material decomposition.

Introduction: Thailand was one of the first low- and middle-income countries to publicly fund seasonal influenza vaccines, but the lack of predictability in the timing of epidemics and difficulty in predicting the dominant influenza subtypes present a challenge for existing vaccines. Next-generation influenza vaccines (NGIVs) are being developed with the dual aims of broadening the strain coverage and conferring longer-lasting immunity. However, there are no economic evaluations of NGIVs in Thailand., Methods: We estimated the health impact and cost-effectiveness of NGIVs in Thailand between 2005 and 2009 using a combined epidemiological and economic model. We fitted the model to data on laboratory-confirmed influenza cases and then simulated the number of influenza infections, symptomatic cases, hospitalisations and deaths under different vaccination scenarios based on WHO-preferred product characteristics for NGIVs. We used previous estimates of costs and disability adjusted life years (DALYs) for influenza health outcomes to estimate incremental net monetary benefit, vaccine threshold prices and budget impact., Results: With the current vaccine programme, there were an estimated 61 million influenza infections. Increasing coverage to 50% using improved vaccines reduced infections to between 23 and 57 million, and with universal vaccines to between 21 and 49 million, depending on the age groups targeted. Depending on the comparator, threshold prices for NGIVs ranged from US$2.80 to US$12.90 per dose for minimally improved vaccines and US$24.60 to US$69.90 for universal vaccines., Conclusion: Influenza immunisation programmes using NGIVs are anticipated to provide considerable health benefits and be cost-effective in Thailand. However, although NGIVs might even be cost-saving in the long run, there could be significant budget implications for the Thai government even if the vaccines can be procured at a substantial discount to the maximum threshold price., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Purpose: Dual-energy (DE) CT enables material decomposition by using two different x-ray energies and may be combined with PET for improved multimodality imaging. However, this increases radiation dose and may require a hardware upgrade due to the added second x-ray CT scan. The recently proposed PET-enabled DECT method allows dual-energy imaging using a conventional PET/CT scanner without the need to change scanner hardware or increase radiation exposure. Here we demonstrate the first-time physical phantom and patient data evaluation of this method., Methods: The PET-enabled DECT method reconstructs a gamma-ray CT (gCT) image at 511 keV from the time-of-flight PET data with the maximum-likelihood attenuation and activity (MLAA) approach and then combines this image with the low-energy x-ray CT images to form a dual-energy image pair for material decomposition. To improve the image quality of gCT, a kernel MLAA method was developed using the x-ray CT as a priori information. Here we developed a general open-source implementation for gCT reconstruction and used this implementation for the first real data validation using both physical phantom study and human-subject study. Results from PET-enabled DECT were compared using x-ray DECT as the reference. Further, we applied the PET-enabled DECT method in another patient study to evaluate bone lesions., Results: Compared to the standard MLAA, results from the kernel MLAA showed significantly improved image quality. PET-enabled DECT with the kernel MLAA was able to generate fractional images that were comparable to the x-ray DECT, with high correlation coefficients for both the phantom study and human subject study (R > 0.99). The application study also indicates that PET-enabled DECT has potential to characterize bone lesions., Conclusion: Results from this study have demonstrated the feasibility of this PET-enabled method for CT imaging and material decomposition. PET-enabled DECT shows promise to provide comparable results to x-ray DECT., Competing Interests: Declarations Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by Institution Review Board at University of California, Davis (IRB#: 1374902). Consent to participate Informed consent was obtained from all participants enrolled in the study. Consent for publication Consent to publish has been received from all participants. Conflict of interest UC Davis has a revenue-sharing agreement with United Imaging Healthcare. No other potential conflicts of interest relevant to this article exist., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The Democratic Republic of Congo (DRC) has faced emerging infectious diseases such as Ebola, Mpox and Yellow fever, and antimicrobial resistance is a growing concern. To address these issues, in 2011 the country embarked on implementing the One Health (OH) approach at the national and provincial levels. This study investigates OH institutionalization and implementation in the DRC, describes the process of OH decentralization, and identifies the opportunities and challenges of sustaining these efforts., Methods: We conducted a qualitative study based on literature, document review and key informant interviews. The literature search targeted PubMed, Google Scholar and the document depository of the national One Health platform (NOHP). Key informant identified at the national level included ministry representatives, OH platform members and donors supporting OH implementation. These interviews were conducted in-person and online, recorded, transcribed, and imported into Dedoose software (version 9.2.006) for coding. Content analysis was performed to identify activities, processes, and achievements during the implementation of OH in DRC., Findings: Results of the literature and document review ( n  = 72) and analysis of stakeholder interviews ( n  = 24) indicate that a national OH platform, initiated in 2011, is hosted at the Ministry of Higher Education and coordinates other sectors. It comprises governmental departments, academic institutions, and civil society organizations working at the human, animal, and environment sectors. The governance structure includes a national coordinator, a permanent secretariat, technical working groups, and subnational entities at provincial and territorial levels. Following the establishment of the national OH platform, a structured process foresees to facilitate OH implementation at the provincial and territorial levels. Achievements up to today include the development of training programs, establishment of OH committees in some provinces, assessments of workforce needs, formulation of a national strategy, development of governance manuals, and support to the Mpox response coordination.Nevertheless, OH implementation in the DRC faces challenges, including leadership tensions at the national level, inadequate domestic funding, limited training and capacity building for professionals, and insufficient infrastructure for data collection and sharing. Strengthening leadership and coordination, advocating for domestic resource mobilization, and strengthening infrastructure for data collection and sharing while ensuring equity across sectors is essential for advancing the OH agenda and ensuring its efficacy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Simon R. Ruegg reports financial support was provided by Canadian International Development Research Centre. Tarra Penny and Chloe Clifford Astbury reports financial support was provided by Canadian Institutes of Health Research. Marc K. Yambayamba reports a relationship with Africa One Health University Network (AFROHUN) that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Improving the use of platinum in propane dehydrogenation catalysts is a crucial aspect to increasing the efficiency and sustainability of propylene production. A known and practiced strategy involves incorporating more abundant metals in supported platinum catalysts, increasing its activity and stability while decreasing the overall loading. Here, using colloidal techniques to control the size and composition of the active phase, we show that Pt/Cu alloy nanoparticles supported on alumina (Pt/Cu/Al 2 O 3 ) displayed elevated rates for propane dehydrogenation at low temperature compared to a monometallic Pt/Al 2 O 3 catalyst. We demonstrate that the enhanced catalytic activity is correlated with a higher surface Cu content and formation of a Pt-rich core and Cu-rich shell that isolates Pt sites and increases their intrinsic activity. However, rates declined on stream because of dynamic metal diffusion processes that led to a more uniform alloy structure. This transformation was only partially inhibited by adding excess hydrogen to the feed stream. Instead, cobalt was introduced to provide trimetallic Pt/Cu/Co catalysts with stabilized surface structure and stable activity and higher rates than the original Pt/Cu system. The structure-activity relationship insights in this work offer improved knowledge of propane dehydrogenation catalyst development featuring reduced Pt loadings and notable thermal stability for propylene production.

