Search

Abstract Energy status and nutrients regulate photosynthetic protein expression. The unicellular green alga Chromochloris zofingiensis switches off photosynthesis in the presence of exogenous glucose (+Glc) in a process that depends on hexokinase (HXK1). Here, we show that this response requires that cells lack sufficient iron (−Fe). Cells grown in −Fe+Glc accumulate triacylglycerol (TAG) while losing photosynthesis and thylakoid membranes. However, cells with an iron supplement (+Fe+Glc) maintain photosynthesis and thylakoids while still accumulating TAG. Proteomic analysis shows that known photosynthetic proteins are most depleted in heterotrophy, alongside hundreds of uncharacterized, conserved proteins. Photosynthesis repression is associated with enzyme and transporter regulation that redirects iron resources to (a) respiratory instead of photosynthetic complexes and (b) a ferredoxin-dependent desaturase pathway supporting TAG accumulation rather than thylakoid lipid synthesis. Combining insights from diverse organisms from green algae to vascular plants, we show how iron and trophic constraints on metabolism aid gene discovery for photosynthesis and biofuel production.

The terrestrial green alga Chromochloris zofingiensis is an emerging model species with potential applications including production of triacylglycerol or astaxanthin. How C. zofingiensis interacts with the diverse substrates during trophic transitions is unknown. To characterize its substrate utilization and secretion dynamics, we cultivated the alga in a soil-based defined medium in transition between conditions with and without glucose supplementation. Then, we examined its exometabolite and endometabolite profiles. This analysis revealed that regardless of trophic modes, C. zofingiensis preferentially uptakes exogenous lysine, arginine, and purines, while secreting orotic acid. Here, we obtained metabolomic evidences that C. zofingiensis may use arginine for putrescine synthesis when in transition to heterotrophy, and for the TCA cycle during transition to photoautotrophy. We also report that glucose and fructose most effectively inhibited photosynthesis among thirteen different sugars. The utilized or secreted metabolites identified in this study provide important information to improve C. zofingiensis cultivation, and to expand its potential industrial and pharmaceutical applications.

In this paper, we focus on investigating the potential of advanced Neural Radiance Fields (NeRFs) and 3D Gaussian Splatting for 3D scene reconstruction from aerial imagery obtained via sensor platforms with an almost nadir-looking camera. Such a setting for image acquisition is convenient for capturing large-scale urban scenes, yet it poses particular challenges arising from imagery with large overlap, very short baselines, similar viewing direction and almost the same but large distance to the scene, and it therefore differs from the usual object-centric scene capture. We apply a traditional approach for image-based 3D reconstruction (COLMAP), a modern NeRF-based approach (Nerfacto) and a representative for the recently introduced 3D Gaussian Splatting approaches (Splatfacto), where the latter two are provided in the Nerfstudio framework. We analyze results achieved on the recently released UseGeo dataset both quantitatively and qualitatively. The achieved results reveal that the traditional COLMAP approach still outperforms Nerfacto and Splatfacto approaches for various scene characteristics, such as less-textured areas, areas with high vegetation, shadowed areas and areas observed from only very few views.

Abstract Primate faces provide information about a range of variant and invariant traits, including some that are relevant for mate choice. For example, faces of males may convey information about their health or genetic quality through symmetry or facial masculinity. Because perceiving and processing such information may have bearing on the reproductive success of an individual, cognitive systems are expected to be sensitive to facial cues of mate quality. However, few studies have investigated this topic in non-human primate species. Orang-utans are an interesting species to test mate-relevant cognitive biases, because they are characterised by male bimaturism: some adult males are fully developed and bear conspicuous flanges on the side of their face, while other males look relatively similar to females. Here, we describe two non-invasive computerised experiments with Bornean orang-utans (Pongo pygmaeus), testing (i) immediate attention towards large flanges and symmetrical faces using a dot-probe task (N = 3 individuals; 2F) and (ii) choice bias for pictures of flanged males over unflanged males using a preference test (N = 6 individuals; 4F). In contrast with our expectations, we found no immediate attentional bias towards either large flanges or symmetrical faces. In addition, individuals did not show a choice bias for stimuli of flanged males. We did find exploratory evidence for a colour bias and energy efficiency trade-offs in the preference task. We discuss our null results and exploratory results in the context of the evolutionary history of Bornean orang-utans, and provide suggestions for a more biocentric approach to the study of orang-utan cognition.

Objective:. We aimed to determine whether n-butyl-2-cyanoacrylate (NB2C) adhesive is a safe and effective mechanism for nonpenetrating mesh and peritoneal fixation during laparoscopic groin hernia repair. Background:. Chronic pain after laparoscopic groin hernia repair has been associated with penetrating fixation, but there had been no US Food and Drug Administration–approved devices for nonpenetrating fixation in this context. Methods:. Patients undergoing laparoscopic transabdominal preperitoneal (TAP) or totally extraperitoneal (TEP) groin hernia repair with mesh at 1 of 5 academic medical centers were randomized to mesh (TAP/TEP) and peritoneal (TAP) fixation with NB2C adhesive or absorbable tacks. The primary outcome was improvement in pain (visual analog scale [VAS]) at 6 months. The noninferiority margin was 0.9 (α = 0.025; β = 80%). Recurrence, successful use of the device, quality of life, and rates of adverse events (AEs) were secondary outcomes. Results:. From 2019 to 2021, 284 patients were randomized to either NB2C adhesive or absorbable tacks (n = 142/142). Patient and hernia characteristics were comparable, and 65% were repaired using a TAP approach. The difference in VAS improvement at 6 months with NB2C adhesive was not inferior to absorbable tacks in intention-to-treat and per-protocol analyses, respectively (0.25 [95% CI, −0.33 to 0.82]; P = 0.013; 0.22 [95% CI, −0.36 to 0.80], noninferiority P = 0.011). There were no differences in secondary outcomes including recurrence, successful use of each device to fixate the mesh and peritoneum, quality of life, and additional VAS pain scores. Rates of adverse and serious AEs were also comparable. Conclusions:. NB2C adhesive is safe and effective for mesh fixation and peritoneal closure during laparoscopic groin hernia repair.

Abstract Considering growing efforts to understand and improve the solute-specific selectivity of nanofiltration (NF) membranes, we explored the ion-specific effects that govern the charge and performance of a loose polyamide NF membrane that is commonly used for solute-solute separations. Specifically, we systematically evaluated the zeta potential of the membrane under different conditions of pH, salinity, and ionic composition, and correlated the obtained data with membrane performance tested under similar conditions. Our results identify the pK a of both carboxylic and amine groups bonded to the membrane surface and suggest that the highly polarizable chloride anions in the solution adsorb to the polyamide, increasing its negative charge. We also show that monovalent cations of different “stickiness” can neutralize the negative membrane charge to different extents due to their varying tendency to sorb to the polymer matrix or screen the fixed carboxyl groups on the membrane surface. Notably, our correlation between zeta potential measurements and permeability experiments indicates the substantial contribution of solution ions to Donnan exclusion in NF membranes.

Abstract Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cell dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cell ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiological substrate of SMYD2 in breast cancer cells. BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl-binding domain present in FMNLs proteins. These actin cytoskeleton regulators are recruited at the cell edges by the SMYD2 methylation signaling and modulate lamellipodia properties. Breast cancer cells with impaired BCAR3 methylation lose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo. Remarkably, SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis.

