Search

Rational: Nickel is one of humans' most prevalent triggers of allergic contact dermatitis. However, the underlying mechanisms of this allergy still need to be fully understood. One aspect that has yet to be explored is the direct impact of common metal allergens on the skin's metabolites and lipids composition., Method: Our study employed matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to analyze spatially resolved metabolic alterations induced by nickel exposure. Cross-sections of ex vivo porcine ear skin exposed to increasing nickel (II) ion concentrations (17-167 μg/cm 2 ) were measured with an AP-SMALDI 5 AF ion source coupled to Q Exactive HF Orbitrap mass spectrometer. Additionally, the penetration of nickel ions into the skin was observed through its pink complexation with dimethylglyoxime under light microscopy., Results: For nickel ion concentrations up to 84 μg/cm 2 , most nickel ions were stopped within the stratum corneum, while only a very small proportion of nickel ions penetrated the viable epidermis and dermis. Stratum corneum locations with high nickel ion concentrations showed a decrease in arginine and ceramides. Furthermore, several phosphatidylcholine and sphingomyelin species were found to be downregulated in the viable epidermis and dermis due to the nickel exposure., Conclusion: Nickel penetrates at a trace level into the viable skin and induces severe metabolomic and lipidomic changes in the stratum corneum, epidermis, and dermis, indicating a change in the skin (barrier) function. These findings contribute to a deeper understanding of nickel-induced skin allergies and provide a solid foundation for further research., (© 2024 The Author(s). Rapid Communications in Mass Spectrometry published by John Wiley & Sons Ltd.)

Russell's diencephalic syndrome is a set of signs and symptoms characterized by extreme weight loss, with no impairment of height or head circumference, without changes in intake or appetite. It is due to hypothalamic dysfunction associated with space-occupying lesions in this region. It is a rare cause of malnutrition in pediatrics, so its diagnosis is often delayed. Here we describe the case of a 17-month-old male patient with weight loss for 3 months who was admitted to the pediatric inpatient ward due to suspected intestinal malabsorption syndrome. After ruling out the most common causes of malnutrition, the patient was diagnosed with pilomyxoid astrocytoma of the brainstem., (Sociedad Argentina de Pediatría.)

Appropriate composition of oral saliva is essential for a healthy milieu that protects mucosa and teeth. Only few studies, with small sample numbers, investigated physiological saliva ion composition in humans. We determined saliva ion composition in a sufficiently large cohort of healthy adults and analyzed the effect of physiological stimulation. We collected saliva from 102 adults under non-stimulated and physiologically stimulated conditions (chewing). Individual flow rates, pH, osmolality, Na + , K + , Cl - , and HCO 3 - concentrations under both conditions as well as the individual changes due to stimulation (Δvalues) were determined. Non-stimulated saliva was hypoosmolal and acidic. Na + , Cl - , and HCO 3 - concentrations remained well below physiological plasma values, whereas K + concentrations exceeded plasma values more than twofold. Stimulation resulted in a doubling of flow rates and substantial increases in pH, HCO 3 - , and Na + concentrations. Overall, stimulation did not considerably affect osmolality nor K + or Cl - concentrations of saliva. An in-depth analysis of stimulation effects, using individual Δvalues, showed no correlation of Δflow rate with Δion concentrations, indicating independent regulation of acinar volume and ductal ion transport. Stimulation-induced Δ[Na + ] correlated with Δ[HCO 3 - ] and Δ[Cl - ] but not with Δ[K + ], indicating common regulation of ductal Na + , Cl - , and HCO 3 - transport. We present a robust data set of human oral saliva ion composition in healthy adults and functional insights into physiological stimulation. Our data show (i) that flow-dependence exists for Na + and HCO 3 - but not for K + and Cl - concentrations, (ii) osmolality is flow-independent, (iii) regulation of Na + , Cl - , and HCO 3 - transport is coupled, (iv) regulation of flow rate and ion concentrations are independent and (v) spatially separated between acini and ducts, respectively., (© 2024. The Author(s).)

A series of low-coordinate cationic 3d metal(I) complexes of the general formula [IPr·M(η 6 -tol)] + is reported (M = Fe, Co, Ni; IPr = [(H)CN(Dip)C:]; Dip = 2,6- i Pr 2 -C 6 H 3 ), employing the weakly coordinating [BAr F 4 ] - counter-anion. The central metal in these complexes is stabilised solely by neutral carbene ( i.e. IPr) and arene ( i.e. toluene) ligands, making them rare examples of such cationic 3d metal(I) complexes, the electronic nature of which is explored by SQUID magnetometry. The utility of these species in [IPr·M I ] + transfer chemistry is demonstrated through the addition of a further equivalent of IPr, leading to formally two-coordinate cationic complexes, [(IPr 2 )·M I ] + .