Fears of negative evaluation (FNEs) and fears of positive evaluation (FPEs) comprise a bivalent model of evaluation that can explain the aetiology and maintenance of Social Anxiety Disorder (SAD). In this study, we examined an extended version of this model which incorporates two related cognitive processes (concerns about reprisal and discounting of positive outcomes) as partial mediators of the effects of FNEs and FPEs. We built on earlier work by including a broader measure of social anxiety across different social situations and comparing models for groups of participants with and without probable SAD. Structural equation modelling was utilised to test the model in a sample of 890 university students (74.8% female, mean age 29.49). We replicated the findings of Cook et al. in the overall sample and in the group with probable SAD. FNEs and FPEs predicted social anxiety directly and were serially mediated by concerns about reprisal and discounting positive outcomes. The model was also a good fit for those without SAD; however, in the model, FNEs were no longer a direct predictor of social anxiety. The findings confirm the utility of the extended bivalent model and have implications for psychoevolutionary accounts of social anxiety.

Introduction: Pancreatic acinar cell carcinoma (pACC) is a rare malignancy with unique clinical and molecular features. The role of chemotherapy in pACC management is not well established., Methods: The National Cancer Database (NCDB) for pACC was used. Cox regression was used in resected pACC patients to identify significant overall survival (OS) predictors. Patients were then divided based on these risk factors into propensity-matched group of surgery versus surgery + chemotherapy and Kaplan-Meier analysis was performed with log-rank tests to compare OS., Results: The NCDB 2004-2020 included 1592 pACC patients, 1553 were selected. Median age was 66 and 1090 (70.2%) were males. 622 (40.1%) received chemotherapy only, 257 (16.5%) had surgery only, and 365 (23.5%) had both. 189 Patients who received surgery were only matched to peers who had surgery + chemotherapy. The median OS for surgery only was 57.8 ± 6.0 versus 54.2 ± 9.9 months for surgery + chemotherapy (p = 0.836). Cox regression identified nodal and margin status as independent predictors of OS. Therefore, subgroups of patients with node-negative, node-positive, margin-negative, and margin-positive resections were similarly matched 1:1 for the receipt of surgery only versus surgery + chemotherapy. Only patients with node-positive disease had a significant OS benefit with the addition of chemotherapy (44.2 ± 7.3 vs. 27.5 ± 10.5 months; p = 0.036)., Conclusion: Our analysis suggests that surgical resection remains the cornerstone of therapy for pACC. Node status and margin status are the primary prognosticators. The addition of chemotherapy provides an OS benefit only in node-positive disease., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Purpose: To report on quality assurance (QA) and protocol adherence (PA) in a multicentre phase III trial for head and neck cancer, evaluate patterns of protocol deviations and investigate the effect of PA on study outcomes., Methods: All 221 patients from the ARTFORCE trial (NCT01504815) were included in this study. Pre- and per-treatment QA measures included protocol guidelines, a dummy run, early case reviews and trial meetings. FDG-PET-guided dose painting and scheduled adaptive radiotherapy were reviewed in patients in the experimental arm (eRT). Patient and disease characteristics, as well as institutes' accrual rate and timing were examined for correlation with PA. Cox regression was used to determine the impact of PA on outcome., Results: The dummy run was completed in all nine institutes and early case reviews were completed in five out of nine institutes that contributed 190 out of 221 patients. Among all patients randomized to eRT, 64 % had at least one deviation of the experimental trial components. Protocol deviations were significantly correlated with the institute patients were treated at (Cramer'sV 0.34-0.48). Despite early identification of institute-specific deviations in QA, these continued during the trial. No significant associations were seen between deviations and accrual timing or rate (P ≥ 0.26). Within eRT, no significant relation was observed between experimental PA and locoregional control (LRC), the primary endpoint of the trial (P≥.15)., Conclusions: Despite QA, protocol deviations persisted during the trial, which were mostly institute-specific. However, deviations of the experimental treatment strategy did not significantly impact LRC and therefore the trial conclusion., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Anna Liza M.P. de Leeuw; PhD-student at the Antoni van Leeuwenhoek hospital. Jordi Giralt; Radiation oncologist at the Vall d'Hebron Unniversity Hospital. Yungan Tao; Radiation oncologist at the Institut Gustave roussy. Sergi Benavente; Radiation oncologist at the Vall d'Hebron Unniversity Hospital. Thanh-Vân France Nguyen; Radiation oncologist at the Institut Gustave roussy. Frank J.P. Hoebers; Radiation oncologist at the Maastro Center. Ann Hoeben; Clinical oncologist at the Maastro Center. Chris H.J. Terhaard; retired radiation oncologist at the University Medical Center Utrecht. Lip Wai Lee; Radiation oncologist at the Christie NHS Foundation Trust. Signe Friesland; Radiation oncologist at the Karolinska Comprehensive Cancer Center. Roel J.H.M. Steenbakkers; Radiation oncologist at the University Medical Center Groningen. Lisa Tans; Radiation oncologist at the Erasmus Medical Center. Simon R. van Kranen; Postdoc at the Antoni van Leeuwenhoek hospital. Jeroen B van de Kamer; Medical physicist at the Antoni van Leeuwenhoek hospital. Harry Bartelink; retired radiation oncologist at the Antoni van Leeuwenhoek hospital. Coen R.N. Rasch; Professor at Leiden University; Radiation oncologist at the Leiden University Medical Center; Jan-Jakob Sonke; Professor by special appointment at University of Amsterdam; senior group leader at Antoni van Leeuwenhoek hospital; ownership of patent/license fees/copyright at Elekta AB; member of the international advisory board at Physics, medicine and biology; editorial board member of Physics & Imaging in Radiation Oncology. Olga Hamming-Vrieze; Radiation oncologist at Antoni van Leeuwenhoek hospital]., (Copyright © 2024. Published by Elsevier B.V.)

A measure of lifetime brain atrophy (LBA) obtained from a single magnetic resonance imaging (MRI) scan could be an attractive candidate to boost statistical power in uncovering novel genetic signals and mechanisms of neurodegeneration. We analysed data from five young and old adult cohorts (MRi-Share, Human Connectome Project, UK Biobank, Generation Scotland Subsample, and Lothian Birth Cohort 1936 [LBC1936]) to test the validity and utility of LBA inferred from cross-sectional MRI data, i.e., a single MRI scan per participant. LBA was simply calculated based on the relationship between total brain volume (TBV) and intracranial volume (ICV), using three computationally distinct approaches: the difference ( ICV-TBV ), ratio ( TBV / ICV ), and regression-residual method (TBV~ICV). LBA derived with all three methods were substantially correlated with well-validated neuroradiological atrophy rating scales ( r = 0.37-0.44). Compared with the difference or ratio method, LBA computed with the residual method most strongly captured phenotypic variance associated with cognitive decline ( r = 0.36), frailty ( r = 0.24), age-moderated brain shrinkage ( r = 0.45), and longitudinally-measured atrophic changes ( r = 0.36). LBA computed using a difference score was strongly correlated with baseline (i.e., ICV; r = 0.81) and yielded GWAS signal similar to ICV ( rg = 0.75). We performed the largest genetic study of LBA to date ( N = 43,110), which was highly heritable ( h 2 SNP GCTA = 41% [95% CI = 38-43%]) and had strong polygenic signal (LDSC h 2 = 26%; mean χ2 = 1.23). The strongest association in our genome-wide association study (GWAS) implicated WNT16 , a gene previously linked with neurodegenerative diseases such as Alzheimer, and Parkinson disease, and amyotrophic lateral sclerosis. This study is the first side-by-side evaluation of different computational approaches to estimate lifetime brain changes and their measurement characteristics. Careful assessment of methods for LBA computation had important implications for the interpretation of existing phenotypic and genetic results, and showed that relying on the residual method to estimate LBA from a single MRI scan captured brain shrinkage rather than current brain size. This makes this computationally-simple definition of LBA a strong candidate for more powerful analyses, promising accelerated genetic discoveries by maximising the use of available cross-sectional data.

