Phase I Study of Intravitreal Injection of Autologous CD34+ Stem Cells from Bone Marrow in Eyes with Vision Loss from Retinitis Pigmentosa.

Purpose: To evaluate the feasibility and safety of intravitreal injection of autologous CD34+ stem cells from bone marrow (BMSCs) in eyes with vision loss from retinitis pigmentosa (RP). Design: Phase I prospective, open-label, single-center study. Participants: Seven eyes (7 patients) with RP with best-corrected visual acuity (BCVA) of 20/60 to 20/400 or visual field constriction to within 10°. Methods: A comprehensive examination with ETDRS BCVA, macular OCT, perimetry, and fluorescein angiography was performed at baseline, 1 to 3 months, and 6 months after study treatment. Bone marrow aspiration, isolation of CD34+ BMSCs under good manufacturing practice conditions, and intravitreal cell injection were performed on the same day. The CD34+ cells were isolated from bone marrow using a Ficoll gradient and the Miltenyi CliniMACS system. Isolated CD34+ cells were released for clinical use if viability, sterility, and purity met the release criteria accepted by the United States Food and Drug Administration for this clinical study. Main Outcome Measures: Number of CD34+ cells isolated for injection and adverse events associated with study treatment during follow-up. Secondary outcome measures are changes in BCVA and perimetry. Results: All isolated CD34+ cells passed the release criteria. A mean of 3.26 ± 0.66 million viable CD34+ cells (range 1.6 to 7.05 million) were injected intravitreally per eye. No adverse event was noted during the study follow-up except for 1 participant who was noted with transient cells in the anterior chamber with mild elevation in intraocular pressure at 18 hours after study injection which normalized by 24 hours. Best-corrected visual acuity remained within 2 lines of baseline or improved in all participants at 6 months follow-up. Perimetry was stable or improved in all eyes during study follow-up except 1 eye with transient improvement at 1 month and worsening of both eyes at 6 months. Conclusions: Intravitreal injection of autologous CD34+ BMSCs is feasible and appears to be well tolerated in eyes with vision loss from RP. A larger randomized prospective study would be needed to evaluate further the safety and potential efficacy of this cell therapy for vision loss associated with RP. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Circulating microRNAs and isomiRs as biomarkers for the initial insult and epileptogenesis in four experimental epilepsy models: The EPITARGET study.

OBJECTIVE: Structural epilepsies can manifest months or years after the occurrence of an initial epileptogenic insult, making them amenable for secondary prevention. However, development of preventive treatments has been challenged by a lack of biomarkers for identifying the subset of individuals with the highest risk of epilepsy after the epileptogenic insult. METHODS: Four different rat models of epileptogenesis were investigated to identify differentially expressed circulating microRNA (miRNA) and isomiR profiles as biomarkers for epileptogenesis. Plasma samples were collected on day 2 and day 9 during the latency period from animals that did or did not develop epilepsy during long-term video-electroencephalographic monitoring. miRNAs and isomiRs were identified and measured in an unsupervised manner, using a genome-wide small RNA sequencing platform. Receiver operating characteristic analysis was performed to determine the performance of putative biomarkers. RESULTS: Two days after an epileptogenic insult, alterations in the levels of several plasma miRNAs and isomiRs predicted epileptogenesis in a model-specific manner. One miRNA, miR-3085, showed good sensitivity (but low specificity) as a prognostic biomarker for epileptogenesis in all four models (area under the curve = .729, sensitivity = 83%, specificity = 64%, p < .05). SIGNIFICANCE: Identified plasma miRNAs and isomiRs are mostly etiology-specific rather than common prognostic biomarkers of epileptogenesis. These data imply that in preclinical and clinical studies, it may be necessary to identify specific biomarkers for different epilepsy etiologies. Importantly, circulating miRNAs like miR-3085 with high negative predictive value for epileptogenesis in different etiologies could be useful candidates for initial screening purposes of epileptogenesis risk.

Long-term Outcome of the Dutch Common Channel Trial (DUCATI): Preservation of Superior Weight Loss Results Without Significant Malnutrition Side Effects.

