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GLUT1 deficiency prevents glucose uptake in T cells resulting in lower intracellular ATP generation and IFNy production., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Ethylene glycol is a promising substrate for bioprocesses which can be derived from widely abundant CO 2 or plastic waste. In this work, we describe the construction of an eight-step synthetic metabolic pathway enabling carbon-conserving biosynthesis of threonine from ethylene glycol. This route extends the previously disclosed synthetic threose-dependent glycolaldehyde assimilation (STEGA) pathway for the synthesis of 2-oxo-4-hydroxybutyrate with three additional reaction steps catalyzed by homoserine transaminase, homoserine kinase, and threonine synthase. We first validated the functionality of the new pathway in an Escherichia coli strain auxotrophic for threonine, which was also employed for discovering a better-performing D-threose dehydrogenase enzyme activity. Subsequently, we transferred the pathway to producer strains and used 13 C-tracer experiments to improve threonine biosynthesis starting from glycolaldehyde. Finally, extending the pathway for ethylene glycol assimilation resulted in the production of up to 6.5 mM (or 0.8 g·L -1 ) threonine by optimized E. coli strains at a yield of 0.10 mol·mol -1 (corresponding to 20 % of the theoretical yield)., (Copyright © 2024. Published by Elsevier Inc.)

Cardiovascular disease and cancer are the leading causes of death in the Western world. The associated risk factors are increased by smoking, hypertension, diabetes, sedentary lifestyle, aging, unbalanced diet, and alcohol consumption. Therefore, the study of cellular metabolism has become of increasing importance, with current research focusing on the alterations and adjustments of the metabolism of cancer patients. This may also affect the efficacy and tolerability of anti-cancer therapies such as immune-checkpoint inhibition (ICI). This review will focus on metabolic adaptations and their consequences for various cell types, including cancer cells, cardiac myocytes, and immune cells. Focusing on ICI, we illustrate how anti-cancer therapies interact with metabolism. In addition to the desired tumor response, we highlight that ICI can also lead to a variety of side effects that may impact metabolism or vice versa. With regard to the cardiovascular system, ICI-induced cardiotoxicity is increasingly recognized as one of the most life-threatening adverse events with a mortality of up to 50%. As such, significant efforts are being made to assess the specific interactions and associated metabolic changes associated with ICIs to improve both efficacy and management of side effects., Competing Interests: Declarations. Conflict of interest: No potential conflict of interest was reported by the authors., (© 2024. The Author(s).)

Companies are not legally obliged to disclose their commitment to Sustainable Development Goals (SDGs). Despite this, many decide to build their competitive position on the basis of marketing communications about sustainability practices. This paper investigates the landscape of sustainability communications practices within ferry operators in the Baltic Sea Region. The authors have developed an index based on two sources of information: (1) an expert assessment of sustainability categories built on the basis of the SDGs, and (2) an assessment of marketing communications of ferry companies. The results of the study identified three distinct patterns of conduct. An analysis revealed that voyage safety and greenhouse gas emissions are the two categories which the ferry companies are most committed to. The results show that marketing communications on the realisation of social goals gives way to that on commitment to the realisation of environmental goals. Beyond insights into the ferry market, the study presents a valuable methodological tool for assessing sustainability communications across diverse industries., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wagner 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.)

Ethylene glycol (EG) is a versatile molecule produced in the petrochemical industry and is widely used to manufacture plastic polymers, anti-freeze, and automotive fluids. Biotechnological production of EG from xylose, a pentose present in lignocellulose biomass hydrolysates, has been achieved by the engineering of bacteria, such as Escherichia coli and Enterobacter cloacae, and the yeast Saccharomyces cerevisiae with synthetic pathways. In the present work, the Dahms pathway was employed to construct Komagataella phaffii strains capable of producing EG from xylose. Different combinations of the four enzymes that compose the synthetic pathway, namely, xylose dehydrogenase, xylonate dehydratase, dehydro-deoxy-xylonate aldolase, and glycolaldehyde reductase, were successfully expressed in K. phaffii. Increased production of EG (1.31 g/L) was achieved by employing a newly identified xylonate dehydratase (xylD-HL). This xylonate dehydratase allowed 30% higher EG production than a previously known xylonate dehydratase (xylD-CC). Further strain engineering demonstrated that K. phaffii possesses native glycolaldehyde reduction and oxidation activities, which lead to pathway deviation from EG to glycolic acid (GA) production. Finally, cultivation conditions that favor the production of EG over GA were determined., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: J.R.M.A., D.T., J. C. B., and C. V. G. C. C. are coauthors of a patent that describes the present work (BR 10 2023 005615). All remaining authors declare that they have no competing interests., (© 2024. The Author(s).)

Background and Aims of the Study: Congenital syphilis is a rare complication of syphilis in pregnant women. Vertical transmission may occur at any time during pregnancy. The incidence of congenital syphilis has been increasing worldwide. Congenital syphilis has been a notifiable disease for many years in Switzerland but reporting does not include maternal features associated with syphilis in pregnancy or infant's subsequent development. We described syphilis cases among pregnant women screened over a 10-year period in Switzerland and subsequent cases of congenital syphilis, in order to identify maternal risk profiles and to optimise prevention. Second, we compared the characteristics of pregnant women screened early (1st trimester) vs late in pregnancy (2nd or 3rd trimester). Finally, we assessed the risk factors for premature birth among these women with syphilis., Methods: A multicentre retrospective study conducted in Swiss hospitals from 2012 to 2021, including pregnant women who screened positive for syphilis (Treponema pallidum haemagglutination assay [TPHA] / T. pallidum particle agglutination assay [TPPA ] ≥1:80) and newborns exposed to T. pallidum in utero and/or congenitally infected and with a positive syphilis serology at birth. Data were collected from medical records., Results: A total of 147 syphilis-positive pregnant women and 102 infants were included. A history of treated syphilis was known for 44% (65/147) of the mothers corresponding to a serological scar and the remaining 56% (82/147) were newly identified syphilis cases. Syphilis screening was done during the first trimester in 54%, second trimester in 29% and third trimester in 13% of cases. Two babies were diagnosed with congenital syphilis (1.96%). Several potential factors that could contribute to women's risk of syphilis during pregnancy were identified such as a foreign origin (93% of mothers), lack of healthcare insurance (25%), no employment status (37%), drug use (5%), co-infection with other sexually transmitted infections (24%) and a late first antenatal consultation (42%). The number of pregnant women without insurance was higher in women diagnosed in the second or third trimester than in those diagnosed in the first trimester (odds ratio 0.41; 95% CI 0.19-0.89; p = 0.024). Syphilis diagnosed in the second or third trimester was associated with a late first antenatal consultation (odds ratio 77.82; 95% CI 9.81-617.21; p <0.001). A high rate of intrauterine growth retardation and of preterm birth was observed in newborns (18% versus 6% in Switzerland in 2022)., Conclusion: Congenital syphilis remains rare in Switzerland. However, we found potential maternal factors associated with a positive syphilis serology during pregnancy, which can help to improve future prevention measures. The study protocol was registered on ClinicalTrials.gov (ID NCT05975502).

Malformations of the brain are common and vary in severity, from negligible to potentially fatal. Their causes have not been fully elucidated. Here, we report pathogenic variants in the core protein-folding machinery TRiC/CCT in individuals with brain malformations, intellectual disability, and seizures. The chaperonin TRiC is an obligate hetero-oligomer, and we identify variants in seven of its eight subunits, all of which impair function or assembly through different mechanisms. Transcriptome and proteome analyses of patient-derived fibroblasts demonstrate the various consequences of TRiC impairment. The results reveal an unexpected and potentially widespread role for protein folding in the development of the central nervous system and define a disease spectrum of "TRiCopathies."