PurposeTo determine the effect of sex as a risk factor regarding presbyopia.MethodsMaximum accommodation was pharmacologically induced (40% cabachol corneal iontophoresis) in 97 rhesus monkeys (49 males and 48 females) ranging in age from 8 to 36 years old. Accommodation was measured by Hartinger coincidence refractometry.ResultsAccommodative amplitude measured refractometrically decreased with age, and the rate of change was not different between males and females (p = 0.827).ConclusionsPresbyopia is essentially sex neutral, and no one is spared. There may be modest variations between different populations for various reasons, but essentially it is monotonously predictable. At present there is no biological therapeutic.

Background & Aims: The diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis relies on non-invasive criteria based on international guidelines. The advent of systemic therapies warrants reconsideration of the role of biopsy specimens in the diagnosis of HCC. Accordingly, we investigated the diagnostic performance of the LI-RADS 2018 and the AASLD 2011 criteria. Methods: Consecutive patients with cirrhosis who underwent a biopsy for suspected HCC between 2015 and 2020 were included. The available imaging studies (computed tomography and/or magnetic resonance imaging) were blindly reviewed by two independent radiologists. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed for LI-RADS, AASLD, and biopsies. Results: In total, 167 patients underwent both available biopsy and imaging. Of the 137 relevant biopsies, 114 patients had HCC (83.2%), 12 (9%) had non-HCC malignant lesions, and 11 (8%) had benign nodules. The PPV and NPV of the biopsies were 100% and 62%, respectively; 30 biopsies were non-contributive. The PPV and NPV of the LI-RADS categories were 89% and 32.8% for LR-5 and 85.5% and 54.5% for LR-4 + 5 + TIV, respectively. The PPV and NPV of the 2011 AASLD criteria were 93.2% and 35.6%, respectively. The interobserver kappa (k = 0.380) for the LR-5 categories was reasonable. Of 100 LR-5 nodules, 11 were misclassified, in particular one case was a colorectal metastasis, and two cases were cholangiocarcinomas, of which nine were identified through biopsy, whereas six were correctly classified according to LI-RADS (LR-M or LR-TIV). Fifty percent of macrotrabecular HCC and 48.4% of poorly differentiated HCC (Edmonson 3 and 4) were not classified as LR-5. Conclusions: LI-RADS 2018 did not outperform the AASLD 2011 score as a non-invasive diagnosis of HCC. Tumor biopsy allowed restoration of an accurate diagnosis in 11% of LR-5 cases. A combined radiological and histological diagnosis should be considered mandatory for good treatment assessment. Impact and Implications: Although biopsy is not required for hepatocellular carcinoma diagnosis when the LI-RADS criteria are met according to current guidelines, our study underscores the limits of radiology and the need for biopsy when hepatocellular carcinoma is suspected. Histological findings could change therapeutics of liver tumors even if only for a small proportion of patients. Histological proof of the type of cancer is a standard in oncology.

Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the NPC1 gene, causing lipid accumulation within late endosomes/lysosomes and resulting in progressive neurodegeneration. Although microglial activation precedes neuronal loss, it remains elusive whether loss of the membrane protein NPC1 in microglia actively contributes to NPC pathology. In a mouse model with depletion of NPC1 in myeloid cells, we report severe alterations in microglial lipidomic profiles, including the enrichment of bis(monoacylglycero)phosphate, increased cholesterol, and a decrease in cholesteryl esters. Lipid dyshomeostasis was associated with microglial hyperactivity, marked by an increase in translocator protein 18 kDa (TSPO). These hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including a shortened life span, motor impairments, astrogliosis, neuroaxonal pathology, and increased neurofilament light chain (NF-L), a neuronal injury biomarker. As observed in the mouse model, patients with NPC showed increased NF-L in the blood and microglial hyperactivity, as visualized by TSPO-PET imaging. Reduced TSPO expression in blood-derived macrophages of patients with NPC was measured after N -acetyl-l-leucine treatment, which has been recently shown to have beneficial effects in patients with NPC, suggesting that TSPO is a potential marker to monitor therapeutic interventions for NPC. Conclusively, these results demonstrate that myeloid dysfunction, driven by the loss of NPC1, contributes to NPC disease and should be further investigated for therapeutic targeting and disease monitoring.