PURPOSE: The optimal bowel limb lengths for laparoscopic Roux-en-Y gastric bypass (LRYGB) to maximize weight loss while minimizing nutritional deficiencies in severe obesity treatment remain a topic of debate. The multi-center Dutch Common Channel Trial (DUCATI) aims to compare the outcomes of a very long Roux Limb Roux-en-Y gastric bypass (VLRL-LRYGB) with a standard Roux-en-Y gastric bypass (S-LRYGB). METHODS: A total of 444 patients were randomly assigned in a 1:1, double-blind manner to undergo either VLRL-RYGB or S-LRYGB. Five-year follow-up data were assessed, concentrating on weight loss, obesity-related medical conditions, complications, re-operations, and malnutrition. RESULTS: Both groups had comparable total alimentary lengths (RL + CC). The VLRL-LRYGB group demonstrated significantly greater %TWL (32.2% vs. 28.6%, p = 0.002) and %EWL (81.2% vs. 70.3%, p = 0.002) at 5 years. Eight (3.6%) patients in the VLRL-LRYGB group versus 2 (0.9%) in the S-LRYGB group (p = 0.055) needed modification surgery for malabsorption. Suboptimal clinical response rate was significantly higher (22.0% vs. 8.3%) in S-LRYGB group. No significant differences for nutrient deficiencies in favor of the S-LRYGB group were found. CONCLUSION: A 100-cm common channel with a relatively long Roux limb provides superior, sustainable weight loss over 5 years, without significantly increased rate of malabsorption-related re-operations. These results suggest that a longer Roux limb can still ensure adequate micronutrient uptake in the total alimentary tract. These findings should be considered in discussions regarding the optimal Roux-en-Y limb length for severe obesity treatment.

Immunotherapy response and resistance in patients with advanced uveal melanoma: a retrospective cohort study.

Metastatic uveal melanoma (mUM) is associated with poor prognosis. Ipilimumab/nivolumab has shown antitumor efficacy in phase II studies. Tebentafusp resulted in longer overall survival (OS) compared to investigator`s choice in a phase III study. We sought to describe the radiological response patterns of mUM patients treated with immunotherapy. Patients with mUM treated with ipilimumab/nivolumab and tebentafusp between July 2018 and December 2022, with available radiological assessment per RECISTv1.1 and/or imPERCIST5, were retrospectively identified and included. Progression-free survival (PFS) and OS rates, liver-specific response and pathological assessment in available liver biopsies were evaluated. In the ipilimumab/nivolumab group, median PFS (mPFS) was 2.9 months (95% CI 2.2-28.6) and mOS 28.9 months (95% CI 12.7-NR). Complete (CMR) and partial (PMR) metabolic response per imPERCIST5, and partial response (PR) per RECISTv1.1 were associated with longer PFS and OS by trend, compared to morphologically and metabolically stable or progressive disease. In the tebentafusp group, mPFS was 2.7 months (95% CI 2.2-3) and mOS 18.6 months (95% CI 11.5-NR). PMR and PR were associated with longer PFS by trend. In both treatments, the overall treatment response was associated with the radiological response at the liver site. In available liver tumor biopsies, differences in pathological and radiological responses were noted. ImPERCIST5 and RECIST v1.1 are valuable tools in the radiological response assessment, but both methods display limitations. Accurate biomarkers to stratify patients at risk for disease progression and future translational studies to investigate mechanisms of response and resistance are required.

Gas gangrene with Clostridium septicum in a neutropenic patient.