Older/unfit adults with AML have worse outcomes and fewer treatment options than their younger/fit counterparts. In vitro studies have found a synergistic effect of hypomethylating agents (HMA) with venetoclax (VEN) on AML cells and since the phase 3 VIALE-A trial demonstrated a survival benefit, HMA + VEN has become the standard of care in the frontline setting for older/unfit adults with AML. Unfortunately, the standard 28-day cycle of VEN is associated with a high degree of myelosuppression leading to treatment delays and dose modifications. Many small retrospective studies have successfully shown comparable outcomes to VIALE-A with reduced dose/duration of VEN. Furthermore, low dose metronomic dosing of HMA + VEN has shown clinical benefit while minimizing myelotoxicity. Future trials are vital to understand the appropriate dose of VEN in combination with HMA, to evaluate HMA + VEN compared to intensive therapy for younger/fit patients, and to explore its utility in the relapsed/refractory setting., Competing Interests: Declaration of competing interest Hannah Levavi receives consulting fees from Sobi. Keith Pratz receives research funding from AbbVie, Agios, Daiichi Sankyo, Millennium; advisory board member for AbbVie, Astellas, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Celgene, Novartis, Roche, Jazz Pharmaceuticals, and Servier. Douglas Tremblay receives contracted research funding paid to his institution from Sobi, Sumitomo, Cogent Biosciences and Gilead and consulting fees from Sobi, Novartis, AbbVie, Pharmaessentia, Sierra Oncology, GSK and Cogent Biosciences. All other authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cardiovascular disease (CVD) is commonly due to the development of atherosclerosis. Endothelial integrity is critical in the prevention of pathogenesis of atherosclerosis. The key to prevention of CVD is understanding the molecular mechanisms responsible for initiation of early atherosclerosis. MiRNAs are mediators of endothelial homeostasis, and their dysregulation could lead to early atherosclerotic disorder. We previously revealed the expression of miR-7975 in early atherosclerotic lesions. The aim of this study was to investigate the novel roles of miR-7975 on endothelial cell proliferation and migration, and in the regulation of metadherin (MTDH) expression. We performed proliferation and migration assays coupled with luciferase assay. We show that miR-7975 promotes proliferation and migration of endothelial cells and that miR-7976 directly regulates (MTDH), previously associated with cancer pathogenesis. In conclusion our results show miR-7975 could be a potential mediator of endothelial homeostasis and that MTDH is a novel target of miR-7975.

Background: Mycoplasma pneumoniae is a major cause of community-acquired pneumonia (CAP) in school-aged children. Macrolides are the first-line treatment for this infection. However, it is unclear whether macrolides are effective in treating M. pneumoniae CAP, mainly due to limitations in microbiological diagnosis of previous studies. The extensive global use of macrolides has led to increasing antimicrobial resistance. The overall objective of this trial is to produce efficacy data for macrolide treatment in children with M. pneumoniae CAP., Methods: The MYTHIC Study is a randomized, double-blind, placebo-controlled, multicenter, non-inferiority trial in 13 Swiss pediatric centers. Previously healthy ambulatory and hospitalized children aged 3-17 years with clinically diagnosed CAP will be screened with a sensitive and commercially available M. pneumoniae-specific IgM lateral flow assay from capillary blood. Mycoplasma pneumoniae infection in screened patients will be verified retrospectively by respiratory PCR (reference test) and IgM antibody-secreting cell enzyme-linked immunospot (ELISpot) assay (confirmatory test for distinguishing between carriage and infection). Patients will be randomized 1:1 to receive a 5-day treatment of macrolides (azithromycin) or placebo. The co-primary endpoints are (1) time to normalization of all vital signs, including body temperature, respiratory rate, heart rate, and saturation of peripheral oxygen (efficacy), and (2) CAP-related change in patient care status (i.e., admission, re-admission, or intensive care unit transfer) within 28 days (safety). Secondary outcomes include adverse events (AEs), as well as antimicrobial and anti-inflammatory effects. For both co-primary endpoints, we aim to show non-inferiority of placebo compared to macrolide treatment. We expect no macrolide effect (hazard ratio of 1, absolute risk difference of 0) and set the corresponding non-inferiority margins to 0.7 and -7.5%. The "at least one" success criterion is used to handle multiplicity with the two co-primary endpoints. With a power of 80% to reject at least one null hypothesis at a one-sided significance level of 1.25%, 376 patients will be required., Discussion: This trial will produce efficacy data for macrolide treatment in children with M. pneumoniae CAP that might help to reduce the prescription of antibiotics and therefore contribute to the global efforts toward reducing antimicrobial resistance., Trial Registration: ClinicalTrials.gov, NCT06325293. Registered on 24 April 2024., (© 2024. The Author(s).)

Since the discovery of RNA splicing and its role in gene expression, researchers have sought a set of rules, an algorithm or a computational model that could predict the splice isoforms, and their frequencies, produced from any transcribed gene in a specific cellular context. Over the past 30 years, these models have evolved from simple position weight matrices to deep-learning models capable of integrating sequence data across vast genomic distances. Most recently, new model architectures are moving the field closer to context-specific alternative splicing predictions, and advances in sequencing technologies are expanding the type of data that can be used to inform and interpret such models. Together, these developments are driving improved understanding of splicing regulatory mechanisms and emerging applications of the splicing code to the rational design of RNA- and splicing-based therapeutics., (© 2024. Springer Nature Limited.)