A large number of clinical studies demonstrate that the ketogenic diet (KD) may be an effective approach to the reduction of epileptic seizures in children and adults. Such dietary therapy could also help pregnant women with epilepsy, especially since most antiseizure drugs have teratogenic action. However, there is a lack of medical data, considering the safety of using KD during gestation for the progeny. Therefore, we examined the influence of KD used prenatally in rats on the elemental composition of the selected brain regions in their offspring. For this purpose, synchrotron radiation-induced X-ray fluorescence (SR-XRF) microscopy was utilized, and elements such as P, S, K, Ca, Fe, and Zn were determined. Moreover, to verify whether the possible effects of KD are temporary or long-term, different stages of animal postnatal development were taken into account in our experiment. The obtained results confirmed the great applicability of SR-XRF microscopy to track the element changes occurring in the brain during postnatal development as well as those induced by prenatal exposure to the high-fat diet. The topographic analysis of the brains taken from offspring of mothers fed with KD during pregnancy and appropriate control individuals showed a potential influence of such dietary treatment on the brain levels of elements such as P and S. In the oldest progeny, a significant reduction of the surface of brain areas characterized by an increased P and S content, which histologically/morphologically correspond to white matter structures, was noticed. In turn, quantitative elemental analysis showed significantly decreased levels of Fe in the striatum and white matter of 30-day-old rats exposed prenatally to KD. This effect was temporary and was not noticed in adult animals. The observed abnormalities may be related to the changes in the accumulation of sphingomyelin and sulfatides and may testify about disturbances in the structure and integrity of the myelin, present in the white matter.

Aims/hypothesis: Glycaemic control and clinical outcomes in diabetes are improved by continuous subcutaneous insulin infusion (CSII). Atmospheric pressure changes during flights may affect insulin delivery from pumps and cause unintended metabolic consequences, including hypoglycaemia, in people with type 1 diabetes. The present report evaluates both hypobaric flight simulation and real-world data in pilots using insulin pumps while flying., Methods: In the flight simulation part of this study, an in vitro study of insulin pumps was conducted in a hypobaric chamber, de-pressurised to 550 mmHg to mimic the atmospheric pressure changes in airliner cabins during commercial flights. Insulin delivery rates and bubble formation were recorded for standard flight protocol. Insulin infusion sets, without pumps, were tested in a simulated rapid decompression scenario. The real-world observational study was a 7.5-year retrospective cohort study in which pre- and in-flight self-monitored blood glucose (SMBG) values were monitored in pilots with insulin-treated diabetes. Commercial and private pilots granted a medical certificate to fly within the European Union Aviation Safety Agency approved protocol and receiving insulin either by pump or multiple daily injections (MDI) were included., Results: In the flight simulation study, full cartridges over-delivered 0.60 U of insulin during a 20 min ascent and under-delivered by 0.51 U during descent compared with ground-level performance. During emergency rapid decompression, 5.6 U of excess insulin was delivered. In the real-world study, seven pilots using CSII recorded 4656 SMBG values during 2345 h of flying across 1081 flights. Only 33 (0.7%) values were outside an acceptable safe range (5.0-15.0 mmol/l [90-270 mg/dl]). No clinically significant fall in the median SMBG concentration was observed after aircraft ascent and no in-flight SMBG values were within the hypoglycaemic range (<4.0 mmol/l [<72 mg/dl]). Compared with pilots receiving MDI therapy, pilots using CSII recorded more SMBG values within the acceptable range (99.3% vs 97.5%), fewer values in the low red range (0.02% vs 0.1%), fewer in-flight out-of-range values (0.2% vs 1.3%) and maintained stricter glycaemic control during flight., Conclusions/interpretation: Ambient pressure reduction during simulated flights results in bubble formation and expansion within insulin cartridges. This causes unintended delivery of small insulin doses independent of pre-determined delivery rates and represents the maximum amount of insulin that could be delivered and retracted. However, in vivo, pilots using CSII in-flight did not experience a fall in blood glucose or episodes of hypoglycaemia during these atmospheric pressure changes and the use of insulin pumps can be endorsed in view of their clinical benefits., (© 2024. The Author(s).)