Gas gangrene is a rare presentation of a necrotizing fasciitis, caused by Clostridium perfringens, C. septicum and other clostridial species. With its rapid progression it is a potentially life-threatening infection, that poses as a challenge in the clinical management requiring an interdisciplinary approach.Here we present a 62-year-old woman, who developed neutropenic fever while undergoing chemotherapy for triple negative breast cancer. She presented with a high fever, reporting little pain in her left thigh accompanied by redness and induration locally. Subsequently the patient developed pain and redness of the back of the left hand. The initial findings suggested cellulitis and immediate empiric treatment with intravenous meropenem was started. Despite the antibiotic treatment the patient rapidly developed septic shock along with progression of the local infection. Emergency surgical debridement revealed extensive necrosis of the soft tissues including extensive myonecrosis of the thigh. On the left hand an extensive debridement was performed, the left lower limb could not be preserved and exarticulation of the left hip was required. Microbiologically C. septicum was isolated in different samples, confirming gas gangrene. As there was no local entry portal on the skin, hematogenous seeding from intestinal translocation in this neutropenic patient was suspected. The empiric antibiotic treatment was tailored to intravenous penicillin and complemented with clindamycin for toxin inhibition. Following radical debridement and antibiotic treatment, the patient could be stabilized. After repetitive debridement wound closure was achieved and the patient was discharged for rehabilitation. Antibiotic treatment was continued for four weeks.This rare case of gas gangrene in a neutropenic patient shows the complexity in the diagnostic and therapeutic management of necrotizing soft tissue infections in immunocompromised patients. It particularly highlights the importance of an interdisciplinary management with fast recognition of the disease and rapid, if needed radical, surgical debridement as well as tailored antibiotic treatment for a successful outcome.

Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

ABSTRACT: The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide Therapeutic Drug Monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.

Mycologists and Virologists Align: Proposing Botrytis cinerea for Global Mycovirus Studies.

Mycoviruses are highly genetically diverse and can significantly change their fungal host's phenotype, yet they are generally under-described in genotypic and biological studies. We propose Botrytis cinerea as a model mycovirus system in which to develop a deeper understanding of mycovirus epidemiology including diversity, impact, and the associated cellular biology of the host and virus interaction. Over 100 mycoviruses have been described in this fungal host. B. cinerea is an ideal model fungus for mycovirology as it has highly tractable characteristics-it is easy to culture, has a worldwide distribution, infects a wide range of host plants, can be transformed and gene-edited, and has an existing depth of biological resources including annotated genomes, transcriptomes, and isolates with gene knockouts. Focusing on a model system for mycoviruses will enable the research community to address deep research questions that cannot be answered in a non-systematic manner. Since B. cinerea is a major plant pathogen, new insights may have immediate utility as well as creating new knowledge that complements and extends the knowledge of mycovirus interactions in other fungi, alone or with their respective plant hosts. In this review, we set out some of the critical steps required to develop B. cinerea as a model mycovirus system and how this may be used in the future.

Molecular imaging supports the development of multispecific cancer antibodies.

Multispecific antibodies are engineered antibody derivatives that can bind to two or more distinct epitopes or antigens. Unlike mixtures of monospecific antibodies, the binding properties of multispecific antibodies enable two specific molecules to be physically linked, a characteristic with important applications in cancer therapy. The field of multispecific antibodies is highly dynamic and expanding rapidly; to date, 15 multispecific antibodies have been approved for clinical use, of which 11 were approved for oncological indications, and more than 100 new antibodies are currently in clinical development. Nevertheless, substantial challenges limit the applications of multispecific antibodies in cancer therapy, particularly inefficient targeting of solid tumours and substantial adverse effects. Both PET and single photon emission CT imaging can reveal the biodistribution and complex pharmacology of radiolabelled multispecific antibodies. This Review summarizes the insights obtained from preclinical and clinical molecular imaging studies of multispecific antibodies, focusing on their structural properties, such as molecular weight, shape, target specificity, affinity and avidity. The opportunities associated with use of molecular imaging studies to support the clinical development of multispecific antibody therapies are also highlighted.

Air-water interfacial and foaming properties of nanoparticles based on commercial and lab-scale isolated maize (Zea mays L.) zein.