Background: Point-of-care (POC) high-sensitivity cardiac troponin (hs-cTn) assays have been shown to provide similar analytical precision despite substantially shorter turnaround times compared with laboratory-based hs-cTn assays. We applied the previously developed machine learning based personalised Artificial Intelligence in Suspected Myocardial Infarction Study (ARTEMIS) algorithm, which can predict the individual probability of myocardial infarction, with a single POC hs-cTn measurement, and compared its diagnostic performance with standard-of-care pathways for rapid rule-out of myocardial infarction., Methods: We retrospectively analysed pooled data from consecutive patients of two prospective observational cohorts in geographically distinct regions (the Safe Emergency Department Discharge Rate cohort from the USA and the Suspected Acute Myocardial Infarction in Emergency cohort from Australia) who presented to the emergency department with suspected myocardial infarction. Patients with ST-segment elevation myocardial infarction were excluded. Safety and efficacy of direct rule-out of myocardial infarction by the ARTEMIS algorithm (at a pre-specified probability threshold of <0·5%) were compared with the European Society of Cardiology (ESC)-recommended and the American College of Cardiology (ACC)-recommended 0 h pathways using a single POC high-sensitivity cardiac troponin I (hs-cTnI) measurement (Siemens Atellica VTLi as investigational assay). The primary diagnostic outcome was an adjudicated index diagnosis of type 1 or type 2 myocardial infarction according to the Fourth Universal Definition of Myocardial Infarction. The safety outcome was a composite of incident myocardial infarction and cardiovascular death (follow-up events) at 30 days. Additional analyses were performed for type I myocardial infarction only (secondary diagnostic outcome), and for each cohort separately. Subgroup analyses were performed for age (<65 years vs ≥65 years), sex, symptom onset (≤3 h vs >3 h), estimated glomerular filtration rate (<60 mL/min per 1·73 m 2 vs ≥60 mL/min per 1·73 m 2 ), and absence or presence of arterial hypertension, diabetes, a history of coronary artery disease, myocardial infarction, or heart failure, smoking, and ischaemic electrocardiogram signs., Findings: Among 2560 patients (1075 [42%] women, median age 58 years [IQR 48·0-69·0]), prevalence of myocardial infarction was 6·5% (166/2560). The ARTEMIS-POC algorithm classified 899 patients (35·1%) as suitable for rapid rule-out with a negative predictive value of 99·96% (95% CI 99·64-99·96) and a sensitivity of 99·68% (97·21-99·70). For type I myocardial infarction only, negative predictive value and sensitivity were both 100%. Proportions of missed index myocardial infarction (0·05% [0·04-0·42]) and follow-up events at 30 days (0·07% [95% CI 0·06-0·59]) were low. While maintaining high safety, the ARTEMIS-POC algorithm identified more than twice as many patients as eligible for direct rule-out compared with guideline-recommended ESC 0 h (15·2%) and ACC 0 h (13·8%) pathways. Superior efficacy persisted across all clinically relevant subgroups., Interpretation: The patient-tailored, medical decision support ARTEMIS-POC algorithm applied with a single POC hs-cTnI measurement allows for very rapid, safe, and more efficient direct rule-out of myocardial infarction than guideline-recommended pathways. It has the potential to expedite the safe discharge of low-risk patients from the emergency department including early presenters with symptom onset less than 3 h at the time of admission and might open new opportunities for the triage of patients with suspected myocardial infarction even in ambulatory, preclinical, or geographically isolated care settings., Funding: The German Center for Cardiovascular Research (DZHK)., Competing Interests: Declaration of interests BT is supported by a grant from the German Foundation of Heart Research and Werner Otto Stiftung; is the co-recipient of a grant from the Ernst und Berta Grimmke-Stiftung (unrelated to this project); and has received travel grants from the German Center for Cardiovascular Research (DZHK). BT is the local representative of the partner sites Hamburg/Kiel/Luebeck in the Use and Access Committee of the DZHK Heart Bank. JHG reports fellowship funding from Advance Queensland and payment by the Emergency Medicine Foundation to her institution. WAP reports that his institution receives consulting fees from Siemens Healthineers. WAP reports acitivities at the Board (executive and horonary treasurer) of the Cardiac Society of Australia and New Zealand. LC reports non-salaried grant support and provision of assays through her institution from Abbott Diagnostics, Abbott Point-of-Care (POC), Radiometer Pacific, Roche Diagnostics, Siemens Healthineers, and Beckman Coulter. LC also reports consulting fees from Siemens Healthineers, Beckman Coulter, Quidel/Ortho, and payment or honoraria from Abbott Diagnostics, Roche Diagnostics, and Glycardial. Both WAP and LC report research funding and provision of assays by Siemens Healthineers. FSA reports doing advisory board or consultant activities for Mindray, Wefen, and Abbott Vascular, and non-salaried grant support through the Hennepin Healthcare Research Institute from Abbott Diagnostics, Abbott POC, Roche Diagnostics, Siemens Healthineers, Beckman Coulter, Quidel/Ortho, Becton Dickinson, and Sysmex, and fees for serving as Associate Editor for Clinical Chemistry. AZ is a Board member of the Basel Biometric Society. AZ and SB are listed as co-inventors of an international patent on the use of a computing device to estimate the probability of myocardial infarction (International Publication Number WO2022043229A1). AZ is scientific director and CEO of Cardio-CARE, SB is scientific advisor of Cardio-CARE, HS was a biostatistician at Cardio-CARE, and EDC is a biostatistician at Cardio-CARE, a 100% non-profit daughter company of the Kühne Foundation. Cardio-CARE is a shareholder of ART-EMIS Hamburg. SB receives consulting fees from Thermo Fisher, and payment or honoraria from Abbott Diagnostics, Amarin, AMGEN, AstraZeneca, Bayer, Bristol Meyers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, LumiraDx, Novartis, Roche Diagnostics, and Thermo Fisher. SB is a member of the advisory board of Thermo Fisher. SB and AZ were co-founders of ARTEMIS in 2022. Both sold their shares in 2023 and have no personal financial or legal relationship to ARTEMIS. KS declares no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Investigating the expression and prognostic significance of adenovirus receptors DSG-2, CXADR and CD46 in head and neck cancer., Methods: 104 patients with HNSCC (77 OPSCC, 27 LSCC) were retrospectively included in the study. Immunohistochemical staining was performed on all selected slides to detect the expression of DSG-2, CXADR, CD46 and the immunoreactive score (IRS) was determined from the number of positively stained tumor cells and their staining intensity. Furthermore, the respective HPV status was determined by immunohistochemical staining against p16 and HPV-PCR., Results: 81.7 % of the tumors showed DSG-2, 34.6 % of the tumors showed CXADR and 57.7 % of the tumors showed CD46 expression. A high DSG-2 IRS correlated significantly with an advanced tumor size (p= 0.003), increased grading (p=0.012) and positive HPV status (p=0.024) in OPSCC. A high CXADR IRS was significantly associated with a positive lymph node status (p= 0.041) in LSCC and an advanced AJCC stage (p= 0.012) and a positive HPV status (p= 0.009) in OPSCC. No significant correlation could be shown regarding CD46 expression and clinical tumor data. There was no effect of DSG-2, CXADR, and CD46 expression on 5-year overall and on 5-year disease-free survival., Conclusion: No prognostic significance of the expression of DSG-2, CXADR or CD46 in HNSCC was seen. DSG-2, CXADR and CD46 are expressed in HNSCC, so that optimization of oncotherapy with adenoviral vectors appears promising. Due to the significantly increased expression of DSG-2 and CXADR in advanced OPSCC tumors, there is potential for optimizing oncotherapy here in particular., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Percutaneous valve therapies (PVT) are performed on a large number of patients. With increasing procedural volume, the need for follow-up has also increased. Follow-up in the heart valve clinic is endorsed by recent guidelines but utilization is unknown, making resource allocation in the clinic difficult. Central follow-up in valve centers may not be feasible for all patients in the future., Methods: In our center, follow-up for PVT patients is scheduled at 1 month and 12 months after the index procedure. Patients are reminded of their appointment by invitation letters or phone calls. We analyzed 150 consecutive patients who underwent transcutaneous aortic valve implantation (TAVI) and MitraClip implantation (n = 300) at our center., Results: At 1 month, 72.7% of patients attended their follow-up, while at 12 months the rate dropped to 58%. Patients who underwent TAVI were older than the MitraClip patients (82.7 vs. 76.1 years) but had lower mean logEuroSCORE (22.6% vs. 25.9%). There was no significant difference in 1‑year mortality between TAVI and MitraClip patients (20% vs. 17.3%). By contrast, the rate of missed follow-up visits was higher for TAVI compared to MitraClip patients (52% vs. 33.3%; p = 0.002). Female patients less frequently attended follow-up (p = 0.005), whereas age, EuroSCORE, NYHA class, ejection fraction, and health status (EQ-5DVAS) were not predictors of attendance in multivariable analysis. Although the result of the EQ-5D assessment was not associated with mortality or attendance, completing the questionnaire was associated with overall survival (p < 0.001)., Conclusion: In our heart valve clinic, we observed a high percentage of missed follow-up appointments (42% at 12 months) despite a structured follow-up plan. Factors significantly associated with non-attendance in multivariable analysis were female gender and having a TAVI rather than MitraClip. Future follow-up concepts should take such findings into account, and decentralized approaches need to be explored., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