Backround: Anterior gradient 2 (AGR2) is a resident endoplasmic reticulum (ER) protein with a vital role in embryonal development, mucus maturation, tissue regeneration, and wound healing., Methods: To determine the prevalence and clinical significance of AGR2 expression in cancer, a tissue microarray containing 14,966 tumors from 134 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry (IHC)., Results: AGR2 positivity was found in 103 of 134 tumor categories, and 83 tumor categories contained at least one strongly positive case. AGR2 expression was most frequently seen in tumors of the female genital tract, particularly adenocarcinomas (up to 100%), various breast cancer subtypes (57.1%-100%), urothelial carcinoma (74.6%-100%), adenocarcinomas of the upper and lower gastrointestinal tract (93.6%-99.6%), and pancreaticobiliary cancers (65.2%-98.2%). AGR2 positivity was slightly less common in squamous cell carcinomas (46.4%-77.3%) and mainly absent in mesenchymal and lymphoid tumors. While AGR2 expression was only weak or absent in the normal thyroid, it was moderate to strong in 46.0% of adenomas, 52.8% of follicular carcinomas, and 81.8% of papillary carcinomas of the thyroid. High AGR2 expression was strongly linked to poor ISUP (p < 0.0001), Fuhrman (p < 0.0001), and Thoenes (p < 0.0001) grades as well as advanced pT stage (p = 0.0035) in clear cell renal cell carcinoma (ccRCC). Low AGR2 expression was associated with high BRE grade in breast cancer (p = 0.0049), nodal metastasis (p = 0.0275) and RAS mutation (p = 0.0136) in colorectal cancer, nodal metastasis (p = 0.0482) in endometrioid endometrial carcinoma, high grade in noninvasive urothelial carcinoma (p = 0.0003), and invasive tumor growth in urothelial carcinoma (p < 0.0001)., Conclusions: It is concluded that AGR2 expression occurs in a broad range of different tumor entities and that AGR2 assessment may serve as a diagnostic aid for the distinction of thyroidal neoplasms and as a prognostic marker in various cancer types., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence 1 . The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived 1,2 . Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN 3-6 . However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors 7 . Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once TNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution. Using a machine learning approach, we developed a classifier that can be used to predict sensitivity. Together, these findings identify a promising therapeutic strategy for this highly aggressive tumour type and illustrate how deregulated epigenetic enzymes can insulate tumours from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit., Competing Interests: Competing interests: K.C. is an advisor at Genentech and serves on the scientific advisory board of Erasca. S.M.T. has consulting or advisory roles at Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, Odonate Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, Certara, Chugai Pharma, Ellipses Pharma, Infinity, 4D Pharma, OncoSec Medical, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics and ARC Therapeutics; and received institutional research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Odonate Therapeutics, Sanofi and Seattle Genetics. P.K.S. is a co-founder and member of the BOD of Glencoe Software, member of the BOD for Applied Biomath, member of the scientific advisory board for RareCyte, NanoString and Montai Health, holds equity in Glencoe, Applied Biomath and RareCyte, consults for Merck, and has received research funding to the institution from Novartis and Merck in the past 5 years. A.C.G.-C. has grant/research funding to institution from Gilead Sciences, AstraZeneca, Daiichi-Sankyo, Merck, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Foundation Medicine and Biovica; serves as a consultant and member of the scientific advisory board for AstraZeneca, Daiichi-Sankyo and Novartis; has received honoraria from AstraZeneca and Daiichi-Sankyo; and has other financial or materials support from Roche/Genentech, Gilead Sciences, AstraZeneca, Novartis and Merck. K.H. is a consultant for and a co-founder of Dania Therapeutics Aps and a scientific advisor for Hannibal Health Innovation. S.R.V.K. is a founder and consultant at Faeth Therapeutics and Transomic Technologies. D.A.B. is a consultant for N of One/QIAGEN and Tango Therapeutics; is a founder and shareholder in Xsphera Biosciences; has received honoraria from Merck, H3 Biomedicine/Esai, EMD Serono, Gilead Sciences, Abbvie and Madalon Consulting; and has received research grants from BMS, Takeda, Novartis, Gilead and Lilly. The other authors declare no competing interests., (© 2024. The Author(s).)

Thyroid transcription factor 1 (TTF-1) immunohistochemistry (IHC) is routinely used for the distinction of primary pulmonary adenocarcinomas. However, TTF-1 can also occur in other malignancies. A tissue microarray containing 17,772 samples from 152 different tumor types was analyzed. Napsin-A, CK20, SATB2, FABP1, and Villin-1 IHC data were available from previous studies. TTF-1 staining was seen in 82 of 152 tumor categories including thyroidal cancers (19-100%), adenocarcinomas (94%), neuroendocrine tumors (67%) of the lung, small cell neuroendocrine carcinomas (71-80%), mesenchymal tumors (up to 42%), and thymomas (39%). Comparative analysis of TTF-1 and Napsin-A revealed a sensitivity/specificity of 94%/86% (TTF-1), 87%/98% (Napsin-A), and 85%/99.1% (TTF-1 and Napsin-A) for the distinction of pulmonary adenocarcinomas. Combined analysis of TTF-1 and enteric markers revealed a positivity for TTF-1 and at least one enteric marker in 22% of pulmonary adenocarcinomas but also a TTF-1 positivity in 6% of colorectal, 2% of pancreatic, and 3% of gastric adenocarcinomas. TTF-1 is a marker of high sensitivity but insufficient specificity for pulmonary adenocarcinomas. A small fraction of TTF-1-positive gastrointestinal adenocarcinomas represents a pitfall mimicking enteric-type pulmonary adenocarcinoma. Combined analysis of TTF-1 and Napsin-A improves the specificity of pulmonary adenocarcinoma diagnosis., Competing Interests: Declarations Ethics approval The usage of archived diagnostic left-over tissues for manufacturing of TMAs and their analysis for research purposes as well as patient data analysis has been approved by local laws (HmbKHG, §12,1) and by the local ethics committee (Ethics commission Hamburg, WF-049/09). All work has been carried out in compliance with the Helsinki Declaration. Conflict of interest The recombinant rabbit monoclonal TTF-1-antibody clone MSVA-312R was provided by MS Validated Antibodies GmbH, Hamburg, Germany (owned by a family member of GS)., (© 2024. The Author(s).)

Background: Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) are becoming more prevalent with advanced medical imaging and account for most of pancreatic cystic neoplasms (PCNs). Most incidental lesions should be surveyed, with resection reserved for specific, high-risk cases. Solid organ transplantation candidates may be high risk of resection before transplant and will require systemic immunosuppression after transplant, which has been theorized to alter the natural history of the IPMN. We aimed to describe the progression in surveilled cysts after solid organ transplantation., Methods: A prospectively maintained database of PCNs was queried for patients with IPMN. Patients who had received a previous solid organ transplantation and with ≥2 imaging studies >6 months apart after transplantation were included. Clinically relevant (CR) progression was defined as symptoms, worrisome/high-risk stigmata, or invasive carcinoma (IC). Growth ≥5 mm in 2 years is considered CR progression; size ≥3 cm alone is not., Results: Between 1997 and 2023, 252 patients received solid organ transplantation (liver, 86; kidney, 113; and lung, 54) and were diagnosed as having an IPMN. This cohort was compared with a set of 770 patients surveilled for IPMN who did not have previous transplantation. Median follow-up period was 3.7 years (IQR, 1.6-6.8). Moreover, 2 transplant patients (0.8%) developed IC, and 4 developed (1.6%) high-grade dysplasia (HGD). Both were less common in transplant patients than the nontransplant population (IC, 3.3%; HGD, 2.9%), although this was not significant on time-to-event analysis (IC, P = .152; HGD, P = .352). The rate of CR progression was high in the transplant cohort (n = 118; 47%). Features of CR progression included size growth (n = 79; 67%), other worrisome/high-risk stigmata (n = 25; 21%), and new main duct involvement (n = 14; 12%). Compared with the nontransplant (n = 128; 17%), transplant patients had a higher rate of CR progression (P < .001), which was mostly explained by a more frequent size growth (31% vs 9%; P < .001). However, no transplant patients with size growth CR progression developed IC. Moreover, 17 (6.7%) required pancreatic surgery for CR progression after transplant vs 58 (7.5%) in the nontransplant population. Furthermore, 6 resected cysts (35%) harbored high-risk pathology after transplant (IC, 2; HGD, 4) vs 40 (69%) in the general population (P < .001; IC, 29; HGD, 11)., Conclusion: Malignant transformation of BD-IPMNs is rare despite systemic immunosuppression in solid organ transplant patients. This supports transplantation in patients with IPMN without fear of worsening their risk of pancreatic cancer, although it was associated with a higher risk of disease progression. Patients with IPMNs should be surveilled with yearly scans after transplant, with pancreatic resection reserved for only high-risk features as we continue to define the optimal criteria for those with CR progression., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neighbourhood disadvantage may be associated with brain health but the importance of exposure at different stages of the life course is poorly understood. Utilising the Lothian Birth Cohort 1936, we explored the relationship between residential neighbourhood deprivation from birth to late adulthood, and global and local neuroimaging measures at age 73. A total of 689 participants had at least one valid brain measures (53% male); to maximise the sample size structural equation models with full information maximum likelihood were conducted. Residing in disadvantaged neighbourhoods in mid- to late adulthood was associated with smaller total brain (β = -0.06; SE = 0.02; sample size[N] = 658; number of pairwise complete observations[n]=390), grey matter (β = -0.11; SE = 0.03; N = 658; n = 390), and normal-appearing white matter volumes (β = -0.07; SE = 0.03; N = 658; n = 390), thinner cortex (β = -0.14; SE = 0.06; N = 636; n = 379), and lower general white matter fractional anisotropy (β = -0.19; SE = 0.06; N = 665; n = 388). We also found some evidence on the accumulating impact of neighbourhood deprivation from birth to late adulthood on age 73 total brain (β = -0.06; SE = 0.02; N = 658; n = 276) and grey matter volumes (β = -0.10; SE = 0.04; N = 658; n = 276). Local analysis identified affected focal cortical areas and specific white matter tracts. Among individuals belonging to lower social classes, the brain-neighbourhood associations were particularly strong, with the impact of neighbourhood deprivation on total brain and grey matter volumes, and general white matter fractional anisotropy accumulating across the life course. Our findings suggest that living in deprived neighbourhoods across the life course, but especially in mid- to late adulthood, is associated with adverse brain morphologies, with lower social class amplifying the vulnerability., (© 2024. The Author(s).)