Maize zein based nanoparticles (ZNPs) can have applications as food dispersion stabilizers. It has not been documented to what extent the used zein isolation method and conditions thereof impact the structure and functionality of nanoparticles (NPs) based thereupon. Here, zein extracted from maize flour on lab scale (LS-zein) was compared with a commercial zein powder (CS-zein). On a dry matter basis, CS-zein contained 96.5% protein, while LS-zein contained 74.5% protein, 12.7% lipid, 2.9% ash, and a residual fraction, likely starch remnants. SE-HPLC analysis showed that 27.8% of CS-zein protein occurred in an aggregated and insoluble form, while LS-zein mainly contained mono-/dimeric proteins but also approximately 30% hydrophilic peptides. These differences resulted in notably different behavior in the functionality of ZNPs based on CS- and LS-zein (CS-ZNPs and LS-ZNPs, respectively) produced via liquid antisolvent precipitation. CS-ZNPs had poor foaming properties regardless of the pH, in line with their low interfacial dilatational moduli (12.9-15.0 mN/m). The foaming properties of LS-ZNPs were notably better. The high LS-ZNP foam stability (FS) at pH 8.0 and 10.0 was attributed to electrostatic repulsive effects between interfaces of adjacent air bubbles due to the adsorption of peptides and to synergistic protein-lipid interaction effects at the air-water interface. The LS-ZNP FS at pH 4.0 was low despite a high interfacial dilatational modulus (52.6 mN/m). It is hypothesized that intact LS-ZNPs in the liquid thin films between gas bubbles negatively affect FS by a bridging de-wetting effect. Overall, it can be concluded that the (partial) co-isolation of lipids with zein may positively influence foaming properties of NPs based thereupon, while extensive zein purification as applied in industrial zein isolation leads to (partial) zein aggregation and overall low foaming capacity of the obtained CS-ZNPs.

A hyper-fast gas chromatograph coupled to an ion mobility spectrometer with high repetition rate and flow-optimized ion source to resolve the short chromatographic peaks.

By combining the high selectivity of a gas chromatograph (GC) with the high sensitivity and decent selectivity of an ion mobility spectrometer (IMS), GC-IMS have become increasingly popular in many applications. However, most GC suffer from long analysis times. In contrast, an hyper-fast GC allows for extremely fast analysis in the tens of seconds while reaching comparably high resolution. In turn, coupling such hyper-fast GC with IMS requires sufficiently high repetition rate of recording full IMS spectra to resolve the short GC peaks. Therefore, we present a drift tube IMS with 100 Hz repetition rate. Key is a small effective detector volume combined with short drift length. Therefore, the ion source of the IMS combines a small reaction region with an extended field-switching ion shutter and optimized gas flows. To resolve even the shortest GC peaks with a full width at half maximum of 100 ms, a short drift length of just 41 mm was used, achieving a measurement time of 10 ms per spectrum and hence ten data points across the shortest GC peak. To avoid condensation of the sample, the entire IMS was heated isothermally to 120 °C. Despite short drift times and high temperatures, the IMS still reaches high resolving power of Rp = 60. The hyper-fast GC-IMS reaches low detection limits in the low ppbV range. For demonstration, ketone mixes and three different hop varieties were analyzed in <30 s.

Monitoring postures and motions of hospitalized patients using sensor technology: a scoping review.

BACKGROUND: Sensor technology could provide solutions to monitor postures and motions and to help hospital patients reach their rehabilitation goals with minimal supervision. Synthesized information on device applications and methodology is lacking. OBJECTIVES: The purpose of this scoping review was to provide an overview of device applications and methodological approaches to monitor postures and motions in hospitalized patients using sensor technology. METHODS: A systematic search of Embase, Medline, Web of Science and Google Scholar was completed in February 2023 and updated in March 2024. Included studies described populations of hospitalized adults with short admission periods and interventions that use sensor technology to objectively monitor postures and motions. Study selection was performed by two authors independently of each other. Data extraction and narrative analysis focused on the applications and methodological approaches of included articles using a personalized standard form to extract information on device, measurement and analysis characteristics of included studies and analyse frequencies and usage. RESULTS: A total of 15.032 articles were found and 49 articles met the inclusion criteria. Devices were most often applied in older adults (n = 14), patients awaiting or after surgery (n = 14), and stroke (n = 6). The main goals were gaining insight into patient physical behavioural patterns (n = 19) and investigating physical behaviour in relation to other parameters such as muscle strength or hospital length of stay (n = 18). The studies had heterogeneous study designs and lacked completeness in reporting on device settings, data analysis, and algorithms. Information on device settings, data analysis, and algorithms was poorly reported. CONCLUSIONS: Studies on monitoring postures and motions are heterogeneous in their population, applications and methodological approaches. More uniformity and transparency in methodology and study reporting would improve reproducibility, interpretation and generalization of results. Clear guidelines for reporting and the collection and sharing of raw data would benefit the field by enabling study comparison and reproduction.