Objective:  This study aimed to assess the desirability, feasibility, and sustainability of integrating a project-based capstone course with the course-based curriculum of an interdisciplinary MSc Health Informatics program guided by a student-partnered steering committee and student-centered approach., Methods:  We conducted an online cross-sectional survey ( n  = 87) and three semistructured focus groups ( n  = 18) of health informatics students and alumni. Survey data were analyzed descriptively. Focus groups were audio-recorded and transcribed verbatim and then analyzed using a general inductive and classic analysis approach., Results:  Most students supported including a capstone project but desired an option to work independently or within a group. Students perceived several benefits to capstone courses while concerned over perceived challenges to capstone implementation, evaluation, and managing group processes. The themes identified were (1) professional development, identity, and career advancement, (2) emulating the real world and learning beyond the classroom, (3) embracing new, full-circle learning, (4) anticipated course structure, delivery, and preparation, (5) balancing student choice, interests, and priorities, and (6) concerns over group dynamics, limitations, and support., Conclusion:  This study demonstrates the value of having students as partners at each stage in the process from methods conception to course curriculum design. With the steering committee and the curriculum developer, we codeveloped a student-centered course that integrates foundational digital health-related project knowledge acquisition with an inquiry-based project that can be completed independently or in small groups. This study demonstrates the potential benefits and challenges that health informatics educators may consider when (re)designing capstone courses., Competing Interests: All of the authors have an affiliation with the MSc eHealth program. N.W., C.L., V.M., N.G.B. (faculty members), and M.L. (internship coordinator) are employees of McMaster University and receive salary through program revenues. R.J., T.B., E.W., S.Z.D., and J.F. are alumni of the program., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Permanent tattooing is the invasive introduction of tattoo ink (pigments) into the dermis. The ink and aftercare cosmetics applied on pre-damaged skin may contain skin sensitisers., Objectives: To identify patient characteristics and the pattern of sensitisation in tattooed patients patch tested within the Information Network of Departments of Dermatology (IVDK)., Patients and Methods: Comparative analysis of patient characteristics and reaction frequencies to baseline series allergens in 1648 consecutive patients with and 8045 consecutive patients without permanent tattoos. Non-overlapping 95%-confidence intervals were considered as significant., Results: Having permanent tattoos was related with female sex, age <40 years, tobacco smoking, atopic dermatitis, (occupational) hand dermatitis and being employed in particular occupational groups (e.g., healthcare workers, mechanics, hairdressers). Sensitisation to nickel was increased in tattooed patients and associated with female sex (OR 4.23 [95%-CI, 3.48-5.18]), age ≥40 years (OR 1.26 [95%-CI, 1.08-1.49]), tobacco smoking (OR 1.19 [95%-CI, 1.01-1.40]) and having permanent tattoos (OR 1.27 [95%-CI, 1.05-1.53])., Conclusions: The association between nickel sensitisation and permanent tattoos is probably confounded by past reactions to pierced costume jewellery. Socio-economic factors most probably contribute to the connection between tattoos, tobacco smoking, occupational or hand dermatitis, and being employed in particular occupational groups., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Children with congenital heart disease (CHD) from low- to middle-income countries (LMIC) are suspected to have a high prevalence of antibiotic-resistant microorganisms (ARMOs) carriage, but data are currently lacking. Carriage of ARMOs could impact the post-operative course in pediatric intensive care unit (PICU). The aim of the study was to assess the prevalence of ARMOs carriage in children with CHD from LMIC and its impact on post-operative outcomes., Methods: This was a retrospective monocentric study from 01/2019 to 12/2022. Included patients were children (0-18 years) from a LMIC admitted after CHD surgery and with AMRO screening performed the week before. Infections and post-operative evolution were compared based on ARMOs carriage status., Findings: Among 224 surgeries (median age 38.5 months (IQR 22-85.5)), ARMOs carriage was evidenced in 95 cases (42.4%). Main organisms isolated were Extended Spectrum Beta-Lactamase (ESBL) producing E. coli (75/224) 33.5%)) and ESBL-K. pneumoniae (30/224) 13.4%)). Median mechanical ventilation duration was 1 day (IQR 0-1), PICU stay 3 days (IQR 2-4) and hospital stay 6.5 days (IQR 5-10). A total of 17 infectious episodes occurred in 15 patients, mostly consisting in hospital-acquired pneumonia (HAP) (12/17). Only two infections were caused by a colonizing ARMO. Occurrence of infections and patients' outcome were similar between ARMO carriers and non-carriers. Higher use of carbapenems (6 (6.3%) vs 1 (0.8%), p = 0.04) and a trend to a higher use of vancomycin (14 (13.7%) vs 9 (6.9%), p = 0.04) in case of ARMOs carriage. Applying current guidelines, negative swab screening could have led to sparing most of empirical vancomycin therapy (11/12) for HAP based on current guidelines., Conclusion: Prevalence of AMROs carriage is high in children from LMIC and has a limited impact on patients' outcome. However, ARMOs carriage leads to higher consumption of antibiotics. Screening may help saving use of broad-spectrum antibiotic in non-carrier patients., (© 2024. The Author(s).)

Background: The first approvals of novel systemic therapies within recent years for metastatic hormone-sensitive (mHSPC) were mainly based on improved overall survival (OS) and time to castration resistance (ttCRPC) in mHSPC patients stratified according to CHAARTED low (LV) versus high volume (HV) and LATITUDE low (LR) versus high-risk (HR) disease., Methods: Relying on our institutional tertiary-care database we identified all mHSPC stratified according to CHAARTED LV versus HV, LATITUDE LR versus HR and the location of the metastatic spread (lymph nodes (M1a) versus bone (M1b) versus visceral/others (M1c) metastases. OS and ttCRPC analyses, as well as Cox regression models were performed according to different metastatic categories., Results: Of 451 mHSPC, 14% versus 27% versus 48% versus 12% were classified as M1a LV versus M1b LV versus M1b HV versus M1c HV with significant differences in median OS: 95 versus 64 versus 50 versus 46 months (p < 0.001). In multivariable Cox regression models HV M1b (Hazard Ratio: 2.4, p = 0.03) and HV M1c (Hazard Ratio: 3.3, p < 0.01) harbored significant worse than M1a LV mHSPC. After stratification according to LATITUDE criteria, also significant differences between M1a LR versus M1b LR versus M1b HR versus M1c HR mHSPC patients were observed (p < 0.01) with M1b HR (Hazard Ratio: 2.7, p = 0.03) and M1c HR (Hazard Ratio: 3.5, p < 0.01), as predictor for worse OS. In comparison between HV M1b and HV M1c, as well as HR M1b versus HR M1c no differences in ttCRPC or OS were observed., Conclusions: Significant differences exist between different metastatic patterns of HV and LV and HR and LR criteria. Best prognosis is observed within M1a LV and LR mHSPC patients., (© 2024 The Author(s). The Prostate published by Wiley Periodicals LLC.)

Purpose: Prospective, multicentric observational cohort study in Switzerland investigating measures to prevent mother-to-child transmission in pregnant women with HIV (WWH) and assessing health and development of their exposed children as well as of children with HIV (CWH) in general., Participants: Between January 1986 and December 2022, a total of 1446 mother-child pairs were enrolled. During the same period, the study also registered 187 CWH and 521 HIV-exposed but uninfected children (HEU), for whom detailed maternal information was not available. Consequently, the cohort comprises a total of 2154 children., Findings to Date: During these 37 years, research by the Swiss Mother and Child HIV Cohort Study (MoCHiV) and its international collaborators has strongly influenced the prevention of vertical transmission of HIV (eg, introduction and discontinuation of elective caesarean section, neonatal postexposure prophylaxis and breastfeeding). Contributions have also been made to the management of diagnostics (eg, p24 antigen assay) and the effects of antiretroviral treatment (eg, prematurity, growth) in HEU and CWH., Future Plans: Most children present within the cohort are now HEU, highlighting the need to investigate other vertically transmitted pathogens such as hepatitis B and C viruses, cytomegalovirus or Treponema pallidum . In addition, analyses are planned on the longitudinal health status of CWH (eg, resistance and prolonged exposure to antiretroviral therapy), on social aspects including stigma in CWH and HEU, and on interventions to further optimise antenatal and postpartum care in WWH., Competing Interests: Competing interests: AB, AT, AS, CRK, IH, PP, NW, LK and CR declare no conflicts of interest. BMT has participated as expert for Glaxo-Smith Kline, Jansen, Medinova, Pierre-Favre. HG has received unrestricted research grants from Gilead Sciences; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, ViiV Healthcare, Johnson and Johnson, Janssen, GSK and Novartis; and grants from SystemsX, and the National Institutes of Health and the Yvonne Jacob Foundation. The institution of E.B. received fees for his participation to Advisory boards and travel grants from Gilead Sciences, MSD, ViiV healthcare, Abbott, Pfizer and Sandoz. AR reports support to his institution for advisory boards and/or travel grants from MSD, Gilead Sciences, Pfizer and Moderna, and an investigator-initiated trial (IIT) grant from Gilead Sciences. All remuneration went to his home institution and not to AR personally, and all remuneration was provided outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

We use a real-space slave-rotor theory of the physics of topological Mott insulators, using the Kane-Mele-Hubbard model as an example, and show that a topological gap in the Green function zeros corresponds to a gap in the bulk spinon spectrum and implies a gapless band of edge zeros and a spinon edge mode. We then consider an interface between a topological Mott insulator and a conventional topological insulator showing how the spinon edge mode of the topological Mott insulator combines with the spin part of the conventional electron topological edge state, leaving a non-Fermi liquid edge mode described by a gapless propagating holon and gapped spinon state. Our work demonstrates the physical meaning of Green function zeros and shows that interfaces between conventional and Mott topological insulators are a rich source of new physics.