The global impacts of pulmonary hypertension (PH) were formally recognised in 1973 at the 1st World Health Organization meeting dedicated to primary pulmonary hypertension, held in Geneva. Investigations into disease pathogenesis and classification led to the development of numerous therapies over the ensuing decades. While the impacts of the disease have been lessened due to treatments, the symptoms and adverse effects of PH and its therapies on patients' wellbeing and mental health remain significant. As such, there is a critical need to enhance understanding of the challenges patients face on a global scale with respect to care access, multidimensional patient support and advocacy. In addition, thoughtful analysis of the potential benefits and utilisation of mechanisms for the incorporation of patient-reported outcomes into diagnosis and treatment plans is needed. A summary of these areas is included here. We present a report of global surveys of patient and provider experiences and challenges regarding care access and discuss possible solutions. Also addressed is the current state of PH patient associations around the world. Potential ways to enhance patient associations and enable them to provide the utmost support are discussed. A summary of relevant patient-reported outcome measures to assess health-related quality of life in PH is presented, with suggestions regarding incorporation of these tools in patient care and research. Finally, information on how current global threats such as pandemics, climate change and armed conflict may impact PH patients is offered, along with insights as to how they may be mitigated with advanced contingency planning., Competing Interests: Conflict of interest: H.J. Ford reports grants from United Therapeutics, Merck, Gossamer Bio, Janssen, Cereno and Enzyvant, consultancy fees from United Therapeutics, Merck, Enzyvant, Liquidia, Janssen and Gossamer Bio, and a leadership role with the Pulmonary Hypertension Association. C. Brunetti reports support for the present work from Pulmonary Hypertension Association (USA), consultancy fees from Bayer and Aerovate, support for attending meetings from Pulmonary Hypertension Association, and a leadership role with Pulmonary Hypertension Association. P. Ferrari has no potential conflicts of interest to disclose. G. Meszaros reports consultancy fees from PHA Europe, EU-PFF and ERN-Lung, payment or honoraria for lectures, presentations, manuscript writing or educational events from Patient Expert Center vzw, and support for attending meetings from ERS. V.M. Moles reports grants from Janssen, Acceleron Pharma, Axon Therapies, Keros Therapeutics and Sumitomo Pharma America/Parexel International LLC, support for attending meetings from Foresee Pharmaceutical, participation on a data safety monitoring board or advisory board with United Therapeutics and Gossamer Bio, and is Assistant Editor at ACC.org Section of Pulmonary Hypertension and Venous Thromboembolism. H. Skara reports participation on a data safety monitoring board or advisory board with Aerovate. A. Torbicki reports consultancy fees from Bayer, Gossamer, Janssen and MSD, payment or honoraria for lectures, presentations, manuscript writing or educational events from AOP, Bayer, Janssen, Pfizer, MSD and Ferrer, support for attending meetings from Pfizer, AOP and Ferrer, and participation on a data safety monitoring board or advisory board with Boston and Janssen. J.S.R. Gibbs reports consultancy fees from Acceleron, Aerovate, Actelion/Janssen, Gossamer Bio, LG Chem, Keros, Merck, Bial Labcorp and United Therapeutics, and participation on a data safety monitoring board or advisory board with Merck, Gossamer Bio, Bial Labcorp, Keros and Actelion., (Copyright ©The authors 2024.)

Magnetic field hyperthermia relies on the intra-tumoural delivery of magnetic nanoparticles by interstitial injection, followed by their heating on exposure to a remotely-applied alternating magnetic field (AMF). This offers a potential sole or adjuvant route to treating drug-resistant tumours for which no alternatives are currently available. However, two challenges in nanoparticle delivery currently hinder the effective clinical translation of this technology: obtaining enough magnetic material within the tumour to enable sufficient heating; and doing this accurately to limit or avoid damage to surrounding healthy tissue. A further complication is the lack of established methods to non-invasively quantify nanoparticle biodistribution, which is necessary to evaluate the performance of improved delivery strategies. Here we employ 111 In radiolabelling and single-photon emission computed tomography (SPECT) to non-invasively quantify distribution of a clinical grade iron-oxide-based nanoparticle in a mouse model of melanoma. We show that compared to manual injection, ultrasound guided delivery together with syringe-pump-controlled infusion improves both the nanoparticle concentration within the tumour, and the accuracy of delivery - reducing off-target peri-tumoural delivery. Following AMF heating, injected melanomas shrank significantly compared to non-injected controls, validating therapeutic efficacy. Systemic off-target delivery was quantified and extrapolated to predict off-target energy absorbance within safe limits for the main sites of background accumulation. With many nanoparticle-based therapies currently in development for cancer, this image-guided delivery strategy has wide potential impact beyond the field of magnetic hyperthermia. Future use in representative patient cohorts would also be enabled by the high clinical availability of both SPECT and ultrasound imaging.