In a clinical setting, wearables are currently used to monitor postures and motions in a wide variety of study applications and hospital populations.Measurement of postures and motions in the hospital setting is characterized by methodological heterogeneity. This poses a significant challenge, impacting the interpretation of results and hindering meaningful comparisons between studiesFollowing guidelines for reporting and the collection and sharing of raw data would benefit the field.

Increased serum interferon activity in sarcoidosis compared to that in tuberculosis: Implication for diagnosis?

Objectives: In this study, we measured serum interferon (IFN) levels and activity in patients with sarcoidosis and tuberculosis (TB) with and without uveitis. We aimed to understand the role of IFN in the pathophysiology of both conditions and explore its potential as a discriminating marker for these clinically similar diseases. Methods: Sera from an Indonesian TB and a Dutch sarcoidosis cohort were used in the analysis. IFNα2 and IFNγ concentrations were measured using Simoa® and Luminex assays, respectively. Serum IFN activity was assessed by incubating THP-1 cells with patient serum and measuring IFN-stimulated gene transcription using qPCR. Anti-IFNα2 and IFNγ autoantibodies were detected via Luminex assay and tested for neutralizing capacity using a flow cytometry-based signal transducer and activator of transcription (STAT) 1 phosphorylation inhibition assay. Results: IFNα2 was detected in 74 % and 64 % of patients with sarcoidosis and pulmonary TB, respectively, while IFNγ was found in 78 % and 23 % of patients with sarcoidosis and TB, respectively. For uveitis cases specifically, IFNα2 was detected in 85 % of sarcoid uveitis (SU) and 33 % of tubercular uveitis (TBU) cases. Similarly, IFNγ was detected in 69 % of SU and 17 % of TBU cases. IFNγ serum concentrations were higher in sarcoidosis than that in TB patients (p < 0.0001). Focusing on patients with uveitis, SU showed increased IFNα2 (p = 0.004) and IFNγ (p < 0.002) serum concentrations compared to that in TBU. Notably, TBU displayed significantly reduced IFNα2 concentrations compared to that in healthy controls (p = 0.006). These results align with the increased interferon stimulated gene (ISG) transcriptional upregulation observed in THP-1 cells stimulated with serum from patients with sarcoidosis. Elevated levels of non-neutralizing anti-IFN autoantibodies were observed in patients with TB; however, these levels were similar to those observed in geographically matched healthy Indonesian controls. Conclusion: Our results suggest decreased serum levels and activity of type I and II IFN in TB compared to those in sarcoidosis. This is indicative of distinct pathophysiological processes in these highly clinically similar diseases. We propose that the assessment of serum IFN levels and IFN activity has the potential to distinguish between sarcoidosis/SU and TB/TBU.

ICON 2023: International Scientific Tendinopathy Symposium Consensus - the core outcome set for Achilles tendinopathy (COS-AT) using a systematic review and a Delphi study of professional participants and patients.