In rats decreased bioavailability of nitric oxide induces oxidative stress and right heart failure. Oxidative stress can activate matrix metalloproteinase-2 (MMP2). We addressed the question whether increasing oxidative defense by administration of the SOD mimetic Tempol or direct inhibition of MMP2 activity by SB-3CT mitigates right heart failure. Rats received l-NAME for four weeks and during week three and four treatment groups received either Tempol or SB-3CT in addition. After four weeks heart function was analyzed by echocardiography, organ weights and expression of NPPB and COL1A1 were analyzed, oxidative stress was monitored by DHE-staining and MMP2 activity was quantified by proteolytic auto-activation, zymography, and troponin I degradation. l-NAME induced oxidative stress and MMP2 activity stronger in the right ventricle than in the left ventricle. Troponin I, a MMP2 substrate, was degraded in right ventricles. Tempol reduced oxidative stress and preferentially affected the expression of fibrotic genes (i.e. COL1A1) and fibrosis. Tempol and SB-3CT mitigated right but not left ventricular hypertrophy. Neither SB-3CT nor Tempol alone strongly improved right ventricular function. In conclusion, both MMP2 activity and oxidative stress contribute to right ventricular failure but neither is MMP2 activation linked to oxidative stress nor does oxidative stress and MMP2 activity have common targets., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Tobacco smoking represents a major cause for preventable death and morbidity. Results from non-randomized studies suggest that smoking cessation therapy in a residential setting might be a new viable way to facilitate smoking abstinence. We aimed to test the effects of residential multicomponent group therapy for smoking cessation compared with outpatient group therapy., Design: Prospective parallel-group open-label randomized superiority trial, with assessments at baseline, 6 and 12 months., Setting: Recruitment throughout Germany via media advertisements., Participants: Adult smokers (≥10 cigarettes/day) randomly assigned to residential (n = 157) or outpatient (n = 158) therapy. 51.8% female; mean age 53.2 years; mean years of smoking 34.4., Intervention and Comparator: Residential 9-day smoking cessation group therapy comprising six daily therapy sessions and supportive interventions for cessation and daily structure embedded in the routines of a somatic rehabilitation center, compared with weekly outpatient smoking cessation group therapy (3-7 weeks) provided in routine care courses close to the participants' places of residence, both including at least 9 h of behavioral therapy., Measurements: Co-primary outcomes were self-reported continuous 6- and 12-month abstinence (hierarchically ordered). Primary analyses were conducted in the therapy-uptake population including participants who started therapy with sensitivity analyses in the intention-to-treat population of all randomized participants., Findings: Intervention uptake rates were 87.3% (n = 137) in the residential and 60.1% (n = 95) in the outpatient group. In the therapy-uptake population, abstinence rates were 46.7% in the residential versus 26.3% in the outpatient group at 6 months (odds ratio [OR] = 2.46, 95% confidence interval [CI] = 1.39-4.33, P = 0.0019) and 39.4% versus 24.2% at 12 months (OR = 2.04, 95% CI = 1.14-3.64, P = 0.017). Biochemically validated abstinence rates at 12 months were 33.1% in the residential versus 17.4% in the outpatient group (OR = 2.35, 95% CI = 1.22-4.51, P = 0.011). In the intention-to-treat population, self-reported and biochemically validated abstinence rates at 12 months were 34.4% in the residential versus 14.6% in the outpatient group (OR = 3.08, 95% CI = 1.77-5.34, P < 0.0001) and 28.6% versus 10.3% (OR = 3.48, 95% CI = 1.85-6.52, P = 0.0001), respectively., Conclusions: Residential therapy exclusively for smoking cessation is feasible and effective and could be a beneficial new treatment for smokers., (© 2024 The Author(s). Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background and Purpose: This study investigated the effects of deep abdominal breathing on cardiovascular parameters and symptoms in patients with postural orthostatic tachycardia syndrome (POTS) during head-up tilt-table (HUT) challenge., Methods: Thirty POTS patients completed two consecutive rounds of 10-min HUT in a crossover design. One round was HUT without intervention, and one round combined the HUT with deep breathing at a rate of 6 breaths/min. Cardiovascular parameters, including mean blood pressure and maximum and mean heart rate (HR), were measured supine and standing. Symptoms were assessed using the Vanderbilt Orthostatic Symptom Score (VOSS)., Results: During the breathing technique, the mean HR increase was -7.35 bpm (95% confidence interval [CI] = -11.71 to -2.98), and the maximum HR increase was -6.27 bpm (95% CI = -11.85 to -0.68, p = 0.041), significantly lower compared to normal breathing. Additionally, improvements were observed in all absolute cardiovascular parameters during standing, with VOSS symptoms simultaneously and significantly decreasing by -5.38 (95% CI = -10.43 to -0.36)., Conclusions: Slow deep abdominal breathing can act as a simple technique to reduce the standing HR increase upon HUT in patients with POTS. This suggests that modulation of the cardiopulmonary neurocircuits and the respiratory pump may reduce HR increase and symptoms in patients with POTS. The findings of this study highlight the use of a safe, zero-cost, and simple behavioral tool to suggest to POTS patients for symptom relief apart from standard treatment. The observed improvements in cardiovascular parameters and symptoms offer a promising therapeutic approach for patients in times of inadequate treatment options., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Circadian clocks are inherent to most organisms, including cryptozoic animals that seldom encounter direct light, and regulate their daily activity cycles. A conserved suite of clock genes underpins these rhythms. In this study, we explore the circadian behaviors of the red flour beetle Tribolium castaneum , a significant pest impacting stored grain globally. We report on how daily light and temperature cues synchronize distinct activity patterns in these beetles, characterized by reduced morning activity and increased evening activity, anticipating the respective environmental transitions. Although less robust, rhythmicity in locomotor activity is maintained in constant dark and constant light conditions. Notably, we observed more robust rhythmic behaviors in males than females with individual variation exceeding those previously reported for other insect species. RNA interference targeting the Clock gene weakened locomotor activity rhythms. Our findings demonstrate the existence of a circadian clock and of clock-controlled behaviors in T. castaneum . Furthermore, they highlight substantial individual differences in circadian activity, laying the groundwork for future research on the relevance of individual variation in circadian rhythms in an ecological and evolutionary context., Competing Interests: Conflict of Interest StatementThe authors have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Natural products (NPs) have long been used as a rich source of bioactive compounds for drug development. Recent technological advancements have revitalised natural products research as evidenced by increased publications in this field. In this editorial review, we highlight key points from the 2020 British Journal of Pharmacology (BJP) practical guide, which outlines standards for natural products research reports, and provide papers published in BJP between years 2020 to 2023 that demonstrate adherence to these guidelines. Looking ahead, we discuss the potential of chemical proteomics approaches to elucidate natural products mechanisms of action and identify therapeutic targets for future research. By fostering innovation, we aim to advance natural products research and contribute to the development of novel therapeutics that will have a significant impact on healthcare., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives: Chronic liver diseases (CLDs) have diverse etiologies. To better classify CLDs, we explored the ability of longitudinal multiparametric MRI (magnetic resonance imaging) in depicting alterations in liver morphology, inflammation, and hepatocyte and macrophage activity in murine high-fat diet (HFD)- and carbon tetrachloride (CCl 4 )-induced CLD models., Materials and Methods: Mice were either untreated, fed an HFD for 24 weeks, or injected with CCl 4 for 8 weeks. Longitudinal multiparametric MRI was performed every 4 weeks using a 7 T MRI scanner, including T1/T2 relaxometry, morphological T1/T2-weighted imaging, and fat-selective imaging. Diffusion-weighted imaging was applied to assess fibrotic remodeling and T1-weighted and T2*-weighted dynamic contrast-enhanced MRI and dynamic susceptibility contrast MRI using gadoxetic acid and ferucarbotran to target hepatocytes and the mononuclear phagocyte system, respectively. Imaging data were associated with histopathological and serological analyses. Principal component analysis and clustering were used to reveal underlying disease patterns., Results: The MRI parameters significantly correlated with histologically confirmed steatosis, fibrosis, and liver damage, with varying importance. No single MRI parameter exclusively correlated with 1 pathophysiological feature, underscoring the necessity for using parameter patterns. Clustering revealed early-stage, model-specific patterns. Although the HFD model exhibited pronounced liver fat content and fibrosis, the CCl 4 model indicated reduced liver fat content and impaired hepatocyte and macrophage function. In both models, MRI biomarkers of inflammation were elevated., Conclusions: Multiparametric MRI patterns can be assigned to pathophysiological processes and used for murine CLD classification and progression tracking. These MRI biomarker patterns can directly be explored clinically to improve early CLD detection and differentiation and to refine treatments., Competing Interests: Conflicts of interest: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Traumatic brain injury (TBI) increases the long-term risk of neurodegenerative diseases, including Alzheimer's disease (AD). Here, we demonstrate that protein variant pathology generated in brain tissue of an experimental TBI mouse model is similar to protein variant pathology observed during early stages of AD, and that subacute accumulation of AD associated variants of amyloid beta (Aβ) and tau in the TBI mouse model correlated with behavioral deficits. Male C57BL/6 mice were subjected to midline fluid percussion injury or to sham injury, after which sensorimotor function (rotarod, neurological severity score), cognitive deficit (novel object recognition), and affective deficits (elevated plus maze, forced swim task) were assessed post-injury (DPI). Protein pathology at 7, 14, and 28 DPI was measured in multiple brain regions using an immunostain panel of reagents selectively targeting different neurodegenerative disease-related variants of Aβ, tau, TDP-43, and alpha-synuclein. Overall, TBI resulted in sensorimotor deficits and accumulation of AD-related protein variant pathology near the impact site, both of which returned to sham levels by 14 DPI. Individual mice, however, showed persistent behavioral deficits and/or accumulation of toxic protein variants at 28 DPI. Behavioral outcomes of each mouse were correlated with levels of seven different protein variants in ten brain regions at specific DPI. Out of 21 significant correlations between protein variant levels and behavioral deficits, 18 were with variants of Aβ or tau. Correlations at 28 DPI were all between a single Aβ or tau variant, both of which are strongly associated with human AD cases. These data provide a direct mechanistic link between protein pathology resulting from TBI and the hallmarks of AD., (© 2024. The Author(s).)

