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Abstract Glucocorticoid receptor (GR) is a transcription factor that plays a crucial role in cancer biology. In this study, we utilized an in silico‐designed GR activity signature to demonstrate that GR relates to the proliferative capacity of numerous primary cancer types. In breast cancer, the GR activity status determines luminal subtype identity and has implications for patient outcomes. We reveal that GR engages with estrogen receptor (ER), leading to redistribution of ER on the chromatin. Notably, GR activation leads to upregulation of the ZBTB16 gene, encoding for a transcriptional repressor, which controls growth in ER‐positive breast cancer and associates with prognosis in luminal A patients. In relation to ZBTB16's repressive nature, GR activation leads to epigenetic remodeling and loss of histone acetylation at sites proximal to cancer‐driving genes. Based on these findings, epigenetic inhibitors reduce viability of ER‐positive breast cancer cells that display absence of GR activity. Our findings provide insights into how GR controls ER‐positive breast cancer growth and may have implications for patients' prognostication and provide novel therapeutic candidates for breast cancer treatment.

Cyclic di-adenylate monophosphate (cyclic di-AMP) is an important second messenger in microorganisms. Cyclic di-AMP regulates bacterial cell volume and turgor via control of potassium and compatible solute transport but is also involved in many other processes, including the activation of the metazoan innate immune response to bacterial infections. We compare the activity of full-length membrane-embedded CdaA, the enzyme that synthesizes cyclic di-AMP, with the water-soluble catalytic domain CdaA-DAC. Purified CdaA from L. lactis was studied in the detergent-solubilized state, and in lipid nanodiscs and vesicles. We show that CdaA is tetrameric and the membrane-bound complex has more than 2-orders of magnitude higher activity than soluble CdaA-DAC. CdaA activity increases with pH but does not strongly depend on the salt or lipid content, factors that are crucial for the control of osmoregulatory transporters. Cryo-EM and in-silico structure prediction of CdaA show that the two DAC dimers engage in a head-to-head interaction, leading to cyclic-di-AMP formation. The inhibitor phosphoglucomutase prevents this active conformation. We observe dynamic flexibility between the catalytic and membrane domains, even in the presence of ATP or non-hydrolyzable substrate ApCpp. This is the first comprehensive functional and structural characterization of a full-length cyclic di-AMP-specific cyclase. Biochemical and structural characterization of the full-length CdaA reveals that efficient synthesis of the second messenger cyclic di-AMP requires membrane-bound cyclase enzyme. [ABSTRACT FROM AUTHOR]

Antibody-dependent complement activation plays a key role in the natural human immune response to infections. Currently, the understanding of which antibody-antigen combinations drive a potent complement response on bacteria is limited. Here, we develop an antigen-agnostic approach to stain and single-cell sort human IgG memory B cells recognizing intact bacterial cells, keeping surface antigens in their natural context. With this method we successfully identified 29 antibodies against K. pneumoniae, a dominant cause of hospital-acquired infections with increasing antibiotic resistance. Combining genetic tools and functional analyses, we reveal that the capacity of antibodies to activate complement on K. pneumoniae critically depends on their antigenic target. Furthermore, we find that antibody combinations can synergistically activate complement on K. pneumoniae by strengthening each other's binding in an Fc-independent manner. Understanding the molecular basis of effective complement activation by antibody combinations to mimic a polyclonal response could accelerate the development of antibody-based therapies against problematic infections. Here, van der Lans et al describe an antigen-agnostic approach to identify antibodies against Klebsiella pneumoniae. Functional analysis of these antibodies indicates that their capacity to activate complement depends on their antigenic target. [ABSTRACT FROM AUTHOR]