To develop a core outcome set for Achilles tendinopathy (COS-AT) for use in clinical trials we performed a five-step process including (1) a systematic review of available outcome measurement instruments, (2) an online survey on truth and feasibility of the available measurement instruments, (3) an assessment of the methodological quality of the selected outcome measurement instruments, (4) an online survey on the outcome measurement instruments as COS and (5) a consensus in-person meeting. Both surveys were completed by healthcare professionals and patients. The Outcome Measures in Rheumatology guidelines with a 70% threshold for consensus were followed. We identified 233 different outcome measurement instruments from 307 included studies; 177 were mapped within the International Scientific Tendinopathy Symposium Consensus core domains. 31 participants (12 patients) completed the first online survey (response rate 94%). 22/177 (12%) outcome measurement instruments were deemed truthful and feasible and their measurement properties were evaluated. 29 participants (12 patients) completed the second online survey (response rate 88%) and three outcome measurement instruments were endorsed: the Victorian Institute of Sports Assessment-Achilles questionnaire, the single-leg heel rise test and evaluating pain after activity using a Visual Analogue Scale (VAS, 0-10). 12 participants (1 patient) attended the final consensus meeting, and 1 additional outcome measurement instrument was endorsed: evaluating pain during activity/loading using a VAS (0-10). It is recommended that the identified COS-AT will be used in future clinical trials evaluating the effectiveness of an intervention. This will facilitate comparing outcomes of intervention strategies, data pooling and further progression of knowledge about AT. As COS-AT is implemented, further evidence on measurement properties of included measures and new outcome measurement instruments should lead to its review and refinement.

Effects of spironolactone on exercise blood pressure in patients at increased risk of developing heart failure: report from the HOMAGE trial.

None of the spironolactone trials in heart failure (HF) assessed the blood pressure (BP) responses to exercise, while conflicting results were reported for exercise capacity. In the HOMAGE trial, 527 patients at increased HF risk were randomized to usual treatment with or without spironolactone (25-50 mg/day). The current substudy included 113 controls and 114 patients assigned spironolactone, who all completed the incremental shuttle walk test at baseline and months 1 and 9. Quality of life (QoL) was assessed by EQ5D questionnaire. Between-group differences (spironolactone minus control [Δs]) were analyzed by repeated measures ANOVA with adjustment for baseline and, if appropriate, additionally for sex, age and body mass index. Δs in the pre-exercise systolic/diastolic BP were -8.00 mm Hg (95% CI, -11.6 to -4.43)/-0.85 mm Hg (-2.96 to 1.26) at month 1 and -9.58 mm Hg (-14.0 to -5.19)/-3.84 mm Hg (-6.22 to -1.47) at month 9. Δs in the post-exercise systolic/diastolic BP were -8.08 mm Hg (-14.2 to -2.01)/-2.07 mm Hg (-5.79 to 1.65) and -13.3 mm Hg (-19.9 to -6.75)/-4.62 mm Hg (-8.07 to -1.17), respectively. For completed shuttles, Δs at months 1 and 9 were 2.15 (-0.10 to 4.40) and 2.49 (-0.79 to 5.67), respectively. Δs in QoL were not significant. The correlations between the exercise-induced BP increases and the number of completed shuttles were similar in both groups. In conclusion, in patients at increased risk of developing HF, spironolactone reduced the pre- and post-exercise BP, but did not improve exercise capacity or QoL.

Disproportionality Analysis and Characterisation of Medication Errors in EudraVigilance: Exploring Findings on Sexes and Age Groups.