The monoclonal antibody rituximab improves clinical outcome in the treatment of CD20-positive lymphomatous neoplasms, and it is an established drug for treatment of these cancers. Successful mRNA COVID-19 (SARS-CoV-2) vaccination is extremely important for lymphoma patients because they tend to be elderly with comorbidities which leaves them at increased risk of poor outcomes once infected by Coronavirus. Anti-CD20 therapies such as rituximab, deplete B-cell populations and can affect vaccine efficacy. Therefore, a knowledge of the effect of COVID-19 vaccination in this group is critical. We followed a cohort of 28 patients with CD20-positive lymphomatous malignancies treated with rituximab that started prior to their course of COVID-19 vaccination, including boosters. We assayed for vaccine "take" in the humoral (IgG and IgA) and cellular compartment. Here, we show that short-term and long-term development of IgG and IgA antibodies directed toward COVID-19 spike protein are reduced in these patients compared to healthy controls. Conversely, the robustness and breath of underlying T-cell response is equal to healthy controls. This response is not limited to specific parts of the spike protein but spans the spike region, including response to the conserved Receptor Binding Domain (RBD). Our data informs on rational vaccine design and bodes well for future vaccination strategies that require strong induction of T-cell responses in these patients., Competing Interests: MH: Advisory Board: Servier, Novartis, AnHeart, Bayer; Steering Committee: Novartis; Honoraria for educational talks: Pfizer (educational talk for Pfizer staff in 2021), Novartis; Data Safety Monitoring Board: Advarra, Parexel. MR: Patent applications have been filed and are currently pending in US, US-2023-0372469, and Europe, EP 4228686 for a T cell vaccine for SARS virus. 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., (Copyright © 2024 Komlodi-Pasztor, Escarra-Senmarti, Bazer, Bhatnagar, Perez Heydrich, Messmer, Ambinder, Gladstone, Clayton, Goodrich, Schoch, Wagner-Johnston, VandenBussche, Huang, Holdhoff and Rosario.)

Competing Interests: PMMS, JT and PKAA have participated in advisory board meetings for Nirsevimab organised by Sanofi. JT has received speaker fees from Sanofi and is member of a data safety monitoring board for mRNA-based RSV vaccines by Moderna.

Background: Pyomyositis, a bacterial muscle infection, is an important differential diagnosis in children and adolescents with musculoskeletal pain. In contrast to tropical regions, it is rarely recognized in temperate countries, but incidence is increasing and major studies are missing., Methods: This retrospective multicenter study included patients <18 years of age hospitalized with pyomyositis in 11 Swiss children's hospitals between January 2010 and December 2022. Cases were identified by ICD-10 code (Myositis; M60-M60.9), and data was extracted from electronic hospital records., Results: Of 331 patients identified, 102 fulfilled the case definition. Patient age at presentation ranged from 2 weeks to 17 years (median 8 years). The majority had no underlying illness and all presented with fever and localized pain. At the respective site of pyomyositis, 100 (98%) had impaired movement and 39 (38%) presented with local swelling. Pelvic (57%) and leg (28%) muscles were mostly affected. Blood or tissue cultures were obtained in 94 (92%) and 59 (57%) patients, respectively. Of those, 55 (58%) blood and 52 (88%) tissue cultures were positive, mainly for Staphylococcus aureus (35 and 19, respectively) and Streptococcus pyogene s (12 and 15, respectively). All patients received antibiotic treatment during hospitalization for a median of 10 days (interquartile range: 7-17), followed by outpatient treatment for a further median of 16 days (interquartile range: 11-22) in 95 (93%) patients. Fifty-nine (57%) patients required surgery., Conclusions: Pyomyositis is a challenging diagnosis that requires a high level of awareness. Blood and/or tissue cultures revealed S. aureus and S. pyogenes as the predominant causative agents., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The landscape of systemic therapies for metastatic hormone-sensitive (mHSPC) and castration resistant prostate cancer (mCRPC) extensively improved within the last decades resulting in a significantly prolonged overall survival. However, subgroup analyses of phase III trials suggest potentially different overall survival outcomes for older adults., Methods: We relied on our institutional metastatic prostate cancer database to identify mHSPC and subsequently mCRPC patients. Older adults were stratified according to age groups 70-74 versus ≥75-79 versus ≥80 years at metastatic occurrence. Subsequently, uni- and multivariable time to mCRPC and overall survival analyses were performed., Results: Of 494 older adults, 217 (44%) were 70-74 versus 180 (36%) 75-79 versus 97 (20%) ≥80 years old. Rates of local prostate cancer treatment differed significantly between all three groups (p < 0.01). Regarding mHSPC treatment, androgen receptor signaling inhibitors (ARSI) were administered in 30-39% of patients and docetaxel with 9% in age group 70-74 years and 6% and 3% in age groups 75-79 years and ≥80 years. Regarding mCRPC treatment, significant differences between treatment proportions were observed (p < 0.01). Most common treatment was ARSI for all three groups. Conversely, chemotherapy was more frequently administered in patients aged 70-74 (16%), relative to 4% and 3% in 75-79 year and ≥80 year aged patients. In univariable and multivariable time to mCRPC analyses, overall survival in mHSPC and OS in mCRPC analyses, no significant differences between all three age groups were observed (all p ≥ 0.3)., Conclusions: Treatment patterns differ significantly between older adults with metastatic prostate cancer. However, these differences may not result in differences of overall life expectancy., (© 2024 The Author(s). Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Background: Hymenoptera venom is one of the most frequent causes of anaphylaxis. Studies from adults indicate the clinical profiles and risk factors of Hymenoptera venom-induced anaphylaxis (VIA). Much less is known about pediatric VIA., Objective: To understand elicitor- and age-related factors determining pediatric VIA by analyzing data from the anaphylaxis registry., Methods: We selected pediatric VIA, pediatric food-induced anaphylaxis (FIA), and adult VIA cohorts from the anaphylaxis registry and performed a comparative data analysis regarding elicitors, symptoms, and management., Results: We identified 725 pediatric patients with VIA, 3,149 with pediatric FIA, and 5,534 with adult VIA. In pediatric VIA, boys were more frequently affected, atopy was not increased, and the onset of the reaction after exposure was fast (≤30 min; 91%) compared with pediatric FIA. Symptoms in pediatric VIA were age dependent, and although respiratory symptoms occurred most frequently besides skin symptoms in both pediatric patients with VIA and FIA, cardiovascular symptoms were more frequently reported in pediatric patients with VIA than pediatric patients with FIA. The analysis of pediatric versus adult VIA revealed clear differences in the frequency of involved organ systems (skin: 93% vs 78%; respiratory: 77% vs 64%; and cardiovascular: 61% vs 85%). For both pediatric and adult VIA, the rates of adrenaline application by a professional were low (29% vs 31%) but hospitalization rates were higher in children than in adults (61% vs 42%). Venom immunotherapy was frequently initiated regardless of age (78% each)., Conclusions: Pediatric VIA is more frequent in boys, symptoms are age dependent, and hospitalization is often required. Adrenaline should be applied according to current guidelines. Venom immunotherapy is an important treatment option in pediatric VIA and should be considered in severely affected children., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cognitive impairment (CI) is common among older patients presenting to the emergency department (ED). The failure to recognize CI at ED presentation constitutes a high risk of additional morbidity, mortality, and functional decline. The Clock Drawing Test (CDT) is a well-established cognitive screening test., Aim: In patients presenting to the ED with non-specific complaints (NSCs), we aimed to investigate the usability of the CDT and its prognostic value regarding length of hospital stay (LOS) and mortality., Method: Secondary analysis of the Basel Non-specific Complaints (BANC) trial, a prospective delayed type cross-sectional study with a 30-day follow-up. In three EDs, patients presenting with NSCs were enrolled. The CDT was administered at enrollment., Results: In the 1,278 patients enrolled, median age was 81 [74, 87] years and 782 were female (61.19%). A valid CDT was obtained in 737 (57.7%) patients. In patients without a valid CDT median LOS was higher (29 [9, 49] days vs. 22 [9, 45] days), and 30-day mortality was significantly higher than in patients with a valid CDT (n = 45 (8.32%) vs. n = 39 (5.29%)). Of all valid CDTs, 154 clocks (20.9%) were classified as normal, 55 (7.5%) as mildly deficient, 297 (40.3%) as moderately deficient, and 231 (31.3%) as severely deficient. Mortality and LOS increased along with the CDT deficits (p = 0.012 for 30-day mortality; p < 0.001 for LOS)., Conclusion: The early identification of patients with CI may lead to improved patient management and resource allocation. The CDT could be used as a risk stratification tool for older ED patients presenting with NSCs, as it is a predictor for 30-day mortality and LOS., Competing Interests: Declaration of competing interest None, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Over the past decade, cancer immunotherapy has significantly advanced through the introduction of immune checkpoint inhibitors and the augmentation of adoptive cell transfer to enhance the innate cancer defense mechanisms. Despite these remarkable achievements, some cancers exhibit resistance to immunotherapy, with limited patient responsiveness and development of therapy resistance. Metabolic adaptations in both immune cells and cancer cells have emerged as central contributors to immunotherapy resistance. In the last few years, new insights emphasized the critical role of cancer and immune cell metabolism in animal models and patients. During therapy, immune cells undergo important metabolic shifts crucial for their acquired effector function against cancer cells. However, cancer cell metabolic rewiring and nutrient competition within tumor microenvironment (TME) alters many immune functions, affecting their fitness, polarization, recruitment, and survival. These interactions have initiated the development of novel therapies targeting tumor cell metabolism and favoring antitumor immunity within the TME. Furthermore, there has been increasing interest in comprehending how diet impacts the response to immunotherapy, given the demonstrated immunomodulatory and antitumor activity of various nutrients. In conclusion, recent advances in preclinical and clinical studies have highlighted the capacity of immune-based cancer therapies. Therefore, further exploration into the metabolic requirements of immune cells within the TME holds significant promise for the development of innovative therapeutic approaches that can effectively combat cancer in patients., (©2024 American Association for Cancer Research.)