Cell line development represents a crucial step in the development process of a therapeutic glycoprotein. Chinese hamster ovary (CHO) cells are the most frequently employed mammalian host cell system for the industrial manufacturing of biologics. The predominant application of CHO cells for heterologous recombinant protein expression lies in the relative simplicity of stably introducing ectopic DNA into the CHO host cell genome. Since CHO cells were first used as expression host for the industrial production of biologics in the late 1980s, stable genomic transgene integration has been achieved almost exclusively by random integration. Since then, random transgene integration had become the gold standard for generating stable CHO production cell lines due to a lack of viable alternatives. However, it was eventually demonstrated that this approach poses significant challenges on the cell line development process such as an increased risk of inducing cell line instability. In recent years, significant discoveries of new and highly potent (semi)-targeted transgene integration systems have paved the way for a technological revolution in the cell line development sector. These advanced methodologies comprise the application of transposase-, recombinase- or Cas9 nuclease-mediated site-specific genomic integration techniques, which enable a scarless transfer of the transgene expression cassette into transcriptionally active loci within the host cell genome. This review summarizes recent advancements in the field of transgene integration technologies for CHO cell line development and compare them to the established random integration approach. Moreover, advantages and limitations of (semi)-targeted integration techniques are discussed, and benefits and opportunities for the biopharmaceutical industry are outlined., Competing Interests: Declaration of competing interest All authors declare that they have no competing financial or personal interests influencing the work reported in this review paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In this study, we develop and validate a new Parkinson's disease (PD) mouse model that can be used to better understand how the disease progresses and to test the effects of new, potentially disease-modifying, PD therapies. Our central hypothesis is that mitochondrial dysfunction intercalates with misfolded α-synuclein (α-syn) accumulation in a vicious cycle, leading to the loss of nigral neurons. Our hypothesis builds on the concept that PD involves multiple molecular insults, including mitochondrial dysfunction and aberrant α-syn handling. We predicted that mitochondrial deficits, due to heterozygous loss of Engrailed-1 (En1+/-), combined with bilateral injections of pathogenic α-syn fibrils (PFFs), will act to generate a highly relevant PD model - the En1/SYN model. Here, En1+/- mice received bilateral intrastriatal stereotaxic injections of either PBS or α-syn fibrils and were analyzed using automated behavioral tests and deep learning-assisted histological analysis at 2, 4, and 6 months post-injection. We observed significant and progressive Lewy body-like inclusion pathology in the amygdala, motor cortex, and cingulate cortex, as well as the loss of tyrosine hydroxylase-positive (TH+) cells in the substantia nigra. The En1/SYN model also exhibited significant motor impairments at 6 months post-injection, which were however not exacerbated as we had expected. Still, this model has a comprehensive number of PD-like phenotypes and is therefore superior when compared to the α-syn PFF or En1+/- models alone., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Inc.)

Lead poisoning is an important global conservation problem for many species of wildlife, especially raptors. Despite the increasing number of individual studies and regional reviews of lead poisoning of raptors, it has been over a decade since this information has been compiled into a comprehensive global review. Here, we summarize the state of knowledge of lead poisoning of raptors, we review developments in manufacturing of non-lead ammunition, the use of which can reduce the most pervasive source of lead these birds encounter, and we compile data on voluntary and regulatory mitigation options and their associated sociological context. We support our literature review with case studies of mitigation actions, largely provided by the conservation practitioners who study or manage these efforts. Our review illustrates the growing awareness and understanding of lead exposure of raptors, and it shows that the science underpinning this understanding has expanded considerably in recent years. We also show that the political and social appetite for managing lead ammunition appears to vary substantially across administrative regions, countries, and continents. Improved understanding of the drivers of this variation could support more effective mitigation of lead exposure of wildlife. This review also shows that mitigation strategies are likely to be most effective when they are outcome driven, consider behavioural theory, local cultures, and environmental conditions, effectively monitor participation, compliance, and levels of raptor exposure, and support both environmental and human health., (© 2024 The Authors. Biological Reviews © 2024 Cambridge Philosophical Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

On global scale, eutrophication is one of the most prevalent environmental threats to water quality, primarily caused by elevated concentration of nutrients in wastewater. This study utilizes aluminum dross (AD), an industrial waste, to create a value-added material by improving its operational feasibility and application for removing phosphate and ammonium from water. The operational challenges of AD such as its powdered nature and effective operation under only extreme pH conditions were addressed by immobilizing in calcium alginate to form calcium alginate aluminium dross (Ca-Alg-Al dross) beads. These Ca-Alg-Al dross beads were further tested for phosphate and ammonium removal from natural wastewater in two different aqueous environment systems: (i) vertical flow constructed wetlands (VF-CWs) followed by Ca-Alg-Al dross beads fixed bed system and (ii) Ca-Alg-Al dross beads mounted floating constructed wetlands (FCW) for remediating polluted lentic ecosystems. Our results show maximum phosphate and ammonium removal of 85 ± 0.41 % and 93.44 %, respectively, in VF-CWs followed by Ca-Alg-Al dross beads fixed bed system. The Ca-Alg-Al dross beads mounted FCW system achieved maximum phosphate removal of 79.18 ± 8.56 % and ammonium removal of 65.45 ± 21.04 %. Furthermore, the treated water from the FCW system was assessed for its potential to inhibit algal growth by artificially inoculating treated water with natural algae to simulate eutrophic conditions. Interestingly, treated water from the FCW system was found capable of arresting the algal growth. Besides, scanning electron microscopy with energy dispersive X-ray (SEM-EDX) and Fourier transform infrared (FTIR) spectroscopy confirmed the functional groups and surface properties and probable participation of multiple mechanisms including ion exchange, electrostatic attraction, and ligand complexation for phosphate and ammonium removal. Overall, these results offer a promising way to utilize AD for high-end applications in wastewater treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work reports financial support was provided by Council of Scientific and Industrial Research Institute of Minerals and Materials Technology. AKY reports a relationship with Council of Scientific and Industrial Research Institute of Minerals and Materials Technology Department of Hydro & ElectroMetallurgy that includes: funding grants. AKY has patent pending to none. Asheesh Kumar Yadav reports financial support, administrative support, equipment, drugs, or supplies, statistical analysis, travel, and writing assistance were provided by Council of Scientific and Industrial Research Institute of Minerals and Materials Technology. Asheesh K Yadav reports financial support was provided by Council for Scientific and Industrial Research. Asheesh K Yadav reports financial support was provided by DST India. Yamini Mittal reports financial support was provided by Council for Scientific and Industrial Research. Asheesh K Yadav and Others has patent pending to CSIR. 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. 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., (Copyright © 2024. Published by Elsevier Ltd.)

Background: In previous studies, breast cancer patients with positive sentinel lymph node(s) (SLN) after neoadjuvant chemotherapy (NAC) frequently had additional nonSLN involvement. Per guidelines, residual SLN disease warrants completion axillary lymph node dissection (cALND), which has increased morbidity. Given recent improvements in NAC, we hypothesized that nonSLN positivity may be lower than previously reported for certain subgroups. Methods: We retrospectively reviewed breast cancer patients who received NAC and had positive lymph nodes on SLN biopsy or targeted axillary dissection and underwent cALND at one institution in 1/2018-8/2023. Associations between nonSLN positivity and clinicopathologic factors were assessed with Fisher's exact test and multivariable logistic regression. Results: There were 122 female patients. Median age was 48 years. Initially, 15 patients (12.3%) were cN0 and 107 patients (87.7%) were cN1. Largest SLN deposit was macrometastasis in 96 patients (78.7%), micrometastasis in 23 patients (18.9%), and isolated tumor cells in 3 patients (2.5%). Overall, 53 patients (43.4%) had nonSLN involvement. NonSLN positivity was higher in patients with cN1, ER+ HER2-, ypT2-3, SLN macrometastasis, and multiple positive SLN. On multivariable analysis, cN1 and ER+ HER2- remained associated with nonSLN positivity. Discussion: Among patients with positive SLN after NAC, clinically node positive and ER+ HER2- patients were more likely to have nonSLN involvement. Our findings support guidelines to consider omitting cALND in clinically node negative patients. With improving NAC, optimal axillary sampling, and radiation, omitting cALND may be safe in some clinically node positive triple negative or HER2+ patients with low volume residual disease, but further research is needed., 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.