BACKGROUND: While medication errors (MEs) have been studied in the European Medicines Agency's EudraVigilance, extensive characterisation and signal detection based on sexes and age groups have not been attempted. OBJECTIVES: The aim of this study was to characterise all ME-related individual case safety reports in EudraVigilance and explore notable signals of disproportionate reporting (SDRs) among sexes and age groups for the 30 most frequently reported drugs. METHODS: Individual case safety reports were used from EudraVigilance reported between 2002 and 2021. An ME was defined as any Preferred Term from the narrow Standardised Medical Dictionary for Regulatory Activities® Query. Signals of disproportionate reporting were selected based on a lower boundary of the 95% confidence interval ≥ 1 of the reporting odds ratio, and at least 3 individual case safety reports. Analysed subgroups were female individuals, male individuals, and age groups 0-1 month, 2 months to 2 years, 3-11 years, 12-17 years, 18-64 years, 65-85 years, and >85 years. Heatmaps were utilised as a visual aid to identify striking SDRs. RESULTS: Of the 9,662,345 EudraVigilance reports, 267,262 (2.8%) contained at least one ME, with a total of 300,324 MEs, for 429,554 drugs. The most reported ME was "Inappropriate schedule of product administration" (52,646; 17.5%), followed by "Incorrect dose administered" (32,379; 10.8%) and "Wrong technique in product usage process" (26,831; 8.9%). Individual case safety reports with MEs were most frequently related to female individuals (148,009; 55.4%), most often submitted by healthcare professionals (155,711; 58.3%), originated predominantly from the USA (98,716; 36.9%), followed by France (26,678; 10.0%), and showed a median reported age of 50 years (interquartile range: 26-68). Most ME individual case safety reports (158,991; 59.5%) were associated with a serious health outcome. A total of 847 SDRs were identified, based on the entire EudraVigilance database; for subgroups, the number of SDRs ranged from 84 for the age group 0-1 month to 749 for female individuals. Signals of disproportionate reporting for female individuals and male individuals were very similar. Most MEs were reported for the vaccine against human papillomavirus (Anatomical Therapeutic Chemical [ATC]: J07BM01; 11,086 MEs, 57% being "inappropriate schedule of product administration"), with reporting odds ratios that range from 1.5 to 47.0 among age groups. The SDR for the live-attenuated vaccine against herpes zoster (ATC: J07BK02) had a reporting odds ratio that ranged from 26.6 to 78.1 among all subgroups. Signals of disproportionate reporting for oxycodone (ATC: N02AA05; 847 cases of "Accidental overdose", 35%), risperidone (ATC: N05AX08; 469 cases "Inappropriate schedule of product administration", 22.3%) and rivaroxaban (ATC: B01AF01; 1,377 cases of "Incorrect dose administered", 34.6%) stood out with higher magnitude SDRs for the age group 2 months to 2 years, with an reporting odds ratio range between 8.2 and 10.7, while for the entire EudraVigilance the reporting odds ratio ranged between 1.3 and 1.6 for the same drugs. CONCLUSIONS: This exploratory research provides an overview of characterised ME individual case safety reports and SDRs from the EudraVigilance database. Most conspicuous SDRs were identified in specific age groups. Signals of disproportionate reporting, not described in the literature, were found for vaccines, oxycodone, rivaroxaban and risperidone, and may prompt further examination by stakeholders. Top-reported MEs ("Inappropriate schedule of product administration", "Incorrect dose administered" and "Wrong technique in product usage process") emerged as a general priority focus to perform a further root-cause analysis involving healthcare providers, manufacturers and regulatory bodies, to improve the understanding and prevention of MEs.

Arteriosclerotic Calcification and Atrial Fibrillation in the General Population: The Rotterdam Study.

Limited population-based data on the gender differences and association between arteriosclerotic calcification at different sites and atrial fibrillation (AF) exist. We aimed to investigate the (gender-specific) associations between arteriosclerotic calcification at different sites with the risk of AF in the general population. Arteriosclerotic calcification was quantified using computed tomography examinations between 2003 and 2006 in 2,259 participants free of AF from the population-based Rotterdam Study. Cox proportional hazards models, adjusted for cardiovascular risk factors, were used to assess the associations of volumes of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial and intracranial carotid arteries, vertebrobasilar arteries, and the aortic valve with incident AF. During a median follow-up of 8.6 years, 182 incident AF cases occurred. A larger CAC was associated with incident AF (hazard ratio [HR], 95% confidence interval [CI] 1.25 1.09 to 1.44, p = 0.0019). The gender-stratified analyses showed that larger CAC in men (HR 1.43, 95% CI 1.10 to 1.86, p = 0.0068) and larger AAC in women were associated with incident AF (HR1.44, 95% CI 1.04 to 2.01, p = 0.0299). In conclusion, CAC in the general population, especially in men, and AAC in women were significantly associated with new-onset AF. Our findings imply that interventions to lower arteriosclerotic calcification, particularly, CAC, carry potential for the prevention of AF in the general population, especially in men.

