A document by Peter Bager. Click on the document to view its contents.

Aims: This study aimed to investigate exposure-response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first-in-class antibody-drug conjugate approved for the treatment of folate receptor-α positive platinum-resistant ovarian cancer. Methods: MIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analyzed in MIRV-treated patients (N=215) in a recent confirmatory, randomized, chemotherapy-controlled MIRASOL trial, and safety was evaluated in patients pooled across all 4 clinical studies (N=757). Results: In the MIRASOL trial, MIRV demonstrated significant benefit over chemotherapy in progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy, and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration-time curve (AUC) was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC were used to justify the clinical dose regimen approved for MIRV. Conclusions: The trough concentration of MIRV correlated with efficacy whereas the AUC was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.

Dulaglutide induced weight loss in a morbidly obese adult with Type 2 diabetes mellitus:  A Case ReportSohail Bade1, Sahil Bade1, Grishma Sharma1, Narayan Bhurtel2, Yadvinder Singh3 Sudip Paudel4, Frena Pulami Magar5, Kshitij Chapagain11 MBBS doctor, Dhulikhel Hospital, Dhulikhel, Nepal2 MBBS doctor, Kathmandu Metro Hospital, Nepal3 MBBS doctor, Swacon International Hospital, Nepal4 MBSS doctor, Tribhuvan University Teaching Hospital, Nepal5 MBBS doctor, Singapore Gurkha Polyclinic Ltd, NepalCorresponding AuthorDr. Sohail Bade, Dhulikhel Hospital, [email protected]

X-ray computed tomography is an extremely useful tool for the non-destructive analysis of additively manufactured (AM) components. AM components often show manufacturing defects such as high porosity, rough surfaces, or a lack of fusion (LoF) between production layers. These imperfections can be detrimental for the fatigue life of components. To better understand how cracks initiate and grow from internal defects, we fabricated Ti-6Al-4V samples with an internal cavity using electron beam powder bed fusion (PBF-EB/M). The samples were tested in the high-cycle fatigue (HCF) and very high-cycle fatigue (VHCF) regime using ultrasonic testing equipment and analyzed with X-ray computed tomography (XCT). X-ray imaging was used to locate crack initiation sites around defects and to measure characteristic properties of the crack and the defects with the aid of deep learning segmentation tools. LoF defects exposed to the outer surface of the samples due to machining and post-processing, were found to be as detrimental to the fatigue life as the printed central artificial defects. The work presented here can benefit industries that utilize the AM of high-strength, light-weight alloys, such as aerospace and medicine, in the design and manufacturing of components by improving part reliability and fatigue life.

Background The benefits of Elexecaftor-Tezacaftor-Ivacaftor (ETI) therapy on the health and wellbeing of people with CF (pwCF) are well documented. Since approval, however, a growing number of potential side effects have emerged in reports from clinical practice. With current understanding of ETI tolerability limited to data from clinical trials, the prevalence of side effects and their impact on care decision making remains poorly categorized. Methods A ten-question survey was developed and distributed to patients 18 years or older who were treated at the Massachusetts General Hospital CF centers. Reports of side effects were measured across twelve distinct categories, and dose adjustments and discontinuation due to side effects were collected. If a patient reported no side effects, they did not have to complete the entire survey. Results Among ninety-two respondents initiated on ETI, 51 respondents (55.4%) reported potential side effects and 41 (44.5%) respondents reported no adverse events. The most commonly reported side effects were mental health, changes in appearance, and gastrointestinal complaints, which were reported by 22.8%, 30.4%, and 21.7% of patients, respectively. Eighteen (19.6%) respondents modified their dosing in response to side effects, and six discontinued treatment permanently (6.52%) due to persistent side effects. Conclusions Responses demonstrated marked heterogeneity, with most respondents reporting at least one side effect following initiation. Dose modification was commonly utilized to mitigate adverse effects, however few respondents had to discontinue treatment. These findings demonstrate the importance of monitoring for potential drug-related side effects of ETI in clinical settings.