Introduction: One of the most common causes of vision loss in the elderly population worldwide is age-related macular degeneration (AMD). Subsequently, the number of people affected by AMD is estimated to reach approximately 288 million by the year 2040. The aim of this study was to develop an ex vivo model that simulates various aspects of the complex AMD pathogenesis., Methods: For this purpose, primary porcine retinal pigment epithelial cells (ppRPE) were isolated and cultured. One group was exposed to medium containing sodium iodate (NaIO 3 ) to induce degeneration. The others were exposed to different supplemented media, such as bovine serum albumin (BSA), homogenized porcine retinas (HPR), or rod outer segments (ROOS) for eight days to promote retinal deposits. Then, these ppRPE cells were cocultured with porcine neuroretina explants for another eight days. To assess the viability of ppRPE cells, live/dead assay was performed at the end of the study. The positive RPE65 and ZO1 area was evaluated by immunocytochemistry and the expression of RLBP1 , RPE65 , and TJP1 was analyzed by RT-qPCR. Additionally, drusen ( APOE ), inflammation ( ITGAM , IL6 , IL8 , NLRP3 , TNF ), oxidative stress ( NFE2L2 , SOD1 , SOD2 ), and hypoxia ( HIF1A ) markers were investigated. The concentration of the inflammatory cytokines IL-6 and IL-8 was determined in medium supernatants from day 16 and 24 via ELISA., Results: Live/dead assay suggests that especially exposure to NaIO 3 and HPR induced damage to ppRPE cells, leading in a significant ppRPE cell loss. All supplemented media resulted in decreased RPE-characteristic markers (RPE65; ZO-1) and gene expression like RLBP1 and RPE65 in the cultured ppRPE cells. Besides, some inflammatory, oxidative as well as hypoxic stress markers were altered in ppRPE cells cultivated with NaIO 3 . The application of HPR induced an enhanced APOE expression. Pre-exposure of the ppRPE cells led to a diminished number of cones in all supplemented media groups compared to controls., Discussion: Overall, this novel coculture model represents an interesting initial approach to incorporating deposits into coculture to mimic AMD pathogenesis. Nevertheless, the effects of the media used need to be investigated in further studies., Competing Interests: The 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., (Copyright © 2024 Wagner, Tsai, Reinehr, Theile, Dick and Joachim.)

Introduction: Public health efforts to reduce opioid overdose fatalities include educating people at risk and expanding access to naloxone, a medication that reverses opioid-induced respiratory depression. People receiving long-term opioid therapy (LTOT) are at increased risk for overdose, yet naloxone uptake in this population remains low. The objective of this study was to determine if a targeted, digital health intervention changed patient risk behavior, increased naloxone uptake, and increased knowledge about opioid overdose prevention and naloxone., Methods: We conducted a pragmatic randomized clinical trial among patients prescribed LTOT in a health care delivery system in Colorado. Participants were randomly assigned to receive an animated overdose prevention and naloxone educational video (intervention arm) or usual care (control arm). The 6-minute video was designed to educate patients about opioid overdose and naloxone, increase overdose risk perception, and prompt them to purchase naloxone from the pharmacy. Over an 8-month follow-up, opioid risk behavior was assessed with the Opioid-Related Behaviors in Treatment survey instrument, and overdose and naloxone knowledge was measured with the Prescription Opioid Overdose Knowledge Scale after viewing the video at baseline. Naloxone dispensations were evaluated using pharmacy data over a 12-month period. Data were analyzed with generalized linear mixed effects and log-binomial regression models., Results: There were 519 participants in the intervention arm and 485 participants in the usual care arm. Opioid risk behavior did not differ between the study arms over time (study arm by time interaction P=0.93). There was no difference in naloxone uptake between the arms (RR = 1.13, 95% CI: 0.77-1.66). Knowledge was significantly greater in the intervention arm compared to usual care (P<0.001)., Conclusions: A targeted, digital health intervention video effectively increased opioid overdose and naloxone knowledge, without increasing opioid risk behavior. Naloxone uptake did not differ between the intervention and usual care arms., Trial Registration: ClinicalTrials.gov number NCT03337009., Competing Interests: All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare support from the National Institutes of Health - National Institute on Drug Abuse for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. Outside of the listed affiliations, I.B. reports royalties from UpToDate, and all remaining authors declare that they do not have a conflict of interest.