Aims: To assess and compare the psychometric properties and acceptability of four diabetes-specific quality of life (QoL) scales among adults with Type 2 diabetes (T2D)., Methods: Adults (≥18 years) with T2D living in the United Kingdom (n = 1465) or Australia (n = 248) completed a cross-sectional, online survey including the following: ADDQoL, DCP, DIDP and Diabetes QoL-Q (presented in randomised order), followed by rating scales to assess clarity, relevance, ease of completion, length and comprehensiveness of each scale. Demographic, clinical and psychosocial characteristics were collected. Acceptability (scale completeness and user ratings), response patterns, structure (exploratory and confirmatory factor analyses) and validity (convergent, confirmatory, divergent and known-groups) were examined. Data were analysed by country to assess cross-country reproducibility., Results: High completion rates (≥89%) and positive user ratings were observed across scales indicating broad acceptability. The DIDP was the strongest performing scale: highest completion rate (97%), user ratings (≥84% positive) and most satisfactory psychometric properties (highest variance explained, consistent factor loadings >0.5 on all items and most permissible model fit parameters). Scale-level floor effects may suggest domain omissions for the brief DIDP., Conclusions: The current study provides novel insights into the acceptability, validity and reliability of diabetes-specific QoL measures for adults with T2D. Consistent with the published Type 1 diabetes cohort findings, the DIDP is recommended as a brief, acceptable and psychometrically sound measure. However, selection needs to be considered in the context of the specific research or clinical aims and further evidence (e.g. responsiveness) may be required before it can be recommended for use in trials or prospective studies., (© 2024 Diabetes UK.)

Staphylococcus aureus can induce trained immunity in murine macrophages offering protection against repeat exposure during S. aureus skin infection. Here we demonstrate that S. aureus exposure can result in non-specific trained immunity in humans and mice, enhancing macrophage responsiveness and bacterial clearance in a heterologous challenge. In humans, the enhanced macrophage responsiveness was accompanied by metabolic changes and histone modification. In mice, the enhanced responsiveness of macrophages occurred in conjunction with enhanced myelopoiesis. This report provides further insights on the host's response to the bacterium S. aureus , indicating that exposure to this organism induces heterologous protection against subsequent gram-negative infection that is provided by macrophages. These findings support the hypothesis that S. aureus has evolved to develop a mutualistic relationship with the host, imbuing the host with enhanced capacity to protect itself from attack by alternative pathogens, while potentially allowing S. aureus to exert its dominance within its niche., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Sequence variation observed in populations of pathogens can be used for important public health and evolutionary genomic analyses, especially outbreak analysis and transmission reconstruction. Identifying this variation is typically achieved by aligning sequence reads to a reference genome, but this approach is susceptible to reference biases and requires careful filtering of called genotypes. There is a need for tools that can process this growing volume of bacterial genome data, providing rapid results, but that remain simple so they can be used without highly trained bioinformaticians, expensive data analysis, and long-term storage and processing of large files. Here we describe split k -mer analysis (SKA2), a method that supports both reference-free and reference-based mapping to quickly and accurately genotype populations of bacteria using sequencing reads or genome assemblies. SKA2 is highly accurate for closely related samples, and in outbreak simulations, we show superior variant recall compared with reference-based methods, with no false positives. SKA2 can also accurately map variants to a reference and be used with recombination detection methods to rapidly reconstruct vertical evolutionary history. SKA2 is many times faster than comparable methods and can be used to add new genomes to an existing call set, allowing sequential use without the need to reanalyze entire collections. With an inherent absence of reference bias, high accuracy, and a robust implementation, SKA2 has the potential to become the tool of choice for genotyping bacteria. SKA2 is implemented in Rust and is freely available as open-source software., (© 2024 Derelle et al.; Published by Cold Spring Harbor Laboratory Press.)

Abstract: Over the past two decades, there has been increasing interest in the diagnosis and management of schwannomas of the inner ear including hearing rehabilitation with cochlear implants. However, tumor nomenclature and classification within the literature have been variable and oftentimes cumbersome. The term "intralabyrinthine schwannoma" is in common use when describing these tumors but is a potential source of confusion given that people often use the term "labyrinth" or "labyrinthine" to refer to the vestibular component of the inner ear only (i.e., labyrinthectomy or the translabyrinthine approach).During the Ninth Quadrennial Conference on Vestibular Schwannoma and Other Cerebellopontine Angle Lesions in Bergen, Norway, in May 2023, a multidisciplinary group of conference participants met and discussed issues pertaining to current terminology and classifications to enhance clarity and to reflect recent advances in tumor management and hearing rehabilitation.Although a variety of terms have been previously used to describe inner ear schwannomas, consensus was achieved on the term "inner ear schwannoma (IES)" to describe eighth nerve schwannomas of the cochlea, vestibule, or semicircular canals. Subgroups under this term comprise intravestibular, intracochlear, or intravestibulocochlear inner ear schwannomas (low complexity tumors), inner ear schwannomas with transfundal extension into the internal auditory canal but without modiolar involvement (intermediate complexity tumors), and inner ear schwannomas with transfundal extension with modiolar involvement (high complexity tumors).The details of the recommendations for an updated and simplified tumor nomenclature centered around tumor control and hearing rehabilitation with cochlear implantation are presented., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)

