Deprescribing search filters aiming at maximizing sensitivity for MEDLINE and for Embase were recently developed. Simultaneously, The US Deprescribing Network (USden) developed a deprescribing search strategy that included a deprescribing search filter for MEDLINE. The aim of this case study was to implement these deprescribing search filters in original search strategies from deprescribing related systematic reviews (SRs) and to calculate their performances. Two deprescribing SRs were included. Authors were asked to repeat the selection process described in SRs original methods. Performances of search strategies implemented with deprescribing search filters (ISS) were calculated and compared to original search strategies (OSS). In MEDLINE, sensitivity for SR 1 was 50% for OSS (Precision: 2.8%), 58% for ISS with maximised sensitivity filter (Precision: 1.7%) and 42% for ISS with USden filter (Precision: 5.1%). Sensitivity for SR 2 was 25% for all search strategies (Precision: 0.1%, 0.2% and 1,2% respectively). In Embase, sensitivity for SR 1 was 33% (Precision: 4,1%) for OSS and 58% for ISS (Precision 2.1%). No articles were included through Embase search strategies for SR 2. Using maximized sensitivity deprescribing filters may increase the exhaustivity of deprescribing SRs. Precision offered by the USDeN deprescribing filter is a convenient alternative for non-systematic reviews.

Severe autoimmune lymphoproliferative syndrome phenotype in a pediatric patient with a germline FAS gene variant Authors: Alexandra Dreyzin MD MS1; Jinjun Cheng MD PhD2, David Leitenberg MD PhD3, and Yaser Diab MBBS1Center for Cancer and Blood Disorders, Children’s National Hospital, Washington, DCDivision of Pathology and Laboratory Medicine, Children’s National Hospital, Washington, DCDepartment of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.

WHEN BONE PAIN AND BLEEDING MEAN MORE THAN LEUKEMIA:

Cancer cell plasticity is the ability of tumor cells to switch phenotypes and is one of the predominant requisites of cancer cells capable of undergoing metastasis. Cancer cell plasticity is also recognised as one of the major contributors to intra-tumoral heterogeneity, a critical factor underlying the progression of malignant tumors which is known to modify tumor response and induce resistance against various modes of therapy thus posing a barrier to efficient cancer management. Cancer cell plasticity is acquired by the subversion of cell signaling pathways like MAPK, PI3K, STAT3, Wnt, Hedgehog and Notch as well as cellular programs such as epithelial to mesenchymal transition (EMT) and phenotypic plasticity. This complex phenomenon has been studied in many cancer types like pancreatic cancer, colon cancer and breast cancer. Some cancers like breast cancer are known to exhibit a hierarchical organization with cancer stem cells (CSCs) at the pinnacle of the pyramid due to their ability to promote tumorigenesis, metastasis and therapy resistance. CSCs which can undergo phenotypic changes resulting in heterogenous cell populations with differing potential to develop programs necessary for the metastatic process lies at the core of the cancer cell plasticity hypothesis. Our expanding knowledge of this field can lead to the development of more therapeutic strategies that can be used in cancer and other solid tumors that exhibit similar mechanisms of plasticity. This review will explore the current understanding we have of breast cancer on the intrinsic molecular mechanisms of cancer cell plasticity and the resistance to various types of cancer therapy that arise as a result of plasticity. We conclude by exploring the potential novel therapies that specifically target the pathways leading to plasticity and can be leveraged to treat patients living with the disease. Keywords: Cancer cell plasticity, Epithelial to Mesenchymal Transition (EMT), therapy resistance, targeted therapy.

Single-nucleotide polymorphism (SNP) analyses are a powerful tool for population genetics, pedigree reconstruction and phenotypic trait mapping. SNPs could also be useful for sexing individuals in species with reduced sexual dimorphism, yet this possibility remains poorly explored. Here, we develop a novel protocol for molecular sexing of birds based on the detection of unique Z- and W-linked SNP markers. Our method is based on the identification of two unique loci, one in each sexual chromosome. Individuals are considered males when they are heterozygotic for the Z-linked SNP and females when they are homozygote for the Z-linked SNP and have the W-linked SNP. We validated the method in the Jackdaw (Corvus monedula), a species whose reduced sexual dimorphism makes it difficult to sex individuals in the wild. We assessed the reliability of the method with 36 individuals of known sex, and found that their sex was correctly assigned in 100% of cases. The sex-linked markers also proved to be widely applicable to discriminate males and females from a sample of 927 genotyped individuals of different maturity stages with an accuracy of 99.5%. Given that SNP markers are increasingly used in quantitative genetic analyses of wild populations, the approach we propose has a great potential to be integrated into broader genetic research programmes without the need of additional sexing techniques.

Aims: Mirvetuximab soravtansine is the first-in-class antibody-drug conjugate approved in November 2022 for the treatment of folate receptor-α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic (PK) model to describe the concentration-time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S-methyl-DM4). Methods: Mirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum-resistant ovarian cancer in three clinical studies, and the plasma drug concentrations were analyzed using a nonlinear mixed-effects modelling approach to estimate the PK parameters, inter-individual variabilities, and residual errors. Stepwise covariate modelling was performed to identify covariates. Results: We developed a semi-mechanistic population PK model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumor cells. The model adequately described the concentration-time profiles for the three analytes. Patient body weight, serum albumin, and age were identified as the major covariates. Exposures in patients with renal or hepatic impairment were estimated. The effect of inhibition of cytochrome P450 (CYP) 3A4 on drug exposures was also evaluated. Conclusions: There is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. The model also showed that dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.