Aims: Clinical guidelines support the use of fixed-dose combinations (FDC) for prevention of cardiovascular disease. Implementation of FDC into clinical care remains challenging, and current population-based data are scarce., Methods and Results: Claims data on dispensed drugs in an outpatient care setting of approximately 87% of the German population were analysed regarding the use of FDC according to time, age of the insured persons, and active ingredients. The overarching trend for all FDC revealed a decrease from 77.3 defined daily doses per 1000 statutory health-insured (SHI) persons per day (DID) in the second half-year of 2018 (2018HY02) to 60.8 DID in the first half-year of 2023 (2023HY01) (Spearman ρ = -0.988; P  < 0.001). The total DID for all antihypertensives (AHT) increased from 590.6 in 2018HY02 to 624.8 in 2023HY01 (ρ = 0.855; P  = 0.002), but the DID for fixed-dose AHT (AHT-FDC) declined from 74.1 in 2018HY02 to 55.0 in 2023HY01 (ρ = -0.988; P  < 0.001). Conversely, the use of all lipid-lowering agents (LLA) and LLA-FDC continuously increased: The total DID of all LLA rose from 92.5 in 2018HY02 to 134.4 in 2023HY01 (ρ = 1.000; P  = 0.000), and for LLA-FDC from 3.1 in 2018HY02 to 5.5 DID in 2023HY01 (ρ = 0.915; P  < 0.001). AHT-FDC and LLA-FDC were less frequently dispensed to patients at least 80 years than to patients less than 80 years. Dispensing of multiple purpose FDC increased from 2018HY02 to 2023HY01 from 0.11 DID to 0.26 DID (ρ = 1.000; P  = 0.000) but remained negligible., Conclusion: Use of AHT-FDC in Germany is declining. In contrast, FDC containing LLA are increasingly prescribed. Dispensing of multiple purpose FDC is very low. Strategies are needed to facilitate the use of FDC as recommended by current guidelines., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The most widely used herbicide glyphosate contaminates surface waters around the globe. Both agriculture and urban applications are discussed as sources for glyphosate. To better delineate these sources, we investigated long-term time series of concentrations of glyphosate and its main transformation product aminomethylphosphonic acid (AMPA) in a large meta-analysis of about 100 sites in the USA and Europe. The U.S. data reveal pulses of glyphosate and AMPA when the discharge of the river is high, likely indicating mobilization by rain after herbicide application. In contrast, European concentration patterns of glyphosate and AMPA show a typical cyclic-seasonal component in their concentration patterns, correlating with patterns of wastewater markers such as pharmaceuticals, which is consistent with the frequent detection of these compounds in wastewater treatment plants. Our large meta-analysis clearly shows that for more than a decade, municipal wastewater was a very important source of glyphosate. In addition, European river water data show rather high and constant base mass fluxes of glyphosate all over the year, not expected from herbicide application. From our meta-analysis, we define criteria for a source of glyphosate, which was hidden so far. AMPA is known to be a transformation product not only of glyphosate but also of aminopolyphosphonates used as antiscalants in many applications. As they are used in laundry detergents in Europe but not in the USA, we hypothesize that glyphosate may also be a transformation product of aminopolyphosphonates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: This individual participant data meta-analysis (IPD-MA) assesses exercise effects on self-reported cognitive functioning (CF) and investigates whether effects differ by patient-, intervention-, and exercise-related characteristics., Methods: IPD from 16 exercise RCTs, including 1987 patients across multiple types of non-metastatic cancer, was pooled. A one-stage IPD-MA using linear mixed-effect models was performed to assess exercise effects on self-reported CF (z-score) and to identify whether the effect was moderated by sociodemographic, clinical, intervention- and exercise-related characteristics, or fatigue, depression, anxiety, and self-reported CF levels at start of the intervention (i.e., baseline). Models were adjusted for baseline CF and included a random intercept at study level to account for clustering of patients within studies. A sensitivity analysis was performed in patients who reported cognitive problems at baseline., Results: Minimal significant beneficial exercise effects on self-reported CF (β=-0.09 [-0.16; -0.02]) were observed, with slightly larger effects when the intervention was delivered post-treatment (n=745, β=-0.13 [-0.24; -0.02]), and no significant effect during cancer treatment (n=1,162, β=-0.08 [-0.18; 0.02]). Larger effects were observed in interventions of 12 weeks or shorter (β=-0.14 [-0.25; -0.04]) or 24 weeks or longer (β=-0.18 [-0.32; -0.02]), whereas no effects were observed in interventions of 12-24 weeks (β=0.01 [-0.13; 0.15]). Exercise interventions were most beneficial when provided to patients without anxiety symptoms (β=-0.10 [-0.19; -0.02]) or after completion of treatment in patients with cognitive problems (β=-0.19 [-0.31; -0.06]). No other significant moderators were identified., Conclusions: This cross-cancer IPD meta-analysis observed small beneficial exercise effects on self-reported CF when the intervention was delivered post-treatment, especially in patients who reported cognitive problems at baseline., Implications for Cancer Survivors: This study provides some evidence to support the prescription of exercise to improve cognitive functioning. Sufficiently powered trials are warranted to make more definitive recommendations and include these in the exercise guidelines for cancer survivors., (© 2023. The Author(s).)

Dementia spousal caregivers are at risk for adverse mental and physical health outcomes. Caregiver burden, anticipatory grief, and proinflammatory cytokine production may contribute to depressive symptoms among caregivers. People who report childhood trauma are more likely to have exaggerated stress responses that may also contribute to depressive symptoms in adulthood. This study aimed to test whether the relationship between whole-blood cytokine production and depressive symptoms is strongest in caregivers who report high levels of childhood trauma., Methods: A sample of 103 dementia spousal caregivers provided self-report data on demographics, health information, caregiver burden, anticipatory grief, and depressive symptoms. We also determined lipopolysaccharide-induced whole-blood cytokine production as the primary measure of immune cell reactivity. We measured interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) and converted z-scores of each cytokine into a composite panel. We regressed depressive symptoms on proinflammatory cytokine production, caregiver burden, and anticipatory grief, adjusting for demographic and health-related covariates., Results: Whole-blood cytokine production and childhood trauma were associated with depressive symptoms. Childhood trauma moderated the relationship between whole-blood cytokine production and depressive symptoms. Whole-blood cytokine production was only associated with depressive symptoms at mean and high levels of childhood trauma, but not at low levels of childhood trauma. The main effects of burden and anticipatory grief on depressive symptoms were strongest for caregivers reporting high levels of childhood trauma., Discussion: Childhood trauma has lasting impacts on psychosocial experiences later in life and has effects that may confer susceptibility to inflammation-related depression. Our findings contribute to ongoing efforts to identify risk factors for adverse mental health in dementia spousal caregivers., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose. This research was conducted within a larger study funded through the National Institutes on Aging [R01AG062690]., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aging is associated with progressive brain atrophy and declines in learning and memory, often attributed to hippocampal or cortical deterioration. The role of brain-derived neurotrophic factor (BDNF) in modulating the structural and functional changes in the brain and visual system, particularly in relation to BDNF Val66Met polymorphism, remains underexplored. In this present cross-sectional observational study, we aimed to assess the effects of BDNF polymorphism on brain structural integrity, cognitive function, and visual pathway alterations. A total of 108 older individuals with no evidence of dementia and a mean (SD) age of 67.3 (9.1) years were recruited from the Optic Nerve Decline and Cognitive Change (ONDCC) study cohort. The BDNF Met allele carriage had a significant association with lower entorhinal cortex volume (6.7% lower compared to the Val/Val genotype, P = 0.02) and posterior cingulate volume (3.2% lower than the Val/Val group, P = 0.03), after adjusting for confounding factors including age, sex and estimated total intracranial volumes (eTIV). No significant associations were identified between the BDNF Val66Met genotype and other brain volumetric or diffusion measures, cognitive performances, or vision parameters except for temporal retinal nerve fibre layer thickness. Small but significant correlations were found between visual structural and functional, cognitive, and brain morphological metrics. Our findings suggest that carriage of BDNF Val66Met polymorphism is associated with lower entorhinal cortex and posterior cingulate volumes and may be involved in modulating the cortical morphology along the aging process.