Background: Hypoxia is a trigger for sympathetic activation and autonomic cardiovascular dysfunction. Pulmonary vascular disease (PVD) is associated with hypoxaemia, which increases with altitude. The aim was to investigate how exposure of patients with PVD to hypobaric hypoxia at altitude affects autonomic cardiovascular regulation., Methods: In a randomised crossover study, patients with PVD were studied for 1 day and one night at an altitude of 2500 m (hypobaric hypoxia) and low altitude at 470 m in a random order. Outcomes were heart rate variability (HRV) in the time domain and in the frequency domain (low frequency (LF)/high frequency (HF) and LF/HF) and heart rate (HR) during day and night and baroreflex sensitivity (BRS)., Results: In 25 patients with PVD (72% pulmonary arterial hypertension and 28% distal chronic thromboembolic pulmonary hypertension; mean±sd age 60.7±13.6 years), exposure to altitude resulted in significant increases in awake HR by 9.4 bpm (95% confidence interval (CI) 6.3-12.4, p<0.001) and nocturnal HR by 9.0 bpm (95% CI 6.6-11.4, p<0.001) and significant changes in awake and particularly nocturnal HRV indicating decreasing parasympathetic and increasing sympathetic activity (change in daytime LF/HF 1.7 (95% CI 0.6-2.8), p=0.004; nocturnal LF/HF 1.9 (95% CI 0.3-3.4), p=0.022) and a significant decrease in BRS (-2.4·mmHg -1 (95% CI -4.3- -0.4, p=0.024))., Conclusion: Exposure of PVD patients to altitude resulted in a significant change in HRV indicating an increase in sympathetic activity and a decrease in BRS. The relative change in HRV at altitude was more pronounced during sleep., Competing Interests: Conflict of interest: S. Ulrich reports grants or contracts from Swiss National Science Foundation, Zurich, and Swiss Lung League; unrestricted grants from Orpha Swiss and MSD, outside the submitted work; consulting fees from Orpha Swiss, MSD SA and Janssen SA, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events for Orpha Swiss, MSD SA, Janssen SA and Novartis SA, outside the submitted work; support for attending meetings and/or travel from Orpha Swiss, MSD SA, Janssen SA and Novartis SA, outside the submitted work; participation on a data safety monitoring or advisory board for Orpha Swiss, MSD SA and Janssen SA, outside the submitted work; leadership or fiduciary roles for the Swiss Society of Pulmonology, European Respiratory Society and Swiss Society of Pulmonary Hypertension, outside the submitted work. Conflict of interest: M. Lichtblau reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from MSD SA, outside the submitted work; support for attending meetings and/or travel from Orpha Swiss, Janssen and MSD, outside the submitted work; and participation on a data safety monitoring or advisory board for MSD SA, outside the submitted work. Conflict of interest: E.I. Schwarz reports receiving lecture fees from ResMed outside the submitted work and is Secretary of Assembly 4 of the European Respiratory Society (unpaid) outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: Patients with pulmonary vascular disease (PVD) often suffer from nocturnal hypoxaemia, but also from sleep apnoea. Short-term use of acetazolamide increases ventilation due to metabolic acidosis and also reduces loop gain. We investigated whether prolonged use of acetazolamide improves sleep disordered breathing in PVD., Methods: In a randomised controlled crossover trial, patients with PVD were randomly assigned to acetazolamide 250 mg and placebo twice daily for 5 weeks. Patients underwent respiratory polygraphy at baseline and at the end of each intervention phase. Outcomes of interest were the effect of acetazolamide on mean nocturnal oxygen saturation ( S pO 2 ), time with oxygen saturation <90% ( t <90 ), apnoea-hypopnoea index (AHI) and sleep apnoea severity., Results: In 20 patients with PVD (55% women, nine with pulmonary arterial hypertension, 11 with distal chronic thromboembolic pulmonary hypertension; mean±sd nocturnal S pO 2 88.8±3.5%, obstructive AHI 12.6±12.3 events·h -1 ), 5 weeks of acetazolamide resulted in a significant improvement in nocturnal oxygenation compared to placebo (mean nocturnal S pO 2 +2.3% (95% CI 1.3-3.3%); p<0.001 and t <90 -18.8% (95% CI -29.6- -8.0%); p=0.001). Acetazolamide increased the proportion of patients with mean nocturnal S pO 2 ≥90% from 45% to 85%. The percentage of patients with AHI >5 events·h -1 was reduced from 75% to 60% and with AHI >15 events·h -1 from 30% to 15%. Two patients discontinued the study because of mild side-effects., Conclusions: Acetazolamide given for 5 weeks reduces nocturnal hypoxaemia in PVD to a clinically relevant level and reduces the proportion of patients with obstructive sleep apnoea., Competing Interests: Conflicts of interest: M. Lichtblau reports being early career member of European Respiratory Society (ERS) Assembly 13 (Pulmonary Vascular Disease), outside the submitted work. K.E. Bloch reports support for the present manuscript from the Swiss National Science Foundation. S. Ulrich reports support for the present manuscript from the Swiss National Science Foundation and is Chair of ERS Group 13.01 (Pulmonary Hypertension), outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Supported metal catalysts are essential to a plethora of processes in the chemical industry. The overall performance of these catalysts depends strongly on the interaction of adsorbates at the atomic level, which can be manipulated and controlled by the different constituents of the active material ( i.e. , support and active metal). The description of catalyst activity and the relationship between active constituent and the support, or metal-support interactions (MSI), in heterogeneous (thermo)catalysts is a complex phenomenon with multivariate (dependent and independent) contributions that are difficult to disentangle, both experimentally and theoretically. So-called "strong metal-support interactions" have been reported for several decades and summarized in excellent review articles. However, in recent years, there has been a proliferation of new findings related to atomically dispersed metal sites, metal oxide defects, and, for example, the generation and evolution of MSI under reaction conditions, which has led to the designation of (sub)classifications of MSI deserving to be critically and systematically evaluated. These include dynamic restructuring under alternating redox and reaction conditions, adsorbate-induced MSI, and evidence of strong interactions in oxide-supported metal oxide catalysts. Here, we review recent literature on MSI in oxide-supported metal particles to provide an up-to-date understanding of the underlying physicochemical principles that dominate the observed effects in supported metal atomic, cluster, and nanoparticle catalysts. Critical evaluation of different subclassifications of MSI is provided, along with discussions on the formation mechanisms, theoretical and characterization advances, and tuning strategies to manipulate catalytic reaction performance. We also provide a perspective on the future of the field, and we discuss the analysis of different MSI effects on catalysis quantitatively.