Antisemitism has been rising for decades and worsened following the events of Oct 7, 2023. Although anecdotal evidence suggests that these trends extend into the US medical community, quantitative data have been lacking. To address this gap, we quantitated publications about antisemitism, analyzed social media posts from the accounts of 220,405 healthcare professionals, and disseminated a survey to members of Jewish medical associations. Publications and social media posts about antisemitism rose > fivefold, while posts promoting antisemitic stereotypes increased 2-fourfold. Most Jewish-identifying medical students and professionals (75.4%) reported exposure to antisemitism. Together, our results suggest that antisemitism is escalating within the US healthcare community., Competing Interests: Declarations. Conflict of interest: Mr. Leiba is a full-time employee of the Foundation to Combat Antisemitism (Foxboro, MA). Dr. Wald is Commissioner, Lancet Commission on Medicine, Nazism, and the Holocaust. Dr. Roth is president of the Healthcare Council of the Coalition for Jewish Values (Baltimore, Maryland), and head of the Publications Committee of the American Jewish Medical Association (New York, NY). Dr. Schwartz, Dr. Spence, Dr. Oratz  and Dr. Feldman are members of the Publications Committee of the American Jewish Medical Association. The opinions expressed herein are those of the authors and not necessarily of their employers or of the Lancet Commission on medicine, Nazism, and the Holocaust. Ethical approval: This study utilized de-identified public social media data and an anonymous, voluntary survey of health professionals. All survey respondents were informed that their data would be used for research. The University of Illinois College of Medicine Institutional Review Board deemed this study “exempt.”, (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Risk prediction models are an established component of the preoperative evaluation. In its guidelines the European Society for Cardiology proposes several risk scores but the benefit of these is mostly unclear for clinicians. This article describes the individual steps in the preparation of a valid prediction model with a focus on the parameters, discrimination, calibration and external validation. The clinical benefits of the risk scores proposed in the guidelines with respect to these parameters was investigated. All proposed risk scores appear to show a good discrimination in the validation cohorts. Only a few reliable data for a good calibration could be compiled. The external validity of the individual models is unclear. The general benefit of the risk scores cannot be recommended as data for calibration or discrimination in external cohorts are lacking. A precise estimation of the risk cannot be expected., Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: Gemäß den Richtlinien des Springer Medizin Verlags werden Autoren und Wissenschaftliche Leitung im Rahmen der Manuskripterstellung und Manuskriptfreigabe aufgefordert, eine vollständige Erklärung zu ihren finanziellen und nichtfinanziellen Interessen abzugeben. Autoren: R. M’Pembele: A. Finanzielle Interessen: René M’Pembele. – B. Nichtfinanzielle Interessen: Facharzt und wissenschaftlicher Mitarbeiter Klinik für Anästhesiologie, Universitätsklinikum Düsseldorf | Mitgliedschaften: DGAI, ESAIC | Leitlinienkoautor „ESAIC focused guidelines for the use of biomarkers in non-cardiac surgery“ | Assistant Editor European Journal of Anaesthesiology. S. Roth: A. Finanzielle Interessen: S. Roth gibt an, dass kein finanzieller Interessenkonflikt besteht. – B. Nichtfinanzielle Interessen: Facharzt und wissenschaftlicher Mitarbeiter der Klinik für Anästhesiologie, Universitätsklinikum Düsseldorf | Mitgliedschaften: DGAI, ESAIC | Leitlinienkoautor „ESAIC focused guidelines for the use of biomarkers in non-cardiac surgery“ | Assistant Editor European Journal of Anaesthesiology. G. Lurati Buse: A. Finanzielle Interessen: G. Lurati-Buse gibt an, dass kein finanzieller Interessenkonflikt besteht. – B. Nichtfinanzielle Interessen: Geschäftsführende Oberärztin der Klinik für Anästhesiologie am Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, Düsseldorf | CARID (Cardiovascular Research Institute Düsseldorf), Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, Düsseldorf. Wissenschaftliche Leitung: Die vollständige Erklärung zum Interessenkonflikt der Wissenschaftlichen Leitung finden Sie am Kurs der zertifizierten Fortbildung auf www.springermedizin.de/cme . Der Verlag: erklärt, dass für die Publikation dieser CME-Fortbildung keine Sponsorengelder an den Verlag fließen. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Alcohol use disorder (AUD) is a highly prevalent, yet heterogenous condition linked to anxiety, reward sensitivity, and cognitive biases. Understanding cognitive mechanisms of specific AUD symptoms is crucial for developing tailored, effective interventions. This pilot study sought to assess whether two potential cognitive correlates of AUD-intolerance of uncertainty and delay discounting-differentially influence the relationship between AUD, anxiety sensitivity, and drinking motives. Individuals with mild-to-moderate AUD ( n = 31) and healthy control participants ( n = 31) completed a single-session lab study in which they performed a decision making under uncertainty task as a behavioral measure of uncertainty tolerance, completed a delay discounting task as a measure of reward sensitivity, and responded to surveys related to anxiety sensitivity, state and trait anxiety, intolerance of uncertainty, and drinking motives. Hierarchical regression results demonstrated a significant interaction between AUD status (AUD vs. control) on both self-reported (β = 0.687, p = .020) and behavioral (β = 0.777, p = .012) intolerance of uncertainty. Greater anxiety sensitivity was associated with heightened intolerance of uncertainty in those with AUD but not controls. Correlations showed that the coping drinking motive was significantly positively associated with anxiety sensitivity ( r = 0.462, p = .010), self-reported ( r = 0.535, p = .002), and behavioral intolerance of uncertainty ( r = 0.396, p < .027) in participants with AUD but not controls. No significant associations between anxiety sensitivity, drinking motives, and delay discounting were observed in either the AUD or the control group. Intolerance of uncertainty may therefore represent a cognitive bias in which individuals with AUD and anxiety sensitivity drink to cope with environmental and internal uncertainty. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Objective: To investigate patency and clinical outcomes of alloplastic and other venous interposition graft materials in pancreatic surgery., Background: Vascular pancreatic surgery is increasingly performed for locally advanced pancreatic neoplasms. Different than other centers, we prefer to use alloplastic vascular graft materials for superior mesenteric vein and portal vein interposition in pancreatic surgery. Advantages are off-the-shelf availability at any customizable length, different diameters, and ring-enforcement but proposed concerns are their thrombogenicity and fatal complications., Methods: Patients who underwent elective pancreatic resections with mesoportal venous interposition grafts (ISGPS type 4) between 2003-2022 were identified from the institutional pancreatectomy registry. Alloplastic vascular grafts imply synthetic materials, either based on polytetrafluorethylene (PTFE) or polyethylene terephthalate (PET). Surgical details, clinicopathological, and follow-up data were analyzed. The patients were followed for graft patency by cross-sectional imaging., Results: In this study, 201 patients with venous interposition grafts were included (23% simultaneous arterial resections). Total pancreatectomy (41%) and pancreatoduodenectomy (35%) were the most frequent procedures. Vascular graft materials were alloplastic in 180 patients (83% PTFE and 17% PET) with a median diameter of 10 mm and a median length of 33 mm (measurement by CT scan). Patency rates among all graft materials at 7-, 30-, and 90-days were 99%, 93%, and 87%. Alloplastic grafts demonstrated superior patency over other materials (hazard ratio 2.7, P=0.009), and PTFE reached a 1-year patency of 78%. The all-cause 90-day mortality rate was 10%. No graft infection occurred., Conclusion: Alloplastic venous vascular grafts are safe and readily available tools in pancreatic surgery, especially for long-segmental mesoportal venous reconstructions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Conscientious objection is a legally protected right of medical professionals to recuse themselves from patient care activities that conflict with their personal values. Anesthesiology is different from most specialties with respect to conscientious objection in that the focus is to facilitate safe, efficient, and successful performance of procedures by others, rather than to perform the treatment in question. This could give rise to a unique, somewhat indirect ethical tension between the application of conscientious objection and potential infringement upon patient autonomy and well-being. While some situations have clear grounds and precedent for conscientious objection (e.g., abortion, or futile procedures), newer procedures, such as gender-affirming surgery and xenotransplantation, may trigger conscientious objection for complex reasons. This review discusses ethical, legal, and practical aspects of conscientious objection; challenges to anesthesia groups, departments, and healthcare organizations when conscientious objection is invoked by anesthesiologists; and strategies to help mitigate the ethical dilemmas., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Background: Despite some recent advances, pancreatic ductal adenocarcinoma (PDAC) remains a growing oncological challenge. New drugs capable of targeting more than one oncogenic pathway may be one way to improve patient outcomes. This study characterizes the effectiveness of Metavert a first-in-class dual inhibitor of GSK3-β and histone deacetylase in treating PDAC as a single agent or in combination with standard cytotoxics., Methods: Thirty-six Patient-Derived Organoids (hPDOs) characterised by RNASeq and whole exome sequencing were treated with Metavert alone or in combination with standard cytotoxics. Transcriptomic signatures (TS) representing sensitivity to Metavert alone or sensitivity to Metavert + irinotecan (IR) were evaluated in 47 patient samples, chemo-naïve in 26 and post-chemotherapy in 21 (gemcitabine=5; FOLFIRINOX=14, both=2) with companion multiplexed immunofluorescence and RNASeq data., Results: Metavert combined with gemcitabine, irinotecan, 5FU, oxaliplatin, and paclitaxel was synergistic in the hPDOs. Basal-subtype hPDOs were more sensitive to Metavert alone whereas the Metavert+IR combination exhibited synergy in Classical-subtype hPDOs with increased apoptosis and autophagy. hPDO-derived TS evaluated in PDAC tissues demonstrated that Metavert-TS Hi samples were enriched for mRNA splicing and DNA repair processes; they were associated with Basal-like tissues but also with GATA6 +ve -chemo-naïve samples and were higher following gemcitabine but not FOLFIRINOX treatment. In contrast, Metavert+IR-TS HI samples were enriched for TP53 pathways; they were associated with Classical-like pretreatment samples and with GATA6 +ve /KRT17 +ve hybrid cell types following FOLFIRINOX, but not gemcitabine treatment, and were unrelated to transcriptional subtypes., Conclusions: Metavert as a single agent and in combination with irinotecan offers novel strategies for treating pancreatic cancer., Competing Interests: Declaration of competing interest ME and SP are involved in clinical development of Metavert with Avenzoar Pharmaceuticals. The remaining authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Objective: The objective of this quality assurance initiative was to internally measure children's perceptions of the book, "All Aboard the Rx-Express!" and knowledge gained from its content., Methods: This pharmacy-focused children's book was read to elementary-age youth at a rural, Pennsylvania elementary school in the Spring of 2022. A brief, optional, anonymous prepost survey was administered to the youth before and after the reading to measure the book's impact on third through fifth graders' perceptions and knowledge of the pharmacy profession. Descriptive statistics, chi squared analysis, independent samples t-tests, and one sample proportions tests were used to analyze survey responses., Results: One hundred ninety-one students participated in the presurvey to assess baseline knowledge about the pharmacy profession before the book was read. One hundred eighty-five students answered the postsurvey. Prepost respondent demographics were collected in aggregate and were not significantly different between the pre- and postcohorts. Survey results demonstrated an increase in all questions that asked about students' perceptions of pharmacists and the profession, and students reported favorable perceptions of the book itself., Conclusion: Early interventions such as this can increase elementary-age youth's perceptions and knowledge of the roles of pharmacists. Future work in early intervention will be needed to increase interest in the profession and admissions to pharmacy schools., Competing Interests: Disclosure The authors declare no relevant conflicts of interest or financial relationships., (Copyright © 2024. Published by Elsevier Inc.)