Background and Objectives: Hearing loss frequently goes undiagnosed and untreated, with serious sequelae. Hearing screening facilitates diagnosis and treatment but is not routinely conducted in primary care. This study addresses the attitudes and insights of patients and primary care clinic personnel relative to the routinization of hearing screening in primary care for older adults., Research Design and Methods: Data presented are from the qualitative portion of a larger study. The main study compared screening completion for 3 approaches to coordinating telephone-based hearing screening with primary care-1 offering hearing screening within the primary care encounter and 2 providing information for at-home screening ( 1 with and 1 without provider encouragement). Focus groups/interviews were conducted with personnel (n = 38) at the 6 participating clinics, patients who completed screening and were referred for diagnosis (n = 14), and patients who did not complete screening (n = 10). Analysis used the general inductive approach., Results: Most patients had unaddressed hearing concerns prior to the study. Negative attitudes toward hearing loss/treatment were common, and experiences of family and friends influenced attitudes, but lack of urgency was the primary barrier to screening completion. Respondents favored routine primary care-based hearing screening for older adults, but clinic personnel noted challenges of time, space, workflow, and reimbursement., Discussion and Implications: Findings favor greater routinization of hearing screening in primary care. Routinization will be enhanced by improved reimbursement for screening and follow-up; specialist engagement with primary care and the public (including leveraging older adults' social networks); and further research on specific integration options., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. 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: Bacterial etiologies of acute otitis media (AOM) have shifted from the introduction of pneumococcal conjugate vaccines (PCVs), antibiotic selection and competition among species. We characterized Streptococcus pneumoniae ( Spn ), Haemophilus influenzae ( Hflu ) and Moraxella catarrhalis ( Mcat ) in the nasopharynx during well-child healthy visits and at the onset of AOM, and in middle ear fluid (MEF) of children with AOM to assess anticipated effects of higher-valency PCVs (PCV15 and PCV20)., Methods: From September 2021 to September 2023, we conducted a prospective longitudinal cohort study of PCV13 immunized children 6-36 months old. MEF was collected via tympanocentesis. Serotyping and antibiotic susceptibility testing were performed on Spn , Hflu and Mcat isolates., Results: We obtained 825 nasopharyngeal and 216 MEF samples from 301 children. The order of frequency of nasopharyngeal colonization was Mcat , Spn and Hflu ; Hflu was the predominant otopathogen in MEF. Among Spn isolates, non-PCV15, non-PCV20 serotypes predominated in the nasopharynx and in MEF; the most frequent serotype was 35B. Among MEF samples, 30% of Spn isolates were amoxicillin nonsusceptible; 23% of Hflu isolates and 100% of Mcat isolates were β-lactamase-producing., Conclusion: The majority of Spn isolates among young children were non-PCV15, non-PCV20 serotypes, especially serotype 35B; therefore, the impact of higher-valency PCVs in reducing pneumococcal colonization or AOM is expected to be limited. Hflu continues to be the most frequent AOM pathogen. Antibiotic susceptibility data suggest a high dose of amoxicillin/clavulanate or alternative drugs that are effective against contemporary mix of otopathogens could be considered for optimal empiric selection to provide the best efficacy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Helicobacter pylori (H. pylori) is a bacterial pathogen that exclusively colonizes the human gastric mucosa and can cause persistent infection. In this process, H. pylori employs various strategies to avoid recognition by the human immune system. These range from passive defense strategies (e.g., altered LPS or flagellin structures) that prevent recognition by pattern recognition receptors (PRRs) to more active approaches, such as inhibition of IL-2 secretion and proliferation of T cells via VacA. Despite the growing evidence that H. pylori actively manipulates the human immune system for its own benefit, the direct interaction of H. pylori with immune cells in situ is poorly studied. Here, we present a novel intravital imaging model of the murine stomach gastric mucosa and show for the first time the in situ recruitment of neutrophils during infection and a direct H. pylori-macrophage interaction. For this purpose, we applied multiphoton intravital microscopy adapted with live drift correction software (VivoFollow) on LysM-eGFP and CX3CR1-eGFP reporter mice strains in which specific subsets of leukocytes are fluorescently labeled. Multiphoton microscopy is proving to be an excellent tool for characterizing interactions between immune cells and pathogens in vivo., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ishikawa-Ankerhold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Although research on nitrosyl (NO) heme complexes and their one-electron reduced form, nitroxyl (or nitroxyl anion, NO - ) derivatives, has been going on for decades, there are still disagreements about the electrical configuration of nitroxyl complexes, and the majority of the work on this topic is based on theoretical calculations. Following the initial nitroxyl iron porphyrin crystal structure, we present two further polymorphic forms of [CoCp 2 ][Fe(TFPPBr 8 )(NO)]. Using the same completely halogenated porphyrin ligand, we also present two polymorphic forms of nitrosyl cobalt(II) complexes, which are another sort of {MNO} 8 structure. In addition to the EXANES and EPR studies of these {FeNO} 7 and {CoNO} 8 complexes, the {FeNO} 8 [CoCp 2 ][Fe(TFPPBr 8 )(NO)] complex is also investigated by temperature-dependent Mössbauer experiments for the first time with the {FeNO} 7 precursor as a control sample. The analysis of the Mössbauer and crystal structural parameters between these two types of {MNO} 8 (M = Fe or Co) species and previously reported analogous ones allow us to conclude that the electronic configuration of [Fe(TFPPBr 8 )(NO)] - is best described as an intermediate between low-spin Fe(II)-NO - and Fe(I)-NO • .

Exposure to polychlorinated biphenyls (PCBs) remains a potential human health risk due to their persistence in the environment, despite a global ban on their production. Understanding the composition of PCB mixtures is essential for the application of a mixtures-based approach to assessing health risks of PCB exposure. This work represents the most extensive effort to date to compile and make publicly available the PCB congener profiles for mixtures with toxicological data, providing a foundation for understanding toxicological potency of PCB mixtures in the environment. We identified published congener profiles across 29 commercial and simulated environmental PCB mixtures, including various Aroclors, Phenoclors, Clophens, and Kanechlors, among others. A total of 117 references containing 401 distinct complete or partial tabularized profiles were found. Aroclor 1254 had the most published profiles, with 79 unique datasets characterizing multiple mixture lots. In contrast, no congener-specific composition data were identified for Fenclors, Clophen C, or Pyralenes. Eighty-seven of the most complete and clearly reported profiles underwent a detailed extraction of the congener data, PCB mixture source, and analytical methods. Challenges encountered during data extraction included congener coelutions, incomplete methods reporting, and inconsistencies in PCB nomenclature. These factors complicate data visualization, comparisons across datasets, and use of the data in subsequent analyses. Where possible, we have converted profiles to the same units and congener numbering convention to allow for easier comparison. The extracted data are publicly available online as interactive visuals and as a downloadable Microsoft Excel® workbook. This dataset provides researchers with an overview of the current PCB mixture profile landscape that can serve as a tool to support efforts to minimize the health impacts of environmental PCB exposure, including the exploration of links between mixture composition and toxicity and the identification of the most efficient and effective remediation strategies at contaminated sites., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Inc.)