Background: Risk factors for in-hospital mortality related to gastrointestinal complications requiring operative intervention after cardiovascular surgery have not been previously described., Methods: Adult patients who underwent cardiovascular surgery followed by gastrointestinal surgery during the same admission between January 2010 and June 2023 were included. Multivariable logistic regression was used to identify predictors of in-hospital mortality. Kaplan-Meier survival analysis was performed to assess overall survival based on identified risk factors., Results: Gastrointestinal complications requiring operative intervention after cardiac surgery occurred in 151 patients, with an overall in-hospital mortality of 35.76% (n = 54). The most common diagnosis was bowel ischemia (50.33%). On multivariable logistic regression, the history of cirrhosis (odds ratio: 37.96, 95% confidence interval: 3.57-543.90) and the clinical condition at the time of emergency general surgery consultation, described by elevated lactate (odds ratio: 5.76, 95% confidence interval: 1.71-22.82), platelets <50 × 10 9 /L (odds ratio: 11.34, 95% confidence interval: 1.60-162.37), ≥3 vasoactive medications (odds ratio: 4.93, 95% CI: 1.29-20.14), and the need for renal replacement therapy (odds ratio: 5.18, 95% confidence interval: 1.46-20.79) were predictive of in-hospital mortality. In-hospital mortality was low when none of the risk factors identified on multivariable analysis were present (2.38%, n = 1 of 42), but in-hospital mortality was universal among patients with 4-5 risk factors (100%, n = 8 of 8)., Conclusions: Gastrointestinal complications after cardiac surgery are disastrous when patient illness becomes severe. Clinicians should maintain a high index of suspicion for gastrointestinal complications to promote early involvement of general surgery. Knowledge of these risk factors could help guide discussions among the multidisciplinary care team, patients, and their families., Competing Interests: Conflict of Interest/Disclosure The authors have no related conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective . This study presents a universal phantom for positron emission tomography (PET) that allows arbitrary static and dynamic activity distributions of various complexities to be generated using a single PET acquisition. Approach . We collected a high-statistics dataset (with a total of 22.4 × 10 9 prompt coincidences and an event density of 2.75 × 10 6 events mm -3 ) by raster-scanning a single plane with a 22 Na point source mounted on a robotic arm in the field-of-view of the uEXPLORER PET/CT scanner. The source position was determined from the reconstructed dynamic frames. Uniquely, true coincidences were separated from scattered and random events based on the distance between their line-of-response and the known source location. Finally, we randomly sampled the dataset to generate the desired activity distributions modeling several different phantoms. Main results . Overall, the target and the reconstructed phantom images had good agreement. The analysis of a simple geometric distribution showed high quantitative accuracy of the phantom, with mean error of <-3.0% relative to the ground truth for activity concentrations ranging from 5.3 to 47.7 kBq ml -1 . The model of a high-resolution 18 F-fluorodeoxyglucose distribution in the brain illustrates the usefulness of the technique in simulating realistic static neuroimaging studies. A dynamic 18 F-florbetaben study was modeled based on the time-activity curves of a human study and a segmented brain phantom with no coincidences repeating between frames. For all time points, the mean voxel-wise errors ranged from -4.4% to -0.7% in grey matter and from -3.9% to +2.8% in white matter. Significance . The proposed phantom technique is highly flexible and allows modeling of static and dynamic brain PET studies with high quantitative accuracy. It overcomes several key limitations of the existing phantoms and has many promising applications for the purposes of image reconstruction, data correction methods, and system performance evaluation, particularly for new high-performance dedicated brain PET scanners., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background: Most schwannomas are isolated tumours occurring in otherwise healthy people. However, bilateral vestibular schwannomas (BVS) or multiple non-vestibular schwannomas indicate an underlying genetic predisposition. This is most commonly NF2 -related schwannomatosis (SWN), but when BVS are absent, this can also indicate SMARCB1 -related or LZTR1 -related SWN., Methods: We assessed the variant detection rates for the three major SWN genes ( NF2 , LZTR1 and SMARCB1 ) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria for NF2 -related SWN at the time of genetic testing., Results: We found that 17 (11%) people from 13 families had a germline SMARCB1 variant and 19 (12%) unrelated individuals had a germline LZTR1 variant. 19 people had an NF2 variant, but 18 of these were mosaic and 17 were only detected when 2 tumours were available for testing. The overall detection rate was 25% using blood alone, but increased to 36% when tumour analysis was included. Another 12 people had a germline variant of uncertain significance (VUS)., Conclusions: There were similar proportions of LZTR1 , SMARCB1 or mosaic NF2 . However, since an NF2 variant was detected in tumours from 103 people, it is likely that further cases of mosaicism would be detected if more people had additional tumours available for analysis. In addition, if further evidence becomes available to show that the VUSs are pathogenic, this would significantly increase the proportion of people with a genetic diagnosis. Our results indicate the importance of comprehensive genetic testing and improved variant classification., Competing Interests: Competing interests: GE has received consultancy fees from AstraZeneca, Springworks and Everything Genetic., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Since the publication of the 2011 European Alliance of Associations for Rheumatology (EULAR) recommendations for patient research partner (PRP) involvement in rheumatology research, the role of PRPs has evolved considerably. Therefore, an update of the 2011 recommendations was deemed necessary., Methods: In accordance with the EULAR Standardised Operational Procedures, a task force comprising 13 researchers, 2 health professionals and 10 PRPs was convened. The process included an online task force meeting, a systematic literature review and an in-person second task force meeting to formulate overarching principles (OAPs) and recommendations. The level of agreement of task force members was assessed anonymously (0-10 scale)., Results: The task force developed five new OAPs, updated seven existing recommendations and formulated three new recommendations. The OAPs address the definition of a PRP, the contribution of PRPs, the role of informal caregivers, the added value of PRPs and the importance of trust and communication in collaborative research efforts. The recommendations address the research type and phases of PRP involvement, the recommended number of PRPs per project, the support necessary for PRPs, training of PRPs and acknowledgement of PRP contributions. New recommendations concern the benefits of support and guidance for researchers, the need for regular evaluation of the patient-researcher collaboration and the role of a designated coordinator to facilitate collaboration. Agreements within the task force were high and ranged between 9.16 and 9.96., Conclusion: The updated EULAR recommendations for PRP involvement are more substantially based on evidence. Together with added OAPs, they should serve as a guide for researchers and PRPs and will ultimately strengthen the involvement of PRPs in rheumatology research., Competing Interests: Competing interests: MdW: over the last 3 years, Stichting Tools has received fees for lectures or consultancy provided by Maarten de Wit from UCB, not related to this project. LG reports grants from AbbVie, Biogen, Lilly, Novartis, UCB, personal fees from AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, non-financial support from AbbVie, Amgen, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB, outside the submitted work. KA: funded by EULAR grant RES005 this project; research grants: UCB; consulting fees: Novartis. ME: congress travel support from Janssen and AstraZeneca outside of the submitted work. DB: Speakers bureau: AbbVie, BMS, Galapagos, Janssen, Lilly, MSD. Research grants: Novartis. Consultancy: Sandoz, UCB. Part-time work in Savana Research. EFM has received consultancy fees from Boehringer Ingelheim Portugal outside of the submitted work, LPCDR has received fees for lectures or consultancy provided by Elsa Mateus from Lilly Portugal, GSK and Novartis, outside of the submitted work. SWT has received research funding, consultancy and/ or speaker fees from: Abbvie, Arthrogen, AstraZeneca, BMS, Celgene, Galapagos, Galvani bioelectronics, GSK, Lilly, MSD, Pfizer, Roche, and Sanofi-Genzyme, all outside the submitted work. WT has received research funding, consultancy and/ or speaker fees from: AbbVie, Amgen, BMS, Celgene, Eli-Lilly, GSK, Janssen, MSD, Novartis, Ono-Pharma, Pfizer and UCB all outside of the submitted work. HB, SB, PB, JP, CD, MF, SK, UK, DPR, JR-C, JS, RS, SRS, AV, T-CW, CZ and JP report no competing interests for this project., (© European Alliance of Associations for Rheumatology, EULAR 2024. Re-use permitted under CC BY-NC-ND. No commercial re-use. No derivatives. See rights and permissions. Published by BMJ on behalf of EULAR.)

The role of dopamine in the regulation of insulin secretion in horses is poorly understood and requires further investigation. Pituitary pars intermedia dysfunction (PPID) is associated with decreased activity of dopaminergic neurons which normally suppress peptide hormone secretion from the pituitary pars intermedia. A high proportion of horses with PPID also have insulin dysregulation (ID), characterised by post-prandial hyperinsulinaemia and/or tissue insulin resistance, which are risk factors for the development of laminitis. The aim of this study was to investigate the effects of alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor that reduces dopamine production, on insulin sensitivity and the post-prandial insulin response to a glucose-containing meal. Six healthy Standardbred horses were enrolled in a placebo-controlled randomised crossover study, in which one dose of AMPT (40 mg/kg BW) or placebo was administered orally, prior to performing an in-feed oral glucose test (OGT) and a frequently sampled intravenous glucose tolerance test (FSIGTT). Dopamine reduction by AMPT was confirmed by an increase in plasma prolactin concentration and the lack of post-prandial increase in plasma dopamine concentration compared to placebo. Post-prandial insulin responses, both peak and AUCi, were increased after AMPT compared to placebo (P=0.048 and P=0.005, respectively), without affecting blood glucose concentrations. However, one dose of AMPT did not appear to affect tissue sensitivity as assessed by the FSIGTT. This study confirmed that dopamine plays a role in the regulation of insulin secretion in horses, as it does in other species, whereby the post-prandial release of dopamine into the circulation may inhibit pancreatic insulin secretion. Further studies are required to evaluate different dosing protocols for AMPT, and to further investigate the links between PPID, ID and laminitis risk in horses., (Copyright © 2024. Published by Elsevier Inc.)