This study presents a portable spectroscopic system compatible with ambient light to assess hepatic steatosis (HS) and macrovesicular steatosis (MaS) in human liver specimens. Traditional assessment methods for MaS are limited, prompting the need for non-invasive alternatives. The study utilized a two-stage approach on thawed snap-frozen liver specimens. Biochemical validation compared fat content from Raman and reflectance intensities with triglyceride (TG) quantifications, while histopathological validation contrasted Raman-derived fat content with pathologist evaluations and an algorithm. Analysis of 16 specimens showed a positive correlation between spectroscopic data and TG quantifications. The Raman system differentiated various degrees of global HS and MaS in an additional 66 specimens. A dual-variable prediction algorithm classified significant discrepancies (≥10%) between algorithm-estimated global HS and pathologist-estimated MaS. This study demonstrates the viability of a portable spectroscopic system for non-invasive HS and MaS assessment to enhance real-time donor liver assessments during recovery to improve transplantation outcomes.

In nature, many organisms exhibit remarkable freezing tolerance and employ rich and intriguing physiological strategies to adapt to low-temperature environments. However, cryopreservation techniques face challenges when it comes to freezing and thawing biological tissues and cells, such as cryo-damage caused by crystallization and cell membrane rupture due to osmotic imbalances. In recent years, there has been growing interest in the molecular mechanisms underlying natural freezing tolerance and artificial cryopreservation processes. This review delves into the adaptive mechanisms observed in freeze-tolerant species and hibernating animals, elucidating the significance of specific genes, proteins, and metabolic pathways for survival. Furthermore, we discuss advancements in cryopreservation technologies, highlighting their impacts on cellular and tissue integrity, and analyzes the adaptive regulation of processes like glucose metabolism, miRNA expression, and cryoprotective protein modulation. Finally, future directions for cryopreservation are proposed.

While advances in catheter design and power delivery combined with increased awareness among operators have given more tools to avoid collateral damage, the results obtained in the accompanied manuscript are a warning that 50W and 90W 4sec LA lesions guided by 400 AI and 5 LSI using TactiCath, STSF, and QDOT MICRO do not provide immunity from significant extracardiac injury.

Two types of short-time Fourier transforms involving respectively nonlinear modulation and nonlinear translation are designed in this note. Some important properties such as twin in time-frequency domain and orthogonality relations are investigated. Moreover, Lieb type inequalities and uncertainty principle are established.

Immunoglobulin E (IgE)-mediated food allergies are reported to affect around 3.5% of children and 2.4% of adults, with symptoms varying in range and severity. While being the gold standard for diagnosis, oral food challenges are burdensome, and diagnostic tools based on specific IgE can be flawed. Furthering our understanding of the mechanisms behind food allergy onset, severity, and persistence could help reveal immune profiles associated with the disease, to ultimately aid in diagnosis. Alterations to cytokine levels and immune cell ratios have been identified, though further research is needed to fully capture the heterogenous nature of food allergy. Moreover, the existence of such immune alterations also raises the question of potential wider systemic effects. For example, recent research has emphasised the existence and impact of neuro-immune interactions and implicated behavioural and neurological changes associated with food allergy. This review will provide an overview of such food allergy-driven neuro-immune interactions, with the aim of emphasising the importance of furthering our understanding of the immune mechanisms underlying IgE-mediated food allergy.