Background and Aims: Despite the success of biological therapies in treating inflammatory bowel disease (IBD), managing patients remains challenging due to the absence of reliable predictors of therapy response., Methods: In this study, we prospectively sampled two cohorts of IBD patients receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry, single-cell RNA sequencing, single-cell V(D)J sequencing, serum proteomics, and multidimensional flow cytometry to comprehensively assess vedolizumab-induced immunological changes in the peripheral blood and their potential associations with treatment response., Results: Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T cell receptor diversity of gut-homing CD4 + memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4 + memory T cells among non-responders prior to treatment compared with responders. This predictive T cell signature demonstrated an activated Th1/Th17 phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab., Conclusion: These findings provide a reliable predictive classifier with significant implications for personalized IBD management., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Neutrophils, the most abundant white blood cells in the human circulation, play crucial roles in various diseases, including kidney disease. Traditionally viewed as short-lived pro-inflammatory phagocytes that release reactive oxygen species, cytokines and neutrophil extracellular traps, recent studies have revealed their complexity and heterogeneity, thereby challenging this perception. Neutrophils are now recognized as transcriptionally active cells capable of proliferation and reverse migration, displaying phenotypic and functional heterogeneity. They respond to a wide range of signals and deploy various cargo to influence the activity of other cells in the circulation and in tissues. They can regulate the behavior of multiple immune cell types, exhibit innate immune memory, and contribute to both acute and chronic inflammatory responses while also promoting inflammation resolution in a context-dependent manner. Here, we explore the origin and heterogeneity of neutrophils, their functional diversity, and the cues that regulate their effector functions. We also examine their emerging role in infectious and non-infectious diseases with a particular emphasis on kidney disease. Understanding the complex behavior of neutrophils during tissue injury and inflammation may provide novel insights, thereby paving the way for potential therapeutic strategies to manage acute and chronic conditions. By deciphering their multifaceted role, targeted interventions can be developed to address the intricacies of neutrophil-mediated immune responses and improve disease outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Science is becoming increasingly interdisciplinary; the widespread emergence of dedicated interdisciplinary journals, conferences, and graduate programs reflects this trend. Interdisciplinary scientific events are extremely valuable in that they offer opportunities for career advancement, especially among early career researchers, for collaboration beyond traditional disciplinary echo chambers, and for the creative generation of innovative solutions to longstanding scientific problems. However, organizing such events can pose unique challenges due to the intentionality required to meaningfully break down the barriers that separate long-independent disciplines. In this paper, we propose five key strategies for organizing and hosting interdisciplinary scientific events. The recommendations offered here apply both to small symposia aiming to contribute an interdisciplinary component to a larger event and to broad interdisciplinary conferences hosting hundreds or thousands of attendees., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.)

Background: Even 90 years after the National Socialist seizure of power and the beginning of the darkest chapter of German psychiatric history, examination of the medical historical past retains great relevance as an ongoing medical responsibility. The interventions in the lives of mentally ill people by the National Socialist regime are a firmly established part of medical historical research; however, little is known about how specific regions proceeded with affected citizens., Objective: The aim of this study was therefore to identify transfer routes of the "euthanasia" transports and places of death of the victims from Bochum as well as their patient characteristics., Materials and Methods: During the timeframe studied, inpatient care for mentally ill patients from the Westphalia region was provided in seven provincial institutions. There was no psychiatric clinic in Bochum at the time, so patients were distributed among these institutions. The investigation was based on the transfer lists of the Westphalian provincial institutions to the killing sites., Results and Conclusion: A total of 366 Bochum citizens affected by "euthanasia" transfers were identified. The transport lists were verified by admission and departure books, death lists, and patient files. The hereditary health files of the city archive were used to examine the relocated Bochum patients to determine whether they were victims of forced sterilization., (© 2024. The Author(s).)

Background: Clinical narratives are essential components of electronic health records. The adoption of electronic health records has increased documentation time for hospital staff, leading to the use of abbreviations and acronyms more frequently. This brevity can potentially hinder comprehension for both professionals and patients., Objective: This review aims to provide an overview of the types of short forms found in clinical narratives, as well as the natural language processing (NLP) techniques used for their identification, expansion, and disambiguation., Methods: In the databases Web of Science, Embase, MEDLINE, EBMR (Evidence-Based Medicine Reviews), and ACL Anthology, publications that met the inclusion criteria were searched according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for a systematic scoping review. Original, peer-reviewed publications focusing on short-form processing in human clinical narratives were included, covering the period from January 2018 to February 2023. Short-form types were extracted, and multidimensional research methodologies were assigned to each target objective (identification, expansion, and disambiguation). NLP study recommendations and study characteristics were systematically assigned occurrence rates for evaluation., Results: Out of a total of 6639 records, only 19 articles were included in the final analysis. Rule-based approaches were predominantly used for identifying short forms, while string similarity and vector representations were applied for expansion. Embeddings and deep learning approaches were used for disambiguation., Conclusions: The scope and types of what constitutes a clinical short form were often not explicitly defined by the authors. This lack of definition poses challenges for reproducibility and for determining whether specific methodologies are suitable for different types of short forms. Analysis of a subset of NLP recommendations for assessing quality and reproducibility revealed only partial adherence to these recommendations. Single-character abbreviations were underrepresented in studies on clinical narrative processing, as were investigations in languages other than English. Future research should focus on these 2 areas, and each paper should include descriptions of the types of content analyzed., (©Amila Kugic, Ingrid Martin, Luise Modersohn, Peter Pallaoro, Markus Kreuzthaler, Stefan Schulz, Martin Boeker. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 26.09.2024.)

Biradicals are important intermediates in the formation and breaking of a chemical bond. Their use as molecular switches is of particular interest. Much less is known about tetraradicals, which can, for example, consist of two biradical(oid) units. Here we report the synthesis of the first persistent phosphorus-centred tetraradical bound to a transition metal fragment. Starting from a zirconocene complex, rac-(ebthi)ZrCl 2 (rac-(ebthi)=1,2-ethylene-1,10-bis(η 5 -tetrahydroindenyl), two cyclo-1,3-diphospha-pentane-1,3-diyls were successfully introduced, which finally led to the isolation of a deep green zirconcene-bridged bis(biradicaloid) complex (5) that can act as a double molecular switch. Under the influence of light (570 nm), this tetraradical forms a transannular bond in each of the two five-membered biradical units, leading to the formation of housane 5 h. Upon irradiation at 415 nm, the reverse reaction is observed, fully recovering tetraradical 5. Through single-crystal-to-single-crystal transformation, both stable species of the molecular switch could be structurally characterised using SCXRD. The switching under the influence of light and the activation of molecular hydrogen were analysed in solution using NMR and UV spectroscopy. It was found that the addition of one or two equivalents of molecular hydrogen can be switched on and off by light., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture., Competing Interests: Declaration of interests W.K.C. is on the Board of Directors of Prime Medicine. The authors declare no additional competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Migraine and Parkinson disease (PD) are common neurologic disorders, which are hypothesized to share some pathophysiologic mechanisms. However, data on the association between migraine and risk of developing PD are sparse. We estimate the effect of migraine, migraine subtypes, and migraine episode frequency on the risk of developing PD in middle-aged and older women., Methods: We used data from the Women's Health Study, a United States-based cohort of women in health professions aged 45 years and older at baseline (1992-1995). Only women with complete self-reported information on migraine and headache and no history of PD were included. Participants were followed up for self-reported physician-diagnosed PD through December 31, 2021. We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and corresponding 95% CIs of the association between migraine, migraine subtypes, and migraine episode frequency and the risk of developing PD., Results: A total of 39,312 women were included in the analyses. Among those, 7,321 women (18.6%) reported any migraine at baseline, of whom 2,153 (5.5%) reported a history of migraine, 2,057 (5.2%) reported migraine with aura, and 3,111 (7.9%) reported migraine without aura. During a mean follow-up of 22.0 years, 685 PD cases were reported. Of those, 128 (18.7%) were reported by women who also reported any migraine and 557 (81.3%) by women without any migraine. After adjusting for confounding, the HR for the association of any migraine on the risk of PD was 1.07 (0.88-1.29). Compared with women without migraine, the HRs (95% CI) for PD were 0.87 (0.59-1.27) for migraine with aura, 1.21 (0.93-1.58) for migraine without aura, and 1.05 (0.76-1.45) for history of migraine. Compared with those with a migraine frequency of less than monthly, the HRs were 1.09 (0.64-1.87) for a monthly frequency and 1.10 (0.44-2.75) for a weekly or greater frequency., Discussion: In this large cohort of women, the risk of developing PD was not elevated among those experiencing migraine, irrespective of migraine subtypes or the frequency of migraine. The generalizability of our findings to other populations, such as men, should be further investigated., Trial Registration Information: ClinicalTrials.gov Identifier: NCT00000479.