Background: Large neck circumference and displacement of the trachea due to pathology increase the risk of failed identification of the cricothyroid membrane and cricothyroidotomy. We investigated whether ultrasound aids in the successful identification of the cricothyroid membrane in a model of an obese neck with midline deviation of the trachea., Methods: We developed silicone neck models that were suitable for both palpation and ultrasonography and where the trachea deviated laterally from the midline to either side. After reading a book chapter and participating in a 25-minute lecture and a 15- to 23-minute hands-on demonstration and rehearsal of ultrasonography for identification of the cricothyroid membrane, anesthesiologists and anesthesiology residents randomly performed identification with either ultrasound or palpation on 1 of 2 neck models., Results: We included 57 participants, of whom 29 and 28 were randomized to palpation and ultrasound, respectively. Correct identification of the cricothyroid membrane was achieved by 21 (75.0%) vs 1 (3.5%) of participants in the ultrasound versus palpation groups (risk ratio [RR], 21.8 [95% confidence interval {CI}, 3.1-151.0]). The tracheal midline position in the sagittal plane was identified correctly by 24 (85.7%) vs 16 (55.2%) of participants in the ultrasound versus palpation groups (RR, 1.6 [95% CI, 1.1-2.2])., Conclusions: Identification of the cricothyroid membrane in a model of an obese neck with midline deviation of the trachea was more often successful with ultrasound compared to palpation. Our study supports the potential use of ultrasound before induction of anesthesia and airway management in this group of patients, and it may even be applied in emergency situations when ultrasound is readily available. Further studies in human subjects should be conducted., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

Introduction: Thick histological samples are difficult to image without proper tissue clearing methods. Among these methods ethyl cinnamate (ECi)-based clearing preserves antigenicity and is compatible with immunofluorescent labeling. In contrast to many other clearing protocols, ECi-based clearing is fast and is done as a final step after standard immunofluorescent labeling protocols., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Efficient city logistics is essential to build smart sustainable cities where inhabitants' well-being is a priority. Meanwhile, despite the great importance of city logistics processes, their improvement is problematic for many cities. Although solutions from the field of emerging technologies are more and more often used, the question is whether implementing technological tools and filling cities with sensors is a sufficient solution that can solve the problems of intensely growing urban freight transport. The aim of the paper is to examine the role of knowledge management in city logistics and identify barriers to the implementation of knowledge-based city logistics. A key element of the research procedure was an expert survey, to which 31 international experts specialising in city logistics issues were invited, characterised by extensive experience working on research projects in the area of interest. Four knowledge management processes have been transferred to the city logistics area. The results of the study show that the difficulties are observed mainly in the processes of data gathering and knowledge acquisition. The main reason for difficulties in that area is the reluctance of city users, retailers, transport and logistics operators to share information. Identifying these processes as the most problematic is a valuable hint for logistics managers, municipalities and academics. To improve knowledge-based city logistics, it is therefore necessary to focus on these processes and look for the best solutions and new forms of organisational and business support. The solution to the problems identified in the study is the proposal to create a city logistics collaborative knowledge base which is a combination of an IT tool - the CL knowledge management platform, and the Freight Quality Partnership., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Iwan 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.)

Abstract: Although it is evident that standard-dose whole-brain radiotherapy as consolidation is associated with significant neurotoxicity, the optimal consolidative strategy for primary central nervous system lymphoma (PCNSL) is not defined. We performed a randomized phase 2 clinical trial via the US Alliance cancer cooperative group to compare myeloablative consolidation supported by autologous stem cell transplantation with nonmyeloablative consolidation after induction therapy for PCNSL. To our knowledge, this is the first randomized trial to be initiated that eliminates whole-brain radiotherapy as a consolidative approach in newly diagnosed PCNSL. Patients aged 18 to 75 years were randomly assigned in a 1:1 manner to induction therapy (methotrexate, temozolomide, rituximab, and cytarabine) followed by consolidation with either thiotepa plus carmustine and autologous stem cell rescue vs induction followed by nonmyeloablative, infusional etoposide plus cytarabine. The primary end point was progression-free survival (PFS). A total of 113 patients were randomized, and 108 (54 in each arm) were evaluable. More patients in the nonmyeloablative arm experienced progressive disease or death during induction (28% vs 11%; P = .05). Thirty-six patients received autologous stem cell transplant, and 34 received nonmyeloablative consolidation. The estimated 2-year PFS was higher in the myeloablative vs nonmyeloablative arm (73% vs 51%; P = .02). However, a planned secondary analysis, landmarked at start of the consolidation, revealed that the estimated 2-year PFS in those who completed consolidation therapy was not significantly different between the arms (86% vs 71%; P = .21). Both consolidative strategies yielded encouraging efficacy and similar toxicity profiles. This trial was registered at www.clininicals.gov as #NCT01511562., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Neonatal sepsis (NS) is a global health issue, particularly in Sub-Saharan Africa, where it accounts for a substantial portion of neonatal morbimortality. This multicountry survey aimed to elucidate current practices, challenges and case definitions in managing NS among clinicians in Sub-Saharan Africa., Methods: The survey targeted physicians and medical practitioners working in neonatal care who participated in a Self-Administered Web Questionnaire. The main objective was to understand NS and infection case definitions and management from the clinician's point of view and to identify challenges and opportunities in sepsis management. Participants were queried on demographics, definitions and diagnostic criteria, treatment approaches, and infection prevention and control (IPC) measures. A total of 136 participants from 93 healthcare structures responded, providing valuable insights into NS management practices., Results: From May to July 2022 across 21 Sub-Saharan African countries, 136 neonatal clinicians with an average from 93 structures with on average 10-year experience took the survey. NS ranked highest among prevalent neonatal conditions. Diagnostic case definitions between sepsis and infection were attributed to clinical signs, anamnesis, C reactive protein, white blood cll count and blood cultures with no statistically significant differences. Early-onset sepsis was defined within 72 hours by 48%, while late-onset varied. Antibiotics were likely on admission (86.4%) and during the stay (82.2%). Treatment abandonment was reported unlikely. The preferred antibiotic regimen for early-onset sepsis was intravenous amoxicillin (or ampicillin), gentamycin and cefotaxime. Blood culture availability and IPC protocols were reported as limited, particularly concerning patient environment, pharmacy protocols and clean-dirty circuits., Conclusions: This NS survey emphasises clinicians' challenges due to limited access to diagnostic tools and raises concerns about antimicrobial overexposure. IPC also seem limited, according to participants. Addressing these challenges can enhance diagnostic practices, antibiotic stewardship and infection control in the region., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Diarrhea is a leading cause of death in children globally, mostly due to inadequate sanitary conditions and overcrowding. Poor housing quality and lack of tenure security that characterize informal settlements are key underlying contributors to these risk factors for childhood diarrhea deaths. The objective of this study is to better understand the physical attributes of informal settlement households in Latin American cities that are associated with childhood diarrhea. We used data from a household survey (Encuesta CAF) conducted by the Corporación Andina de Fomento (CAF), using responses from sampled individuals in eleven cities. We created a household deprivation score based on household water and sewage infrastructure, overcrowding, flooring and wall material, and security of tenure. We fitted a multivariable logistic regression model to estimate odds ratios (OR) and 95% confidence intervals (95% CI) to test the association between the deprivation score and its individual components and childhood diarrhea during the prior 2 weeks. We included a total of 4732 households with children, out of which 12.2% had diarrhea in the 2-week period prior to completing the survey. After adjusting for respondent age, gender, and city, we found a higher risk of diarrhea associated with higher household deprivation scores. Specifically, we found that the odds of diarrhea for children living in a mild and severe deprived household were 1.04 (95% CI 0.84-1.28) and 3.19 times (95% CI 1.80-5.63) higher, respectively, in comparison to households with no deprivation. These results highlight the connections between childhood health and deprived living conditions common in informal settlements., (© 2024. The Author(s).)