Abstract Drug-drug interactions (DDIs) are common in cancer management and complicate the choice of anticoagulation in cancer-associated thrombosis. Cancer patients incur an increased risk of thrombotic events. Also, more bleeding events are observed in those who receive anticoagulation compared to those without cancer. In the treatment of cancer-associated thrombosis, non-vitamin K oral anticoagulants (NOACs) are at least as effective as low-molecular weight heparins, which became the standard of care after several trials demonstrated superiority over vitamin K antagonists. Non-inferiority has been shown for rivaroxaban, edoxaban and apixaban with a signal of fewer recurrent thrombotic events, albeit with an increase in bleeding events. Yet, potentially major drug-drug interactions have been identified as a reason to withhold NOACs and to rather choose an alternative. Furthermore, practical guidance on what constitutes a major interaction and/or how to deal with these interactions in clinical practice is limited. Hence, here we have provided a framework to allow clinicians to better deal with drug-drug interactions between NOACs and cancer therapies in the management of cancer-associated thrombosis. In this review we have discussed the current literature, how the pharmacokinetic profile links to the label information on DDI, and have provided a practical proposal, applied to a clinical case. Key words: drug-drug interactions, anticoagulation, non-vitamin K oral anticoagulants, cancer, cancer associated thrombosis

It is difficult to anatomically understand the three-dimensional structure of the middle ear and temporal bone during surgery, and great surgical technique are required. Therefore, complications are avoided through simulation using a three-dimensional printer, which was effective in not only safe and reliable surgery but also educating young physicians.

The search for robust, reliable biomarkers of schizophrenia remains a high priority in psychiatry. Biomarkers are valuable because they can reveal the underlying mechanisms of symptoms and monitor treatment progress, and may predict future risk of developing schizophrenia. Despite the existence of various promising biomarkers that relate to symptoms across the schizophrenia-spectrum, and despite published recommendations encouraging multivariate metrics, they are rarely investigated simultaneously within the same individuals. In those with schizophrenia, the magnitude of purported biomarkers is complicated by comorbid diagnoses, medications, and other treatments. Here, we argue three points. First, we reiterate the importance of assessing multiple biomarkers simultaneously. Second, we argue that investigating biomarkers in those with schizophrenia-related traits (schizotypy) in the general population can accelerate progress in understanding the mechanisms of schizophrenia. We focus on biomarkers of sensory and working memory in schizophrenia and their smaller effects in individuals with nonclinical schizotypy. Third, we note irregularities across research domains leading to the current situation in which there is a preponderance of data on auditory sensory memory and visual working memory, but markedly less in visual (iconic) memory and auditory working memory, particularly when focusing on schizotypy where data are either scarce or inconsistent. Together, this review highlights opportunities for researchers without access to clinical populations to address gaps in knowledge. We conclude by highlighting the theory that early sensory memory deficits contribute negatively to working memory and vice versa. This presents a mechanistic perspective where biomarkers may interact with one another and impact schizophrenia-related symptoms.

A woman presented with intermittent left lower abdominal pain associated with a mass and didn't have any other symptoms. During the operation, a local inflammatory mass was found in left lower quarter of abdominal cavity. There are two bony foreign bodies in it. Postoperative pathology suggested an inflammatory mass.

Dopamine transmission in the striatum is a critical mediator of the rewarding and reinforcing effects of commonly misused psychoactive drugs. G protein-coupled receptors (GPCRs) that bind a variety of neuromodulators including dopamine, endocannabinoids, acetylcholine, and endogenous opioid peptides regulate dopamine release by acting on several components of dopaminergic circuitry. Striatal dopamine release can be driven by both somatic action potential firing and local mechanisms that depend on acetylcholine released from striatal cholinergic interneurons. GPCRs that primarily regulate somatic firing of dopamine neurons via direct effects or modulation of synaptic inputs are likely to impact distinct aspects of behavior and psychoactive drug actions compared with GPCRs that primarily regulate local acetylcholine-dependent dopamine release in striatal regions. This review will highlight mechanisms by which GPCRs modulate dopaminergic transmission and the relevance of these findings to psychoactive drugs involved in substance use disorders.

HNF4α is a master regulator gene belonging to the nuclear receptor superfamily involved in regulating a wide range of critical biological processes in different organs. Structurally, the HNF4A locus is organized with two independent promoters and is subjected to alternative splicing with the production of twelve distinct isoforms. Little is known about the mechanisms each isoform uses to regulate transcription and their biological impact, with some reports addressing these aspects. Proteomic analyses have led to identifying proteins that interact with specific HNF4α isoforms. The identification and validation of these interactions and their role in co-regulating targeted gene expression are essential to understand better the role of this transcription factor in different biological processes and pathologies. This review addresses the historical origin of HNF4α isoforms, some of the main functions of the P1 and P2 isoform subgroups and provide information on the most recent hot topic research on the nature and function of proteins associated with each of the isoforms in some biological contexts.