Injurie to the lateral clavicle and acromioclavicular joint (ACJ) are frequent events which are relevant to everyday life and particularly affect active adults at the age of 20-40 years. The Rockwood classification has been established for the classification of ACJ injuries. Lateral clavicle fractures are classified according to the Neer classification or the Jäger and Breitner classification. A newly established classification is the Cho classification. Depending on the injury pattern and in particular the presence of instability, various conservative and surgical care strategies are used. This article provides an overview of the various treatment concepts., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Primary cutaneous acral CD8+ T-cell lymphoproliferative disorder (TLPD) is a rare and indolent lymphoma entity. Although TLPD was first identified many years ago, the molecular pathogenesis is still not fully understood., Objectives: In order to better understand the molecular pathogenesis of cutaneous acral CD8+ TLPD and to identify further discriminatory markers to differentiate this lymphoma subtype from other CD8+ cutaneous lymphomas, we analysed five cases of cutaneous acral CD8+ TLPD for putative molecular alterations., Methods: Somatic alterations were assessed using whole-exome and targeted sequencing of paraffin-embedded tissue. Results were evaluated using immunohistochemical staining of respective relevant proteins. CD8+ cutaneous T-cell lymphomas (n = 12) served as control for KIR3DL1 staining., Results: Copy number variation analysis revealed a homozygous deletion of the KIR3DL1 gene in two of the analysed cases. This resulted in loss of KIR3DL1 protein expression, which was observed in all cases of cutaneous acral CD8+ TLPD. In contrast, KIR3DL1 expression was more variable in other CD8+ cutaneous T-cell lymphomas with 50% of analysed cases (n = 12) found to be positive. In addition, one further case of acral CD8+ TLPD harboured a loss-of-function mutation in the PIK3R1 gene, presumably activating the phosphoinositide 3-kinase-AKT pathway., Conclusions: Alterations of the KIR3DL1 gene may be of pathogenetic relevance for acral CD8+ TLPD. Loss of KIR3DL1 protein expression may support the diagnosis of this indolent lymphoma entity; however, this is not a subtype-specific discriminative feature., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Portal vein (PV) resection and reconstruction, which includes the resection and reconstruction of the PV and superior mesenteric vein, enable surgical removal of borderline resectable and locally advanced pancreatic cancer. Thrombosis of the reconstructed PV represents a major cause of early postoperative and long-term morbidity and mortality. No universally accepted standard for anticoagulation exists. This study aimed to assess early and late thrombosis rates after PV reconstruction with special regard to the type of PV reconstruction and anticoagulation regimen and to comprehensively assess thrombotic events and their clinical effect in patients receiving pancreatic surgery with venous resection and reconstruction., Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies reporting on PV resection and reconstruction providing data on thrombosis rates were included. The following parameters were assessed: study type, year of publication, number of patients, type/number of PV reconstruction, follow-up period, postoperative mortality, thrombosis rate of the reconstructed PV axis, intraoperative blood loss, and anticoagulation., Results: A total of 23 studies with 2751 patients were included in the final analysis. Of note, 670 patients received tangential resection of the PV with venorrhaphy or patch repair, 1505 patients had segmental resection with end-to-end reconstruction, and 576 patients received reconstruction with an interposition graft/conduit. The pooled overall thrombosis rate was 15%. Reconstruction of tangential defects with either venorrhaphy or patch repair and end-to-end repair of segmental defects resulted in a thrombosis rate of 12%. Subgroup analysis according to the type of graft reconstruction revealed the highest occlusion rates of 55% in patients with allogeneic grafts, followed by up to 27% in patients with synthetic PV conduits. Autologous conduits had a thrombosis rate of 10%. Early thrombotic events were detected in 5% of patients after venorrhaphy/patch reconstruction and end-to-end reconstruction. Early events were most common in the allogeneic graft subgroup (22%), followed by synthetic conduits (15%). There were fewer early events in the autologous graft group (7%). Early PV thrombosis was associated with relevant mortality of up to 26%. Anticoagulation regimens varied between studies., Conclusion: The overall thrombosis rate after PV resection is low. However, among the different reconstruction techniques, allogeneic interposition grafts/conduits had the highest thrombosis rates among the different types of reconstruction after PV resection. No specific anticoagulation strategy can be considered beneficial based on the existing literature., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Complex head and neck defects involving composite defects can be reconstructed using chimeric flaps or multiple flaps with separate anastomoses. Limited comparisons exist between chimeric and multiple flap reconstructions. We compare outcomes between chimeric and multiple flap reconstructions in oral cavity reconstruction., Data Sources: PubMed (NLM), Embase (Elsevier), Web of Science (Clarivate Analytics), and Cochrane CENTRAL (Wiley)., Methods: A systematic review was conducted, including English articles reporting outcomes of oral cavity reconstruction with either chimeric flaps or multiple flaps. Data extraction included patient characteristics, flap type, and outcomes such as flap survival, partial flap loss, operating room time, hospital length of stay, and postoperative complications., Results: Forty-seven articles comprising 1435 patients were included. Notably, 552 patients underwent multiple flaps, while 883 received chimeric flaps. Meta-analysis revealed no statistically significant difference in flap survival between chimeric and multiple flap patients (98% vs. 99%, p = 0.198). Multiple flap patients had higher rates of operating room take-backs for anastomotic issues and longer hospital stays compared with chimeric flap patients. There were no significant differences in partial flap failure, resumption of diet and speech, need for subsequent flaps, fistula formation, or general complications., Conclusion: This large-scale meta-analysis demonstrates equivalent flap survival between chimeric and multiple flaps in the reconstruction of composite oral cavity defects. Both approaches appear to be safe and acceptable, with comparable outcomes in terms of diet and speech resumption, rates of fistulization, and general postoperative complications. Multiple flap patients had higher rates of operating room take-backs and longer hospital stays., Level of Evidence: NA Laryngoscope, 134:4196-4202, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Our previous studies have shown the benefit of intravitreal injection of a mesenchymal stem cell (MSC)- derived secretome to treat visual deficits in a mild traumatic brain injury (mTBI) mouse model. In this study, we have addressed whether MSC-derived extracellular vesicles (EV) overexpressing miR424, which particularly targets neuroinflammation, show similar benefits in the mTBI model. Adult C57BL/6 mice were subjected to a 50-psi air pulse on the left side, overlying the forebrain, resulting in mTBI. Sham-blast mice were controls. Within an hour of blast injury, 3 μl (∼7.5 × 10 8 particles) of miR424-EVs, native-EVs, or saline was delivered intravitreally. One month later, retinal morphology was observed through optical coherence tomography (OCT); visual function was assessed using optokinetic nystagmus (OKN) and electroretinogram (ERG), followed by immunohistological analysis. A separate study in adult mice tested the dose-response of EVs for safety. Blast injury mice with saline showed decreased visual acuity compared with the sham group (0.30 ± 0.03 vs. 0.39 ± 0.01 c/d, p < 0.02), improved with miR424-EVs (0.39 ± 0.02 c/d, p < 0.01) but not native-EVs (0.33 ± 0.04 c/d, p > 0.05). Contrast sensitivity thresholds of blast mice receiving saline increased compared with the sham group (85.3 ± 5.9 vs. 19.9 ± 4.8, %, p < 0.001), rescued by miR424-EVs (23.6 ± 7.3 %, p < 0.001) and native-EVs (45.6 ± 10.7 %, p < 0.01). Blast injury decreased "b" wave amplitude compared to sham mice (94.6 ± 24.0 vs. 279.2 ± 25.3 μV, p < 0.001), improved with miR424-EVs (173.0 ± 27.2 μV, p < 0.03) and native-EVs (230.2 ± 37.2 μV, p < 0.01) with a similar decrease in a-wave amplitude in blast mice improved with both miR424-EVs and native-EVs. Immunohistology showed increased GFAP and IBA1 in blast mice with saline compared with sham (GFAP: 11.9 ± 1.49 vs. 9.1 ± 0.8, mean intensity/100,000 μm 2 area, p < 0.03; IBA1: 36.08 ± 4.3 vs. 24.0 ± 1.54, mean intensity/100,000 μm 2 area, p < 0.01), with no changes with native-EVs (GFAP: 12.6 ± 0.79, p > 0.05; IBA1: 32.8 ± 2.9, p > 0.05), and miR424-EV (GFAP: 13.14 ± 0.76, p > 0.05; IBA1: 31.4 ± 2.7, p > 0.05). Both native-EVs and miR424-EVs exhibited vitreous aggregation, as evidenced by particulates in the vitreous by OCT, and increased vascular structures, as evidenced by αSMA and CD31 immunostainings. The number of capillary lumens in the ganglion cell layer increased with increased particles in the eye, with native EVs showing the worst effects. In conclusion, our study highlights the promise of EV-based therapies for treating visual dysfunction caused by mTBI, with miR424-EVs showing particularly strong neuroprotective benefits. Both miR424-EVs and native-EVs provided similar protection, but issues with EV aggregation and astrogliosis or microglial/macrophage activation at the current dosage call for improved delivery methods and dosage adjustments. Future research should investigate the mechanisms behind EVs' effects and optimize miR424 delivery strategies to enhance therapeutic outcomes and reduce complications., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Cemented total knee arthroplasty (TKA) is the gold standard treatment for osteoarthritis, but uncemented TKA offers benefits like improved osseointegration and reduced complications from cement debris. This study aimed to investigate (1) if there has been a rise in uncemented TKA from 2017 to 2021 and (2) if there are differences in early complications between cemented and uncemented TKA., Methods: A retrospective data review was performed on the Michigan Arthroplasty Registry Collaborative Quality Initiative database of TKA patients from 2017 to 2021 at 6 hospitals. Patients with revision or partial knee arthroplasty were excluded. Patients were divided into 2 groups: uncemented and cemented. Hybrid and reverse hybrid fixation data were collected for incidence, but not for demographics or complications. All patient demographics and 90-day postoperative events were collected and analyzed., Results: A retrospective study of 18,749 primary TKAs found that 89.7% were cemented, 9.7% uncemented, and 0.7% hybrid or reverse hybrid. Uncemented patients were younger, men, heavier, current smokers, and diabetics than cemented patients ( P < .0001, P  = .03). They also had a shorter length of stay ( P ≤ .0001) and were on fewer preoperative medications: anticoagulants ( P  = .0059), antiplatelets ( P ≤ .0001), opioids ( P  = .0091), and steroids ( P  = .0039). The rate of uncemented TKA increased from 3.3% to 17.1%, while the rate of cemented TKA fell from 96.2% to 81.9% ( P  = .0048). The readmission rate was higher in cemented TKAs (4.0%) than in uncemented TKAs (2.6%) ( P  = .0048)., Conclusions: The use of uncemented TKA increased from 3.3% in 2017 to 17.1% in 2021, while cemented fixation decreased from 96.7% to 81.9%. There were no significant differences in short-term complications between groups. Uncemented patients were younger, men, took fewer medications, had a shorter length of stay, and were less likely to be readmitted. However, they were more likely to have comorbidities than the cemented group., (© 2024 The Authors.)