Activation of autonomic and hypothalamo-pituitary-adrenal (HPA) systems occur interdependently with behavioral adjustments under varying environmental demands. Nevertheless, laboratory rodent studies examining the neural bases of stress responses have generally attributed increments in these systems to be monolithic, regardless of whether an active or passive coping strategy is employed. Using the shock probe defensive burying test (SPDB) to measure stress-coping features naturalistically in male and female rats, we identify a neural pathway whereby activity changes may promote distinctive response patterns of hemodynamic and HPA indices typifying active and passive coping phenotypes. Optogenetic excitation of the rostral medial prefrontal cortex (mPFC) input to the ventrolateral periaqueductal gray (vlPAG) decreased passive behavior (immobility), attenuated the glucocorticoid hormone response, but did not prevent arterial pressure and heart rate increases associated with rats' active behavioral (defensive burying) engagement during the SPDB. By contrast, inhibition of the same pathway increased behavioral immobility and attenuated hemodynamic output but did not affect glucocorticoid increases. Correlational analyses confirmed that hemodynamic increments occurred preferentially during active behaviors, and decrements during immobility epochs, whereas pathway manipulations, regardless of the directionality of effect, weakened the correlational relationship. Finally, neuroanatomical evidence indicated that the influence of the rostral mPFC-vlPAG pathway on coping response patterns are mediated predominantly through GABAergic neurons within vlPAG. These data highlight the importance of this prefrontal-midbrain connection in organizing stress-coping responses, and in coordinating bodily systems with behavioral output for adaptation to aversive experiences. Significance statement Organisms maximize fitness by exhibiting distinct stress-coping responses that are specific to a particular challenge. However, the neurobiology underlying cortical control over coping styles is poorly understood. We reveal a novel role for a prefrontal-to-ventrolateral periaqueductal gray pathway in regulating active versus passive stress-coping response patterns in rats. Optogenetic excitation of this pathway decreased behavioral passivity, attenuated stress-induced glucocorticoid increases, but did not prevent associated increases in autonomic output. Pathway inhibition increased behavioral passivity, attenuated autonomic output, but did not affect glucocorticoid increases. These data highlight the importance of this prefrontal-midbrain connection in organizing stress-coping responses, and in coordinating bodily systems with behavioral output for adaptation to aversive experiences., (Copyright © 2024 the authors.)

We are encouraged by the many positive commentaries on our target article. In this response, we recapitulate some of the points raised and identify synergies between them. We have arranged our response based on the tension between data and architecture that arises in the meta-learning framework. We additionally provide a short discussion that touches upon connections to foundation models.

Isolated perfused rat liver (IPRL) experiments have been used to answer clearance-related questions, including evaluating the impact of pathological and physiological processes on hepatic clearance ( CL H ). However, to date, IPRL data has not been evaluated for in vivo CL H prediction accuracy.In addition to a detailed overview of available IPRL literature, we present an in-depth analysis of the performance of IPRL in CL H prediction.While the entire dataset poorly predicted CL H (GAFE = 3.2; 64% within 3-fold), IPRL conducted under optimal experimental conditions, such as in the presence of plasma proteins and with a perfusion rate within 2-fold of physiological liver blood flow and corrected for unbound fraction in the presence of red blood cells, can accurately predict rat CL H (GAFE = 2.0; 78% within 3-fold). Careful consideration of experimental conditions is needed to allow proper data analysis.Further, isolated perfused liver experiments in other species, including human livers, may allow us to address the current in vitro - in vivo disconnects of hepatic metabolic clearance and improve our methodology for CL H predictions.

Introduction: Considering recent and proposed bans on menthol cigarettes, methods are needed to understand the substitutability of potential menthol cigarette alternatives (MCAs) for menthol cigarettes. This study examined the prospective relationship between behavioral economic demand indices and subjective effects of usual brand menthol cigarettes (UBMC) and preferred MCAs with subsequent performance on a laboratory-based concurrent-choice task comparing UBMC and MCAs., Methods: Eighty participants who typically smoked menthol cigarettes completed this clinical laboratory study. After sampling each product, participants completed the cigarette purchase task (CPT) and modified cigarette evaluation questionnaire (mCEQ). Following 1 week of substituting their preferred MCA for their UBMC, participants completed a 90-minute concurrent-choice self-administration (SA) task comparing their UBMC and preferred MCA. Linear regression models explored associations between CPT demand indices and mCEQ subjective effects in the laboratory with subsequent response effort for UBMCs on the concurrent-choice task., Results: Three demand indices for UBMC were positively associated with UBMC response effort: essential value (EV; p = .02), Omax (p = .02), and breakpoint (p = .04). Four CPT demand indices for the preferred MCA significantly corresponded with UBMC response effort: EV (p = .03), price associated with maximal expenditure (Pmax) (p = .04), maximal expenditure (Omax) (p = .03), and breakpoint (p = .03). Subjective effects captured by the mCEQ were not associated with response effort., Conclusions: Demand indices reflecting Persistence (ie, sensitivity to escalating price) predicted effort to obtain UBMC puffs on the concurrent-choice task. Among this sample, the CPT captured information on the relative reinforcing value (ie, addiction potential) of combustible tobacco products similar to the longer SA task., Implications: In an ever-changing product market, assessing the reinforcing efficacy of menthol cigarettes and putative substitutes quickly and with validity is an important methodological tool for understanding abuse liability. Results suggest that behavioral economic demand indices of CPT efficiently capture information on the relative reinforcing value of UBMC and plausible alternative tobacco products, similar to a 90-minute in-laboratory SA task., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. 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.)

Most heritable diseases are polygenic. To comprehend the underlying genetic architecture, it is crucial to discover the clinically relevant epistatic interactions (EIs) between genomic single nucleotide polymorphisms (SNPs) (1-3). Existing statistical computational methods for EI detection are mostly limited to pairs of SNPs due to the combinatorial explosion of higher-order EIs. With NeEDL (network-based epistasis detection via local search), we leverage network medicine to inform the selection of EIs that are an order of magnitude more statistically significant compared to existing tools and consist, on average, of five SNPs. We further show that this computationally demanding task can be substantially accelerated once quantum computing hardware becomes available. We apply NeEDL to eight different diseases and discover genes (affected by EIs of SNPs) that are partly known to affect the disease, additionally, these results are reproducible across independent cohorts. EIs for these eight diseases can be interactively explored in the Epistasis Disease Atlas (https://epistasis-disease-atlas.com). In summary, NeEDL demonstrates the potential of seamlessly integrated quantum computing techniques to accelerate biomedical research. Our network medicine approach detects higher-order EIs with unprecedented statistical and biological evidence, yielding unique insights into polygenic diseases and providing a basis for the development of improved risk scores and combination therapies., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objectives: The LYMQOL is the most frequently translated, validated, objective tool for assessing Health-Related Quality of Life (HRQoL) in individuals with upper limb lymphedema (ULL). There have been adaptations and validations in a number of different countries. While a German version of LYMQOL Leg for lower limb lymphedema is available, a validated translation of LYMQOL Arm to German is lacking. We aimed to perform a cross-cultural adaption and translation according to ISPOR principles. Methods: Patients suffering from ULL from Germany, Austria, and Switzerland (n = 52) were questioned twice using the translated LYMQOL Arm, SF-36, and an evaluation questionnaire. The assessment of the content validity and face validity proved this version of LYMQOL Arm to be acceptable for interviewing German-speaking patients with ULL in Germany. Results: Comparison of LYMQOL Arm and SF-36 demonstrated good construct validity. Test-retest reliability was moderate to good (intraclass correlation coefficients 0.66-0.73). Cronbach's alpha values varied between 0.79 and 0.89 in both interviews, indicating good internal consistency. Factor analysis revealed a cumulative variance of 59.5% for the four domains of the questionnaire. Conclusion: There was no significant association between lymphedema stage and LYMQOL Arm score. This trial tested the appropriateness of the German version of the LYMQOL Arm for measuring HRQoL in German-speaking individuals with ULL.