not-yet-known not-yet-known not-yet-known unknown The hepatitis E virus (HEV) is an important causative agent of acute hepatitis (AH). Despite reports of human infection in Brazil, the investigation is not routinely conducted, even in cases of elevated liver enzymes. In this study, two groups were evaluated: group 1 - patients with acute hepatitis A (n=48); group 2 - patients with non-A-C AH (n=47). They were tested by enzyme immunoassay for anti-HEV IgM/IgG and by real-time PCR for HEV RNA detection. The positive sample for HEV RNA was submitted for sequencing. The seroprevalence of anti-HEV IgM and IgG in group 1 was 4% (2/48) and 14.5% (7/48), respectively. Viral RNA was not detected in any sample. In group 2, the anti-HEV IgM positivity was 4.3% (2/47) and IgG 14.9% (7/47). RNA was detectable in one case, which presented a viral load of 222.4 IU/μL and positive anti-HEV IgM/IgG. In the phylogenetic analysis, the genotype identified was HEV-3f. These results indicate that HEV infection should be considered a possible diagnosis in cases of non-A-C AH. The patient identified with acute hepatitis E had recently traveled to Northeast region of Brazil (Garanhuns city in Pernambuco state), where there are reports of high HEV seroprevalence among pigs. The close phylogenetic relationship observed between the sequence characterized in this study and strains isolated from pigs in nearby cities where the patient went suggested a possible zoonotic transmission in this region. This study highlights the importance of expanding studies and improving surveillance to understand and manage HEV infections nationwide better.

A document by Sever Yildiz G. Click on the document to view its contents.

Plant-microbe associations are ubiquitous, but parsing the contributions of dispersal, host filtering, competition, and the environment on microbial community composition is challenging. Floral nectar-inhabiting microbes offer a tractable system to disentangle community assembly processes. We inoculated a synthetic community of yeasts and bacteria into nectars of 31 phylogenetically diverse plant species while excluding pollinators. We monitored weather conditions and, after 24 hours, collected and cultured communities. We found a strong signature of plant species on resulting microbial abundance and community composition, in part explained by plant phylogeny and nectar peroxide content, but not measured floral morphological traits. Higher maximum and minimum temperatures increased microbial growth overall and favored certain microbes over others. Our work supports the roles of plant identity and abiotic conditions in assembly and growth of plant-associated microbial communities and finds evidence for diversity-productivity relationships within plant-associated microbiomes.

The comprehension of the reciprocal interaction between root development and its co-adapted beneficial microbes in response to elevated CO 2 (eCO 2) will facilitate the identification of nutrient-efficient cultivars for a sustainable agriculture. Here systemically morphological, anatomical, chemical and gene expression assays performed under eCO 2 highlight the divergent root differentiation driven endodermal barrier development with respect to the L-/S-shaped lateral roots under low nitrogen conditions in rice. Next, by metabolome and endodermal-cell specific RNA sequencing we showed that rice adapted to eCO 2 by spatially recruiting diazotrophs through flavonoid secretion in L-shaped lateral roots. To the end, using a rice Casparian strip mutant Oscasp1-1 we validated such root differentiation driven specific recruitment of a diazotrophic family Oxalobacteraceae implicated in plant tolerance to low nitrogen availability. Our work indicates that rice could coordinate nutrient uptake and root differentiation by the recruitment of diazotrophs in L-shaped lateral roots under climate change.

Alfalfa ( Medicago sativa L.) is a crucial and widely grown forage legume that faces yield challenges due to salinity stress. In this study, an R2R3-MYB transcription factor (TF), MsEOBI was characterized from alfalfa. Its function and gene regulatory pathways were studied in alfalfa seedlings. The nuclear-localized MsEOBI acts as a transcriptional activator. MsEOBI enhances salinity tolerance of alfalfa by promoting flavonoids and lignin biosynthesis, as well as scavenging reactive oxygen species (ROS). MsEOBI also promote pollinator attraction and seed yield by activating volatile phenylpropanoid biosynthesis. Yeast one-hybrid, dual-luciferase, and ChIP-qPCR assays showed that MsEOBI binds directly to the promoter of MsPAL1, a key enzyme in the phenylpropanoid pathway to activate its expression. Overexpression of MsPAL1 in alfalfa enhances salinity tolerance. These findings shed light on the functions of the MsEOBI-MsPAL1 module in alfalfa and offer valuable genetic resources for the breeding of salt stress-resistant varieties in the future.