Reducing CO 2 emissions is one of the greatest challenges of the century. Among the means employed to tackle CO 2 emissions, the photocatalytic conversion of CO 2 is an appealing way to valorize CO 2 since it uses the sun energy, which is abundant. However, nowadays, the best photocatalytic systems still report too low efficiencies, and use expensive materials, so they cannot be readily industrialized for use at large scale. In this report, we first highlight general industrial and process challenges (including operating conditions). Then, focusing on MoS 2 /TiO 2 heterojunction systems, we analyze advantages and limitations of such systems and open perspectives on Mo oxysulfides supported on TiO 2 discussing their potential to reach higher efficiency for CO 2 photoconversion., (© 2024 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

Background: Cardiac risk evaluation prior to noncardiac surgery is fundamental to tailor peri-operative management to patient's estimated risk. Data on the degree of adherence to guidelines in patients at cardiovascular risk in Europe and factors influencing adherence are underexplored., Objectives: The aim of this analysis was to describe the degree of adherence to [2014 European Society of Cardiology (ESC)/European Society of Anaesthesiology (ESA) guidelines] recommendations on rest echocardiography [transthoracic echocardiography (TTE)] and to stress imaging prior to noncardiac surgery in a large European sample and to assess factors potentially affecting adherence., Design: Secondary analysis of a multicentre, international, prospective cohort study (MET-REPAIR)., Setting: Twenty-five European centres of all levels of care that enrolled patients between 2017 and 2020., Patients: With elevated cardiovascular risk undergoing in-hospital elective, noncardiac surgery., Main Outcome Measures: (Non)adherence to each pre-operative TTE and stress imaging recommendations classified as guideline-adherent, overuse and underuse. We performed descriptive analysis. To explore the impact of patients' sex, age, geographical region, and hospital teaching status, we conducted multivariate multinominal regression analysis., Results: Out of 15 983 patients, 15 529 were analysed (61% men, mean age 72 ± 8 years). Overuse (conduction in spite of class III) and underuse (nonconduction in spite of class I recommendation) for pre-operative TTE amounted to 16.6% (2542/15 344) and 6.6% (1015/15 344), respectively. Stress imaging overuse and underuse amounted to 1.7% (241/14 202) and 0.4% (52/14 202) respectively. Male sex, some age categories and some geographical regions were significantly associated with TTE overuse. Male sex and some regions were also associated with TTE underuse. Age and regions were associated with overuse of stress imaging. Male sex, age, and some regions were associated with stress imaging underuse., Conclusion: Adherence to pre-operative stress imaging recommendation was high. In contrast, adherence to TTE recommendations was moderate. Both patients' and geographical factors affected adherence to joint ESC/ESA guidelines., Trial Registration: NCT03016936., (Copyright © 2024 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Background: The American Heart Association (AHA) recently defined the cardiovascular-kidney-metabolic syndrome (CKM) as a new entity to address the complex interactions between heart, kidneys, and metabolism. The aim of this study was to assess the outcome impact of CKM syndrome in patients undergoing noncardiac surgery., Methods: This is a secondary analysis of a prospective international cohort study including patients aged ≥45 years with increased cardiovascular risk undergoing noncardiac surgery. Main exposure was CKM syndrome according to the AHA definition. The primary end point was a composite of major adverse cardiovascular events (MACE) 30 days after surgery. Secondary end points included all-cause mortality and non-MACE complications (Clavien-Dindo class ≥3)., Results: This analysis included 14,634 patients (60.8% male, mean age = 72±8 years). MACE occurred in 308 patients (2.1%), and 335 patients (2.3%) died. MACE incidence by CKM stage was as follows: CKM 0: 5/367 = 1.4% (95% confidence interval [CI], 0.4%-3.2%); CKM 1: 3/367 = 0.8% (95% CI, 0.2%-2.4%); CKM 2: 102/7440 = 1.4% (95% CI, 1.1%-1.7%); CKM 3: 27/953 = 2.8% (95% CI, 1.9%-4.1%); CKM 4a: 164/5357 = 3.1% (95% CI, 2.6%-3.6%); CKM 4b: 7/150 = 4.7% (95% CI, 1.9%-9.4%). In multivariate logistic regression, CKM stage ≥3 was independently associated with MACE, mortality, and non-MACE complications, respectively (MACE: OR 2.26 [95% CI, 1.78-2.87]; mortality: OR 1.42 [95% CI: 1.13 -1.78]; non-MACE complications: OR 1.11 [95% CI: 1.03-1.20])., Conclusion: The newly defined CKM syndrome is associated with increased morbidity and mortality after non-cardiac surgery. Thus, cardiovascular, renal, and metabolic disorders should be regarded in mutual context in this setting., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies 1 . Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events 1,2 . However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET-DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events., (© 2024. The Author(s).)

The use of ordnance gelatine has been widespread in the field of ballistics as a simulant for soft tissue when assessing ballistic threats. However, the traditional method of preparing ordnance gelatine is time-consuming and requires precision to ensure that the final mold meets the required specifications. Furthermore, temperature control is necessary post-production, and there are limitations on its usage duration. To address these issues, manufacturers have developed pre-mixed, gelatine-like products that are stable at room temperature and require less preparation time. Nonetheless, it is uncertain whether these new products can perform in the same manner as the gold standard of ordnance gelatine. This study used five types of blocks, including ordnance gelatine (10% and 20%), Clear Ballistics (10% and 20%) and Perma-Gel (10%) and subjected them to 9 mm, 0.380 Auto fired from a universal receiver and a 5.56 × 45 mm ammunition fired by a certified firearms instructor. Delta-V and total energy dissipation were measured after each test using data collected from ballistic chronographs placed in front of and behind each block. High-speed video was recorded, and a cut-down analysis conducted. The findings revealed variations in energy dissipation and fissure formation within the block, with greater energy based on fissure formation observed in the ordnance gelatine. Additionally, the high-speed video showed the occurrence of secondary combustions occurring in the premixed gelatines., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1β was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1β or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1β-mediated comorbidities, offering a framework for secondary prevention immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dye-encoded bead-based assays are widely used for diagnostics. Multiple bead populations are required for multiplexing and can be produced using different dye colors, labeling levels, or combinations of dye ratios. Ready-to-use multiplex bead populations restrict users to specific targets, are costly, or require specialized instrumentation. In-house methods produce few bead plexes or require many fine-tuning steps. To expand bead encoding strategies, we present a simple, safe, and cost-effective bench-top system for generating bead populations using photobleaching. By photobleaching commercially available dye-encoded magnetic beads for different durations, we produce three times as many differentiable bead populations on flow cytometry from a single dye color. Our photobleaching system uses a high-power LED module connected to a light concentrator and a heat sink. The beads are photobleached in solution homogeneously by constant mixing. We demonstrate this photobleaching method can be utilized for cross-testing antibodies, which is the first step in developing immunoassays. The assay uses multiple photobleached encoded beads conjugated with capture antibodies to test many binding pairs simultaneously. To further expand the number of antibodies that can be tested at once, several antibodies were conjugated to the same bead, forming a pooled assay. Our assay predicts the performance of antibody pairs used in ultrasensitive Simoa assays, narrowing the number of cross-tested pairs that need to be tested by at least two-thirds and, therefore, providing a rapid alternative for an initial antibody pair screening. The photobleaching system can be utilized for other applications, such as multiplexing, and for photobleaching other particles in solution.

Background: The use of smartphone apps in cancer patients undergoing systemic treatment can promote the early detection of symptoms and therapy side effects and may be supported by machine learning (ML) for timely adaptation of therapies and reduction of adverse events and unplanned admissions., Objective: We aimed to create an Early Warning System (EWS) to predict situations where supportive interventions become necessary to prevent unplanned visits. For this, dynamically collected standardized electronic patient reported outcome (ePRO) data were analyzed in context with the patient's individual journey. Information on well-being, vital parameters, medication, and free text were also considered for establishing a hybrid ML model. The goal was to integrate both the strengths of ML in sifting through large amounts of data and the long-standing experience of human experts. Given the limitations of highly imbalanced datasets (where only very few adverse events are present) and the limitations of humans in overseeing all possible cause of such events, we hypothesize that it should be possible to combine both in order to partially overcome these limitations., Methods: The prediction of unplanned visits was achieved by employing a white-box ML algorithm (i.e., rule learner), which learned rules from patient data (i.e., ePROs, vital parameters, free text) that were captured via a medical device smartphone app. Those rules indicated situations where patients experienced unplanned visits and, hence, were captured as alert triggers in the EWS. Each rule was evaluated based on a cost matrix, where false negatives (FNs) have higher costs than false positives (FPs, i.e., false alarms). Rules were then ranked according to the costs and priority was given to the least expensive ones. Finally, the rules with higher priority were reviewed by two oncological experts for plausibility check and for extending them with additional conditions. This hybrid approach comprised the application of a sensitive ML algorithm producing several potentially unreliable, but fully human-interpretable and -modifiable rules, which could then be adjusted by human experts., Results: From a cohort of 214 patients and more than 16'000 available data entries, the machine-learned rule set achieved a recall of 19% on the entire dataset and a precision of 5%. We compared this performance to a set of conditions that a human expert had defined to predict adverse events. This "human baseline" did not discover any of the adverse events recorded in our dataset, i.e., it came with a recall and precision of 0%. Despite more plentiful results were expected by our machine learning approach, the involved medical experts a) had understood and were able to make sense of the rules and b) felt capable to suggest modification to the rules, some of which could potentially increase their precision. Suggested modifications of rules included e.g., adding or tightening certain conditions to make them less sensitive or changing the rule consequences: sometimes further monitoring the situation, applying certain test (such as a CRP test) or applying some simple pain-relieving measures was deemed sufficient, making a costly consultation with the physician unnecessary. We can thus conclude that it is possible to apply machine learning as an inspirational tool that can help human experts to formulate rules for an EWS. While humans seem to lack the ability to define such rules without such support, they are capable of modifying the rules to increase their precision and generalizability., Conclusions: Learning rules from dynamic ePRO datasets may be used to assist human experts in establishing an early warning system for cancer patients in outpatient settings., Competing Interests: AT is co-founder, stock owner and Chief Medical Officer of mobile Health AG, a start-up company that has developed, maintains and operates the mediduxTM platform. CJ was employed by Sana Klinikum Offenbach GmbH. YK is employee at mobileHealth AG which runs the medidux app. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Trojan, Laurenzi, Jüngling, Roth, Kiessling, Atassi, Kadvany, Mannhart, Jackisch, Kullak-Ublick and Witschel.)