The bacterial wilt pathogen Ralstonia pseudosolanacearum (Rps) colonizes plant xylem vessels and blocks the flow of xylem sap by its biofilm (comprising of bacterial cells and extracellular material), resulting in devastating wilt disease across many economically important host plants including tomatoes. The technical challenges of imaging the xylem environment, along with the use of artificial cell culture plates and media in existing in vitro systems, limit the understanding of Rps biofilm formation and its infection dynamics. In this study, we designed and built a microfluidic system that mimicked the physical and chemical conditions of the tomato xylem vessels, and allowed us to dissect Rps responses to different xylem-like conditions. The system, incorporating functional surface coatings of carboxymethyl cellulose-dopamine, provided a bioactive environment that significantly enhanced Rps attachment and biofilm formation in the presence of tomato xylem sap. Using computational approaches, we confirmed that Rps experienced linear increasing drag forces in xylem-mimicking channels at higher flow rates. Consistently, attachment and biofilm assays conducted in our microfluidic system revealed that both seeding time and flow rates were critical for bacterial adhesion to surface and biofilm formation inside the channels. These findings provided insights into the Rps attachment and biofilm formation processes, contributing to a better understanding of plant-pathogen interactions during wilt disease development., Competing Interests: The 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., (Copyright © 2024 Chu, Laxman, Abdelhamed, Pirlo, Fan, Wagner, Tran and Bui.)

Background: Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging., Methods: To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3760 patients spanning 24 disease entities. Taking advantage of our dataset size, we focused on discovering rare regulatory aberrations. Therefore, we called expression and splicing outliers using an extension of the workflow DROP (Detection of RNA Outliers Pipeline) and AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained a machine learning model integrating these results to prioritize new candidate disease-specific driver genes., Results: We found a median of seven expression outlier genes, two splicing outlier genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for already well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. On held-out data, our integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Remarkably, we found a truncated form of the low density lipoprotein receptor LRP1B transcript to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggests LRP1B as a novel marker for a HCL-V subclass and a yet unreported functional role of LRP1B within these rare entities., Conclusions: Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers., (© 2024. The Author(s).)

Human erythropoietin (hEPO) is one of the most in-demand biopharmaceuticals, however, its production is challenging. When produced in a plant expression system, hEPO results in extensive plant tissue damage and low expression. It is demonstrated that the modulation of the plant protein synthesis machinery enhances hEPO production. Co-expression of basic leucine zipper transcription factors with hEPO prevents plant tissue damage, boosts expression, and increases hEPO solubility. bZIP28 co-expression up-regulates genes associated with the unfolded protein response, indicating that the plant tissue damage caused by hEPO expression is due to the native protein folding machinery being overwhelmed and that this can be overcome by co-expressing bZIP28., (© 2024 Wiley‐VCH GmbH.)

Background: Aluminum (Al) adjuvants have been used in vaccines and subcutaneous immunotherapy (SCIT) for decades. Despite indisputable neurotoxic properties of Al, there is no clear evidence of a causal relationship between their use and any neurotoxic side effects. However, recent rat studies have shown an accumulation of Al from adjuvants in tissues, especially in bones., Objectives: Since the human toxicokinetics of Al-adjuvants are poorly understood, this study aimed to evaluate whether up-dosed or long-term SCIT with Al-coupled extracts leads to increased Al load in humans., Methods: This observational cross-sectional case-control study explored Al excretion in hymenoptera venom allergy patients recruited in 2020 before initiation (n = 10) and during ongoing (n = 12) SCIT with Al-based preparations. Urine samples were collected before and 24 h after the SCIT injections and analyzed for aluminum content by using atomic absorption spectrometry. The cumulative administered Al dose was extracted from patient records. Patients receiving long-term immunotherapy were treated between 2.8 and 13.6 years (mean 7.1). Other potential sources of Al exposure were surveyed., Results: Patients who had received Al-coupled immunotherapy for several years showed significantly (p < 0.001) higher Al excretion than the controls at initiation of immunotherapy (mean 18.2 μg/gC vs. 7.9 μg/gC) and predominantly (73%) were above the 95th percentile of the general populations' exposure (>15 μg/gC), however, without reaching levels of toxicological concern (>50 μg/gC). Taking both groups together excreted Al levels correlated with the cumulative administered Al dose from SCIT (linear regression: Al urine  = 8.258 + 0.133*Al cum ; p = 0.001)., Discussion: These results suggest a relevant iatrogenic contribution of long-term SCIT to human internal Al burden and potential accumulation. Considering the medical benefits of Al-adjuvants and SCIT a differentiated risk-benefit analysis is needed. For certain scenarios of potential toxicological concern in clinical practice biomonitoring might be advisable., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Nicola Wagner reports a relationship with ALK-Abelló, Novartis Pharma GmbH, Allergopharma GmbH & Co KG, Sanofi-Aventis Deutschland GmbH, Shire/Takeda, Blueprint, AbbVie Deutschland GmbH & Co KG and with Biocryst that includes: consulting or advisory, funding grants, and speaking and lecture fees., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Competing Interests: The authors declare that they do not have any conflicts of interest.

The genus Xanthomonas has been primarily studied for pathogenic interactions with plants. However, besides host and tissue-specific pathogenic strains, this genus also comprises nonpathogenic strains isolated from a broad range of hosts, sometimes in association with pathogenic strains, and other environments, including rainwater. Based on their incapacity or limited capacity to cause symptoms on the host of isolation, nonpathogenic xanthomonads can be further characterized as commensal and weakly pathogenic. This study aimed to understand the diversity and evolution of nonpathogenic xanthomonads compared to their pathogenic counterparts based on their cooccurrence and phylogenetic relationship and to identify genomic traits that form the basis of a life history framework that groups xanthomonads by ecological strategies. We sequenced genomes of 83 strains spanning the genus phylogeny and identified eight novel species, indicating unexplored diversity. While some nonpathogenic species have experienced a recent loss of a type III secretion system, specifically the hrp2 cluster, we observed an apparent lack of association of the hrp2 cluster with lifestyles of diverse species. We performed association analysis on a large data set of 337 Xanthomonas strains to explain how xanthomonads may have established association with the plants across the continuum of lifestyles from commensals to weak pathogens to pathogens. Presence of distinct transcriptional regulators, distinct nutrient utilization and assimilation genes, transcriptional regulators, and chemotaxis genes may explain lifestyle-specific adaptations of xanthomonads., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies 1-9 . Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival 10,11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor β-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity 12 , making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells 13,14 . Here we demonstrate that CAR T cells are lost due to killing by the patient's normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody-drug conjugate that could kill TRBC1 + cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Various mechanisms contributing to the activity of chronic spontaneous urticaria (CU) have been postulated. Associated comorbidities are increasingly leading to the discovery of further signaling pathways which may support the activity of chronic urticaria or contribute to low-grade systemic inflammation. Moreover psychoimmunological factors may also be involved. The aim of this work is to improve the clinical care of patients with CU by increasing knowledge regarding optional influencing factors due to comorbidities and to possibly influence disease activity. Chronic urticaria due to autoimmune mechanisms may dispose to other autoimmune diseases, especially autoimmune thyroiditis, which can trigger chronic disease. Association of CU with metabolic syndrome has received little attention to date. Obesity may contribute to low-grade systemic inflammation by cytokine-secreting adipose tissue and hence to mediator-release of mast cells. Furthermore, neuroimmunological pathways, especially increased release of substance P, an activating ligand of Mas-related G protein-coupled receptor X2 (MRGPX2) on mast cells, should be addressed when optimizing therapy., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: The increasing resistance of Enterobacterales to third-generation cephalosporins and carbapenems in sub-Saharan Africa (SSA) is a major public health concern. We did a systematic review and meta-analysis of studies to estimate the carriage prevalence of Enterobacterales not susceptible to third-generation cephalosporins or carbapenems among paediatric populations in SSA., Methods: We performed a systematic literature review and meta-analysis of cross-sectional and cohort studies to estimate the prevalence of childhood (0-18 years old) carriage of extended-spectrum cephalosporin-resistant Enterobacterales (ESCR-E) or carbapenem-resistant Enterobacterales (CRE) in SSA. Medline, EMBASE and the Cochrane Library were searched for studies published from 1 January 2005 to 1 June 2022. Studies with <10 occurrences per bacteria, case reports, and meta-analyses were excluded. Quality and risk of bias were assessed using the Newcastle-Ottawa scale. Meta-analyses of prevalences and odds ratios were calculated using generalised linear mixed-effects models. Heterogeneity was assessed using I 2 statistics. The protocol is available on PROSPERO (CRD42021260157)., Findings: Of 1111 studies examined, 40 met our inclusion criteria, reporting on the carriage prevalence of Enterobacterales in 9408 children. The pooled carriage prevalence of ESCR-E was 32.2% (95% CI: 25.2%-40.2%). Between-study heterogeneity was high (I 2  = 96%). The main sources of bias pertained to participant selection and the heterogeneity of the microbiological specimens. Carriage proportions were higher among sick children than healthy ones (35.7% vs 16.9%). The pooled proportion of nosocomial acquisition was 53.8% (95% CI: 32.1%-74.1%) among the 922 children without ESCR-E carriage at hospital admission. The pooled odds ratio of ESCR-E carriage after antibiotic treatment within the previous 3 months was 3.20 (95% CI: 2.10-4.88). The proportion of pooled carbapenem-resistant for Enterobacterales was 3.6% (95% CI: 0.7%-16.4%)., Interpretation: This study suggests that ESCR-E carriage among children in SSA is frequent. Microbiology capacity and infection control must be scaled-up to reduce the spread of those multidrug-resistant microorganisms., Funding: There was no funding source for this study., Competing Interests: We declare no competing interests., (© 2024 The Authors.)