Process-based models for range dynamics are urgently needed due to increasing intensity of human-induced biodiversity change. Despite a few existing models that focus on demographic processes, their use remains limited compared to the widespread application of correlative approaches. This slow adoption is largely due to the challenges in calibrating biological parameters and the high computational demands for large-scale applications. Moreover, increasing the number of simulated processes (i.e. mechanistic complexity) may further exacerbate those reasons of delay. Therefore, balancing mechanistic complexity and computational effectiveness of process-based models is a key area for improvement. A promising research direction is to expand demographically-explicit metapopulation models by integrating metabolic constraints. We translated and expanded a previously developed R metapopulation model to Julia language and published it as a Julia module. The model integrates species-specific parameters such as preferred environmental conditions, biomass, and dispersal ability with demographic rates (e.g. reproductive and mortality rates) derived from local temperature and biomass via the metabolic theory of ecology. We provide a simple application example for the model in which we illustrate a typical use case by predicting the future occurrence of Orchis militaris in Bavaria under different climate change scenarios. Our results show that climate change reduces habitat suitability overall, but some regions like the Franconian Forest and the Alps see increased suitability and abundance, confirming their role as refugia. Simulating metapopulation dynamics reveals that local population dynamics and dispersal are crucial for accurate predictions. For instance, increasing dispersal distance reduces overall abundance loss but also lessens population growth in refugia. This highlights the importance of measuring traits like dispersal ability to improve climate change forecasts.

Weeds are among the most significant factors contributing to decreases in crop yield and quality. Glufosinate, a nonselective, broad-spectrum herbicide, has been extensively utilized for weed control in recent decades. However, crops are usually sensitive to glufosinate. Therefore, the development of glufosinate-resistant crops is crucial for effective weed management in agriculture. In this study, we characterized a SQUAMOSA promoter-binding-like (SPL) factor, OsSPL8, which acts as a negative regulator of glufosinate resistance by inhibiting the transcription of OsGS1;1 and OsGS2 and consequently reducing GS activity. Furthermore, the loss of OsSPL8 function enhanced tolerance to drought and salt stresses. Transcriptomic comparisons between the gar18-3 mutant and wild type revealed that OsSPL8 largely downregulates stress-responsive genes and upregulates growth-related genes. We demonstrated that OsSPL8 directly regulates OsOMTN6 and OsNAC17, which influence drought tolerance. Additionally, OsSPL8 directly represses the expression of salt stress tolerance-related genes such as OsHKT1.1 and OsTPP1. Collectively, our results demonstrate that OsSPL8 is a negative regulator of both glufosinate resistance and abiotic stress tolerance.

Background/Purpose Implantable loop recorders (ILR) are increasingly used in cardiac rhythm monitoring and diagnostic work-up of unexplained syncope. ILR battery longevity according to manufacturers’ product performance specifications typically ranges between two to four years, but real-world data in this population are lacking. Methods This monocentric, prospective, observational study included consecutive patients with unexplained syncope undergoing ILR implantation between 10/2007 and 10/2019 The main purpose was to determine real-world battery longevity of ILR. Diagnostic yield and relationship between arrhythmogenic diagnosis and duration of ILR-monitoring was explored. Results The study included 309 patients (59 years [38-73], 49% female) with ILR implantation for unexplained syncope. Median battery longevity was 42 [40-45] months. 99.5% of ILR reached prespecified battery longevity. The time to end-of-life varied by up to 33 months among the same ILR models. Overall arrhythmogenic diagnostic yield counted 27% (73% sick sinus syndrome, 20% atrioventricular block and 7% ventricular tachycardia). Median time to diagnosis was 10 [2-25] months, with the latest event at 43 months. The cumulative diagnostic yield for arrhythmogenic event was 15.7%, 22.9%, 34.9% , 54.2%, 72.3% and 100% at 1, 2, 6, 12, 24 and 48 months respectively. In univariate analysis, 1 st degree AV-block and prolonged HV time on EP study were predictors of diagnosis, while QRS duration abnormality borderline missed significance. Conclusions Real-world battery longevity of ILRs matched industry projected longevity in 99.5% of patients implanted with ILR for unexplained syncope. A battery longevity of minimum 3.5 years is recommended to maximize the diagnostic yield in this population.