Purpose: To determine if an improvement in cord-level intraoperative neuromonitoring (IONM) data following data loss results in a reduced risk for new postoperative motor deficit in pediatric and adult spinal deformity surgery., Methods: A consecutive series of 1106 patients underwent spine surgery from 2015 to 2023 by a single surgeon. Cord alerts were defined by Somatosensory-Evoked Potentials (SSEP; warning criteria: 10% increase in latency or > 50% loss in amplitude) and Motor-Evoked Potentials (MEP; warning criteria: 75% loss in amplitude without return to acceptable limits after stimulation up 100 V above baseline level). Timing of IONM loss and recovery, interventions, and baseline/postoperative day 1 (POD1) lower extremity motor scores were analyzed., Results: IONM Cord loss was noted in 4.8% (53/11,06) of patients and 34% (18/53) with cord alerts had a POD1 deficit compared to preoperative motor exam. MEP and SSEP loss attributed to 98.1% (52/53) and 39.6% (21/53) of cord alerts, respectively. Abnormal descending neurogenic-evoked potential (DNEP) was seen in 85.7% (12/14) and detected 91.7% (11/12) with POD1 deficit. Abnormal wake-up test (WUT) was seen in 38.5% (5/13) and detected 100% (5/5) with POD1 deficit. Most cord alerts occurred during a three-column osteotomy (N = 23/53, 43%); decompression (N = 12), compression (N = 7), exposure (N = 4), and rod placement (N = 14). Interventions were performed in all 53 patients with cord loss and included removing rods/less correction (N = 11), increasing mean arterial pressure alone (N = 10), and further decompression with three-column osteotomy (N = 9). After intervention, IONM data improved in 45(84.9%) patients (Full improvement: N = 28; Partial improvement: 17). For those with full and partial IONM improvement, the POD1 deficit was 10.7% (3/28) and 41.2% (7/17), respectively. For those without any IONM improvement (15.1%, 8/53), 100% (8/8) had a POD1 deficit, P < 0.001., Conclusion: A full or partial improvement in IONM data loss after intraoperative intervention was significantly associated with a lower risk for POD1 deficit with an absolute risk reduction of 89.3% and 58.8%, respectively. All patients without IONM improvement had a POD1 neurologic deficit., (© 2024. The Author(s), under exclusive licence to Scoliosis Research Society.)

Objective: Our investigation on in-hospital mortality after 4474 pancreatoduodenectomies aimed to identify time-dependent risks as well as windows of opportunity to rescue patients from complications., Background: Pancreatoduodenectomy is generally considered a safe procedure with a 1-10% perioperative mortality based on complexity and surgical volume. Yet, patients are susceptible for life-threatening complications particularly with extended resections. Recognition of distinct vulnerabilities over time while patients recover is required to permit focused monitoring, sophisticated resource allocation, and greatest surgical safety., Methods: Patients who deceased in-hospital after pancreatoduodenectomy between 2003-2021 were retrieved from the institutional pancreatectomy registry and analyzed in detail with respect to their postoperative course., Results: Among 4474 pancreatoduodenectomies, 156 patients deceased in-hospital (3.5%). When assessing root causes of mortality, we observed 3 different clusters of complications which were postpancreatectomy-specific (47.4%), visceral vasculature-associated (25.6%), or cardiopulmonary in origin (23.7%). The median times of root cause onset in the 3 categories were postoperative day (POD) 9, POD 4.5 ( P =0.008) and POD 3 ( P <0.001), and medians of in-hospital mortality were POD 31, POD 18 ( P =0.009) and POD 8 ( P <0.001), respectively. Intervals between root cause onset and mortality varied with medians of 23 days, 11 days ( P =0.017), and 1 days ( P <0.001). The 3 categories were similarly distributed between different types of surgical complexity., Conclusion: Postpancreatectomy-specific complications prompt almost half of in-hospital mortalities after pancreatoduodenectomy, with rather long intervals for interventions to prevent failure to rescue. In contrast, visceral vasculature-related events and cardiopulmonary complications dominate early in-hospital mortalities with short intervals until mortality, demanding rigorous management of such events or preoperative conditioning. These data externally validate a previous high-volume initiative and highlight distinct windows of opportunity to optimize perioperative safety., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting. Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARα) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARα signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against NASH and subsequent liver cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

An autologous heterogeneous skin construct (AHSC) has been developed and used clinically as an alternative to traditional skin grafting techniques for treatment of cutaneous defects. AHSC is manufactured from a small piece of healthy skin in a manner that preserves endogenous regenerative cellular populations. To date however, specific cellular and non-cellular contributions of AHSC to the epidermal and dermal layers of closed wounds have not been well characterized given limited clinical opportunity for graft biopsy following wound closure. To address this limitation, a three-part mouse full-thickness excisional wound model was developed for histologic and macroscopic graft tracing. First, fluorescent mouse-derived AHSC (mHSC) was allografted onto non-fluorescent recipient mice to enable macroscopic and histologic time course evaluation of wound closure. Next, mHSC-derived from haired pigmented mice was allografted onto gender- and major histocompatibility complex (MHC)-mismatched athymic nude mouse recipients. Resulting grafts were distinguished from recipient murine skin via immunohistochemistry. Finally, human-derived AHSC (hHSC) was xenografted onto athymic nude mice to evaluate engraftment and hHSC contribution to wound closure. Experiments demonstrated that mHSC and hHSC facilitated wound closure through production of viable, proliferative cellular material and promoted full-thickness skin regeneration, including hair follicles and glands in dermal compartments. This combined macroscopic and histologic approach to tracing AHSC-treated wounds from engraftment to closure enabled robust profiling of regenerated architecture and further understanding of processes underlying AHSC mechanism of action. These models may be applied to a variety of wound care investigations, including those requiring longitudinal assessments of healing and targeted identification of donor and recipient tissue contributions., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The ability to cope with concussion symptoms and manage stress is an important determinant of risk for prolonged symptoms., Objective: This open-label mixed-methods pilot study assessed the acceptability and credibility of a mindfulness-based intervention delivered through a digital therapeutic (DTx; therapeutic smartphone app) for pediatric concussion., Methods: Participants aged 12 to 18 years were recruited from an emergency department within 48 hours of a concussion (acute cohort) or from a tertiary care clinic at least 1-month post-concussion (persisting symptoms cohort). Participants completed a novel 4-week mindfulness-based intervention, for 10 to 15 minutes/day, at a minimum of 4 days/week. At 2 weeks, participants completed a credibility and expectancy questionnaire. At 4 weeks, participants completed questionnaires assessing satisfaction, usability and working alliance, as well as a semi-structured phone interview., Results: Ten participants completed the study outcomes (7 acute; 3 persisting symptoms). The intervention was perceived as credible (median/max possible = 6.50/9.00 [6.83,8.75]) and DTx was usable (median/max possible = 70.00/100.00 [55.00,82.50]). Participants rated their satisfaction with the DTx (median/max possible = 27.00/32.00 [24.50,29.50]) and the working alliance with the digital mindfulness guides (median/max possible = 3.92/5.00 [3.38-4.33]) as high. Four themes were identified from the qualitative data: (a) positive attributes; (b) negative attributes; (c) ideas for modifications; and (d) technical issues., Conclusion: Results show modifications to the DTx, instructions and mindfulness intervention, and potential ways to increase adherence by leveraging positive attributes. A randomized control trial will assess the effectiveness of the DTx MBI to decrease the risk of persisting symptoms and reduce the symptom burden following pediatric concussion., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AAL reported being one of the authors of the Mindfulness-Based Intervention for Concussion protocol used in this study, she did not receive any financial benefit. AAL received funding from the Ontario Brain Institute NERD program for a separate component of the study. AAL has no other conflict of interest to disclose. BJS is the Chief Scientist and CEO of Mobio Interactive PTE LTD (Singapore), the parent company of Mobio Interactive Inc. (Toronto, Canada), and he owned approximately 22% of the company at the time of manuscript submission. BJS exclusively served as a technical liaison for the study and did not contribute to the specific study design, or select the outcome measures, nor did he directly contribute to, or have influence over, data collection or analysis. RZ is the cofounder, Scientific Director, and a minority shareholder in 360 Concussion Care, an interdisciplinary concussion clinic. RZ holds a Clinical Research Chair in Pediatric Concussion from University of Ottawa, and is on the concussion advisory board for Parachute Canada (a non-profit injury prevention charity). VS receives royalties for the publication of a book on concussion by Flammarion. The remaining authors have no conflicts of interest to report., (© The Author(s) 2024.)