Background: The burden of antimicrobial resistance (AMR) has been estimated to be the highest in sub-Saharan Africa (SSA). The current study estimated the proportion of drug-resistant Enterobacterales causing infections in SSA children., Methods: We searched MEDLINE/PubMed, Embase and the Cochrane Library to identify retrospective and prospective studies published from 01/01/2005 to 01/06/2022 reporting AMR of Enterobacterales causing infections in sub-Saharan children (0-18 years old). Studies were excluded if they had unclear documentation of antimicrobial susceptibility testing methods or fewer than ten observations per bacteria. Data extraction and quality appraisal were conducted by two authors independently. The primary outcome was the proportion of Enterobacterales resistant to antibiotics commonly used in paediatrics. Proportions were combined across studies using mixed-effects logistic regression models per bacteria and per antibiotic. Between-study heterogeneity was assessed using the I 2 statistic. The protocol was registered with PROSPERO (CRD42021260157)., Findings: After screening 1111 records, 122 relevant studies were included, providing data on more than 30,000 blood, urine and stool isolates. Escherichia coli and Klebsiella spp. were the predominant species, both presenting high proportions of resistance to third-generation cephalosporins, especially in blood cultures: 40.6% (95% CI: 27.7%-55%; I 2 : 85.7%, number of isolates (n): 1032) and 84.9% (72.8%-92.2%; I 2 : 94.1%, n: 2067), respectively. High proportions of resistance to other commonly used antibiotics were also observed. E. coli had high proportions of resistance, especially for ampicillin (92.5%; 95% CI: 76.4%-97.9%; I 2 : 89.8%, n: 888) and gentamicin (42.7%; 95% CI: 30%-56.5%; I 2 : 71.9%, n: 968). Gentamicin-resistant Klebsiella spp. were also frequently reported (77.6%; 95% CI: 65.5%-86.3%; I 2 : 91.6%, n: 1886)., Interpretation: High proportions of resistance to antibiotics commonly used for empirical treatment of infectious syndromes were found for Enterobacterales in sub-Saharan children. There is a critical need to better identify local patterns of AMR to inform and update clinical guidelines for better treatment outcomes., Funding: No funding was received., Competing Interests: We declare no competing interests., (© 2024 The Authors.)

Program evaluation is an essential, but often neglected, activity in any transformational educational change. Competence by Design was a large-scale change initiative to implement a competency-based time-variable educational system in Canadian postgraduate medical education. A program evaluation strategy was an integral part of the build and implementation plan for CBD from the beginning, providing insights into implementation progress, challenges, unexpected outcomes, and impact. The Competence by Design program evaluation strategy was built upon a logic model and three pillars of evaluation: readiness to implement, fidelity and integrity of implementation, and outcomes of implementation. The program evaluation strategy harvested from both internally driven studies and those performed by partners and invested others. A dashboard for the program evaluation strategy was created to transparently display a real-time view of Competence by Design implementation and facilitate continuous adaptation and improvement. The findings of the program evaluation for Competence by Design drove changes to all aspects of the Competence by Design implementation, aided engagement of partners, supported change management, and deepened our understanding of the journey required for transformational educational change in a complex national postgraduate medical education system. The program evaluation strategy for Competence by Design provides a framework for program evaluation for any large-scale change in health professions education., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

The immune and fibrotic responses have evolved to work in tandem to respond to pathogen clearance and promote tissue repair. However, excessive immune and fibrotic responses lead to chronic inflammation and fibrosis, respectively, both of which are key pathological drivers of organ pathophysiology. Fibroblasts and immune cells are central to these responses, and evidence of these two cell types communicating through soluble mediators or adopting functions from each other through direct contact is constantly emerging. Here, we review complex junctions of fibroblast-immune cell cross talk, such as immune cell modulation of fibroblast physiology and fibroblast acquisition of immune cell-like functions, as well as how these systems of communication contribute to organ pathophysiology. We review the concept of antigen presentation by fibroblasts among different organs with different regenerative capacities, and then focus on the inflammation-fibrosis axis in the heart in the complex syndrome of heart failure. We discuss the need to develop anti-inflammatory and antifibrotic therapies, so far unsuccessful to date, that target novel mechanisms that sit at the crossroads of the fibrotic and immune responses.

Targeted delivery and cell-type-specific expression of gene-editing proteins in various cell types in vivo represent major challenges for all viral and non-viral delivery platforms developed to date. Here, we describe the development and analysis of artificial vectors for intravascular delivery (AVIDs), an engineered adenovirus-based gene delivery platform that allows for highly targeted, safe, and efficient gene delivery to human hematopoietic stem and progenitor cells (HSPCs) in vivo after intravenous vector administration. Due to a set of refined structural modifications, intravenous administration of AVIDs did not trigger cytokine storm, hepatotoxicity, or thrombocytopenia. Single intravenous administration of AVIDs to humanized mice, grafted with human CD34 + cells, led to up to 20% transduction of CD34 + CD38 - CD45RA - HSPC subsets in the bone marrow. Importantly, targeted in vivo transduction of CD34 + CD38 - CD45RA - CD90 - CD49f + subsets, highly enriched for human hematopoietic stem cells (HSCs), reached up to 19%, which represented a 1,900-fold selectivity in gene delivery to HSC-enriched over lineage-committed CD34-negative cell populations. Because the AVID platform allows for regulated, cell-type-specific expression of gene-editing technologies as well as expression of immunomodulatory proteins to ensure persistence of corrected HSCs in vivo, the HSC-targeted AVID platform may enable development of curative therapies through in vivo gene correction in human HSCs after a single intravenous administration., Competing Interests: Declaration of interests The AVID vector platform was co-developed by Emory University and AdCure Bio and described in the provisional patent application 63/497,106, which was licensed to AdCure Bio. D.M.S. and N.C.D.P. are listed as co-inventors on provisional patent application 63/497,106 and issued US patents #10,376,549 and #9,982,276 and European patent #3247807. D.M.S. and N.C.D.P. are co-founders and shareholders of AdCure Bio, which develops adenovirus technologies for therapeutic use., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)