Plant community productivity generally increases with biodiversity, but the strength of this relationship exhibits strong empirical variation. In meta-food-web simulations, we addressed if the spatial overlap in plants' resource access and movement of animals can explain such variability. We found that spatial overlap of plant resource access is a prerequisite for positive diversity-productivity relationships, but causes exploitative competition that can lead to competitive exclusion. Movement of herbivores causes apparent competition among plants, resulting in negative relationships. However, movement of larger top predators integrates sub-food-webs composed of smaller species, offsetting the negative effects of exploitative and apparent competition and leading to strongly positive diversity-productivity relationships. Overall, our results show that spatial overlap of plant resource access and animal movement can greatly alter the strength and sign of such relationships. In particular, the scaling of animal movement effects opens new perspectives for linking landscape processes without effects on biodiversity to productivity patterns.

1. The structure, composition, and shape of teeth have been related to dietary specialization in many vertebrate species, except snakes. Yet, snakes have diverse dietary habits that may impact the shape of their teeth. We hypothesize that prey properties, such as hardness and shape, as well as feeding behavior, such as aquatic or arboreal predation, or holding vigorous prey, impose constraints on the evolution of tooth shape in snakes. 2. We compared the morphology of the dentary teeth of 63 species that cover the phylogenetic and dietary diversity of snakes, using 3D geometric morphometrics and linear measurements. 3. Our results show that prey hardness, foraging substrate and the main mechanical challenge are important drivers of tooth shape, size, and curvature. 4. Overall, long, slender, curved teeth with a thin layer of hard tissue are observed in species that need to maintain a grip on their prey. Short, stout, less curved teeth are associated with species that undergo high or repeated loads. 5. Our study demonstrates the diversity of tooth morphology in snakes and the need to investigate its underlying functional implications to better understand the evolution of teeth in vertebrates.

Pre-packed chromatography columns and cassette filtration units offer many advantages in bioprocessing. These include reduced labor costs and processing times, ease of storage, and enhanced process flexibility. Rectangular formats are particularly attractive as they can be stacked and multiplexed together for continuous processing. Cylindrical chromatography beds have historically been favored even though their bed support and pressure-flow performance vary with bed dimensions. This work presents the performance of rectangular chromatography devices with novel internally supported beds. They are compatible with existing chromatography workstations and can be packed with any standard commercial resin. The devices offer pressure-flow characteristics independent of container-volume, simple multiplexing, and separation performance comparable to cylindrical columns. Their internal bed support allows mechanically less-rigid resins to be used at up to 4 times higher maximal linear velocities, and productivities approaching 200 g/L/h for affinity resins, compared to the 20 g/L/h typical of many column-based devices. Three 5 L devices should allow processing of up to 3 kg of monoclonal antibody per hour.

Immunodeficient patients are less prone to develop serious complications of COVID-19 and cytokine storm. However, they are more likely to develop opportunistic infections that can mimic the symptoms of the SARS-CoV-2. we presented a 27-year-old male case of SARS-CoV-2, who was complicated with Pneumocystis jirovecii pneumonia, following treatment with rituximab.

It is well accepted that a lithiophilic interface can effectively regulate Li deposition behaviors, but the influence of the lithiophilic interface is gradually diminished upon continuous Li deposition that completely isolates Li from the lithiophilic metals. Herein, we perform in-depth studies on the creation of dynamic alloy interface upon Li deposition, arising from the exceptionally high diffusion coefficient of Hg in the amalgam solid solution. As a comparison, other metals such as Au, Ag and Zn have typical diffusion coefficients of 10-20 orders of magnitude lower than for Hg in the similar solid solution phases. This difference induced compact Li deposition pattern with an amalgam substrate even with a high areal capacity of 55 mAh cm-2. This finding provides new insight into the rational design of Li anode substrate for the stable cycling of Li metal batteries.

The ever-increasing complexity of environmental pollutants urgently warrants the development of new detection technologies. In this context, sensors based on the optical properties of hydrogels enabling fast and easy in situ detection are attracting increasing attention. Herein, the target recognition and sensing mechanisms of two main types of optical hydrogels (OHs) are reviewed and discussed: photonic crystal hydrogels (PCHs) and fluorescent hydrogels (FHs). For PCHs, the environmental stimulus response, target receptors, inverse opal structures, and molecular imprinting techniques related to PCHs are reviewed and summarized. Furthermore, the different types of fluorophores (i.e., compound probes, biomacromolecules, quantum dots, and luminescent microbes) of FHs are summarized. Finally, the data from 138 papers about different OHs are extracted for secondary statistical analysis. The detection performance and potential of various OH types in different environmental pollutant detection scenarios are evaluated, and compared them to those obtained using the standard detection method. Based on this analysis, some possible development directions are proposed, including the fusion of various OHs, introduction of more hydrogel technologies from the biomedical field to the environmental pollutant detection field, and development of multifunctional sensor arrays.