Detecting low concentrations of biomarkers is essential in clinical laboratories. To improve analytical sensitivity, especially in identifying fluorescently labeled molecules, typical optical detection systems, consisting of a photodetector or camera, utilize time-resolved measurements. Taking a different approach, magnetic modulation biosensing (MMB) is a novel technology that combines fluorescently labeled probes and magnetic particles to create a sandwich assay with the target molecules. By concentrating the target molecules and then using time-resolved measurements, MMB provides the rapid and highly sensitive detection of various biomarkers. Here, we propose a novel signal-processing algorithm that enhances the detection and estimation of target molecules at low concentrations. By incorporating both temporally and spatially resolved measurements using human interleukin-8 as a target molecule, we show that the new algorithm provides a 2-4-fold improvement in the limit of detection and an ~25% gain in quantitative resolution.

Importance: Cardiopulmonary resuscitation (CPR) is an exceptional physical situation and may lead to significant psychological, spiritual, and social distress in patients and their next of kin. Furthermore, clinicians might experience distress related to a CPR event. Specialist palliative care (sPC) integration could address these aspects but is not part of routine care., Objectives: This study aimed to explore perspectives on sPC integration during and after CPR. A needs assessment for sPC, possible triggers indicating need, and implementation strategies were addressed., Design Setting and Participants: A multiprofessional qualitative semistructured focus group study was conducted in a German urban academic teaching hospital. Participants were clinicians (nursing staff, residents, and consultants) working in the emergency department and ICUs (internal medicine and surgical)., Analysis: The focus groups were recorded and subsequently transcribed. Data material was analyzed using the content-structuring content analysis according to Kuckartz., Results: Seven focus groups with 18 participants in total were conducted online from July to November 2022. Six main categories (two to five subcategories) were identified: understanding (of palliative care and death), general CPR conditions (e.g., team, debriefing, and strains), prognosis (e.g., preexisting situation, use of extracorporeal support), next of kin (e.g., communication, presence during CPR), treatment plan (patient will and decision-making), and implementation of sPC (e.g., timing, trigger factors)., Conclusions: Perceptions about the need for sPC to support during and after CPR depend on roles, areas of practice, and individual understanding of sPC. Although some participants perceive CPR itself as a trigger for sPC, others define, for example, pre-CPR-existing multimorbidity or complex family dynamics as possible triggers. Suggestions for implementation are multifaceted, especially communication by sPC is emphasized. Specific challenges of extracorporeal CPR need to be explored further. Overall, the focus groups show that the topic is considered relevant, and studies on outcomes are warranted., Competing Interests: Dr. Tenge has received a grant (Walter Benjamin Fellowship, TE 1567/1-1) from the German Research Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Trastuzumab has had a major impact on the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). Anti-HER2 biosimilars such as Ogivri have demonstrated safety and clinical equivalence to trastuzumab (using Herceptin as the reference product) in clinical trials. To our knowledge, there has been no real-world report of the side effects and quality of life (QoL) in patients treated with biosimilars using electronic patient-reported outcomes (ePROs)., Objective: The primary objective of this prospective observational study (OGIPRO study) was to compare the ePRO data related to treatment side effects collected with the medidux app in patients with HER2-positive BC treated with the trastuzumab biosimilar Ogivri (prospective cohort) to those obtained from historical cohorts treated with Herceptin alone or combined with pertuzumab and/or chemotherapy (ClinicalTrials.gov NCT02004496 and NCT03578731)., Methods: Patients were treated with Ogivri alone or combined with pertuzumab and/or chemotherapy and hormone therapy in (neo)adjuvant and palliative settings. Patients used the medidux app to dynamically record symptoms (according to the Common Terminology Criteria for Adverse Events [CTCAE]), well-being (according to the Eastern Cooperative Oncology Group Performance Status scale), QoL (using the EQ-5D-5L questionnaire), cognitive capabilities, and vital parameters over 6 weeks. The primary endpoint was the mean CTCAE score. Key secondary endpoints included the mean well-being score. Data of this prospective cohort were compared with those of the historical cohorts (n=38 patients; median age 51, range 31-78 years)., Results: Overall, 53 female patients with a median age of 54 years (range 31-87 years) were enrolled in the OGIPRO study. The mean CTCAE score was analyzed in 50 patients with available data on symptoms, while the mean well-being score was evaluated in 52 patients with available data. The most common symptoms reported in both cohorts included fatigue, taste disorder, nausea, diarrhea, dry mucosa, joint discomfort, tingling, sleep disorder, headache, and appetite loss. Most patients experienced minimal (grade 0) or mild (grade 1) toxicities in both cohorts. The mean CTCAE score was comparable between the prospective and historical cohorts (29.0 and 30.3, respectively; mean difference -1.27, 95% CI -7.24 to 4.70; P=.68). Similarly, no significant difference was found for the mean well-being score between the groups treated with the trastuzumab biosimilar Ogivri and Herceptin (74.3 and 69.8, respectively; mean difference 4.45, 95% CI -3.53 to 12.44; P=.28)., Conclusions: Treatment of patients with HER2-positive BC with the trastuzumab biosimilar Ogivri resulted in equivalent symptoms, adverse events, and well-being as found for patients treated with Herceptin as determined by ePRO data. Hence, integration of an ePRO system into research and clinical practice can provide reliable information when investigating the real-world tolerability and outcomes of similar therapeutic compounds., Trial Registration: ClinicalTrials.gov NCT05234021; https://clinicaltrials.gov/study/NCT05234021., (©Andreas Trojan, Sven Roth, Ziad Atassi, Michael Kiessling, Reinhard Zenhaeusern, Yannick Kadvany, Johannes Schumacher, Gerd A Kullak-Ublick, Matti Aapro, Alexandru Eniu. Originally published in JMIR Cancer (https://cancer.jmir.org), 04.04.2024.)