Evaluation of cell death-inducing activity of Monilinia spp. effectors in several plants using a modified TRV expression system.

Introduction: Brown rot is the most important fungal disease affecting stone fruit and it is mainly caused by Monilinia fructicola, M. laxa and M. fructigena. Monilinia spp. are necrotrophic plant pathogens with the ability to induce plant cell death by the secretion of different phytotoxic molecules, including proteins or metabolites that are collectively referred to as necrotrophic effectors (NEs). Methods: We exploited the genomes of M. fructicola, M. laxa and M. fructigena to identify their common group of secreted effector proteins and tested the ability of a selected set of effectors to induce cell death in Nicotiana benthamiana, Solanum lycopersicum and Prunus spp. leaves. Results: Fourteen candidate effector genes of M. fructicola, which displayed high expression during infection, were transiently expressed in plants by agroinfiltration using a modified Tobacco Rattle Virus (TRV)-based expression system. Some, but not all, effectors triggered leaf discoloration or cell death in N. benthamiana and S. lycopersicum, which are non-hosts for Monilinia and in Prunus spp., which are the natural hosts. The effector MFRU_030g00190 induced cell death in almost all Prunus genotypes tested, but not in the Solanaceous plants, while MFRU_014g02060, which is an ortholog to BcNep1, caused necrosis in all plant species tested. Conclusion: This method provides opportunities for screening Prunus germplasm with Monilinia effector proteins, to serve as a tool for identifying genetic loci that confer susceptibility to brown rot disease.

Microbiome signature suggestive of lactose-intolerance in rhesus macaques (Macaca mulatta) with intermittent chronic diarrhea.

BACKGROUND: Chronic diarrhea is a common cause of mortality and morbidity in captive rhesus macaques (Macaca mulatta). The exact etiology of chronic diarrhea in macaques remains unidentified. The occurrence of diarrhea is frequently linked to dysbiosis within the gut microbiome. Research into microbiome signatures correlated with diarrhea in macaques have predominantly been conducted with single sample collections. Our analysis was based on the metagenomic composition of longitudinally acquired fecal samples from rhesus macaques with chronic diarrhea and clinically healthy rhesus macaques that were obtained over the course of two years. We aimed to investigate potential relationships between the macaque gut microbiome, the presence of diarrhea and diet interventions with a selection of commercially available monkey diets. RESULTS: The microbiome signature of macaques with intermittent chronic diarrhea showed a significant increase in lactate producing bacteria e.g. lactobacilli, and an increase in fermenters of lactate and succinate. Strikingly, two lactose free diets were associated with a lower incidence of diarrhea. CONCLUSION: A lactose intolerance mechanism is suggested in these animals by the bloom of Lactobacillus in the presence of lactose resulting in an overproduction of intermediate fermentation products likely led to osmotically induced diarrhea. This study provides new insights into suspected microbiome-lactose intolerance relationship in rhesus macaques with intermittent chronic diarrhea. The integration of machine learning with metagenomic data analysis holds potential for developing targeted dietary interventions and therapeutic strategies and therefore ensuring a healthier and more resilient primate population.

Facts and hopes for PET imaging-derived immunotherapy biomarkers.

Current immunotherapies have brought major progress in cancer treatments, but not all patients benefit. Therefore, insight into reasons for treatment failure and optimal biomarkers for patient selection are warranted. Current approved biomarkers for cancer immunotherapy do not provide insight into characteristics across tumor lesions in a patient or their heterogeneity. Here, whole-body positron emission tomography (PET) imaging with specific tracers may provide support. Moreover, the biodistribution of cell therapies and complex molecules, such as bispecific antibodies, can be visualized by PET imaging, and repeat PET imaging allows to study the whole-body kinetics of the immune response. In this review, we present the status of using PET imaging-derived biomarkers for patients with cancer receiving immunotherapy. Next, the hopes and scientific challenges ahead to optimize current PET imaging biomarker development and to discover novel PET-derived baseline and dynamic biomarkers to potentially guide us in drug development and more precise patient and therapy selection will be discussed.