Purpose: To study the long-term outcome of revision microdiscectomy after classic microdiscectomy for lumbosacral radicular syndrome (LSRS). Methods: Eighty-eight of 216 patients (41%) who underwent a revision microdiscectomy between 2007 and 2010 for MRI disc-related LSRS participated in this study. Questionnaires included visual analogue scores (VAS) for leg pain, RDQ, OLBD, RAND-36, and seven-point Likert scores for recovery, leg pain, and back pain. Any further lumbar re-revision operation(s) were recorded. Results: Mean (SD) age was 59.8 (12.8), and median [IQR] time of follow-up was 10.0 years [9.0–11.0]. A favourable general perceived recovery was reported by 35 patients (40%). A favourable outcome with respect to perceived leg pain was present in 39 patients (45%), and 35 patients (41%) reported a favourable outcome concerning back pain. The median VAS for leg and back pain was worse in the unfavourable group (48.0/100 mm (IQR 16.0–71.0) vs. 3.0/100 mm (IQR 2.0–5.0) and 56.0/100 mm (IQR 27.0–74.0) vs. 4.0/100 mm (IQR 2.0–17.0), respectively; both p < 0.001). Re-revision operation occurred in 31 (35%) patients (24% same level same side); there was no significant difference in the rate of favourable outcome between patients with or without a re-revision operation. Conclusion: The long-term results after revision microdiscectomy for LSRS show an unfavourable outcome in the majority of patients and a high risk of re-revision microdiscectomy, with similar results. Based on also the disappointing results of alternative treatments, revision microdiscectomy for recurrent LSRS seems to still be a valid treatment. The results of our study may be useful to counsel patients in making appropriate treatment choices. [ABSTRACT FROM AUTHOR]

After severe brain injury, zolpidem is known to cause spectacular, often short-lived, restorations of brain functions in a small subgroup of patients. Previously, we showed that these zolpidem-induced neurological recoveries can be paralleled by significant changes in functional connectivity throughout the brain. Deep brain stimulation (DBS) is a neurosurgical intervention known to modulate functional connectivity in a wide variety of neurological disorders. In this study, we used DBS to restore arousal and motivation in a zolpidem-responsive patient with severe brain injury and a concomitant disorder of diminished motivation, more than 10 years after surviving hypoxic ischemia. We found that DBS of the central thalamus, targeted at the centromedian-parafascicular complex, immediately restored arousal and was able to transition the patient from a state of deep sleep to full wakefulness. Moreover, DBS was associated with temporary restoration of communication and ability to walk and eat in an otherwise wheelchair-bound and mute patient. With the use of magnetoencephalography (MEG), we revealed that DBS was generally associated with a marked decrease in aberrantly high levels of functional connectivity throughout the brain, mimicking the effects of zolpidem. These results imply that ‘pathological hyperconnectivity’ after severe brain injury can be associated with reduced arousal and behavioral performance and that DBS is able to modulate connectivity towards a ‘healthier baseline’ with lower synchronization, and, can restore functional brain networks long after severe brain injury. The presence of hyperconnectivity after brain injury may be a possible future marker for a patient’s responsiveness for restorative interventions, such as DBS, and suggests that lower degrees of overall brain synchronization may be conducive to cognition and behavioral responsiveness. [ABSTRACT FROM AUTHOR]

Youth in foster care experience high rates of social, emotional, and behavioral challenges that are complicated by trauma and grief. To address these concerns, the current intervention study examines the efficacy of a newly developed peer grief support program, the L.Y.G.H.T. program, for youth in foster care, using an embedded sequential mixed methods design. Forty-two youth residing in three separate foster care group homes ("community sites") in a southeastern state participated in this study. Youth were randomly assigned to either the treatment program or a waitlist control group. Baseline and post-intervention (after 6 weeks) assessments of the Children's Hope Scale, the Inventory of Social Support, the Rosenberg Self-Esteem Scale, and the Strengths and Difficulties Questionnaire-Self Report were administered. After each weekly group, participants completed a survey to assess trauma-informed program environment and facilitators completed a survey to assess fidelity to the intervention. Focus groups (n = 3) were conducted at each of the community sites after the post-intervention assessments were completed. To examine program impact, we evaluated whether increases in well-being (i.e., social support, hopefulness, and self-worth) and decreases in total problem behaviors would be found for participants in the treatment group. Social support, hopefulness, and self-worth increased and total problems remained the same for youth in the treatment program. Large effects were found for program helpfulness, a trauma-informed program environment, and reduction in perceived problems. Focus group feedback explained why youth were initially interested in the program, perceived program benefits, program dislikes, barriers to program participation, recommendation of the program, and additional feedback. The findings suggest that the L.Y.G.H.T. program is an efficacious intervention which addresses loss and grief and enhances the well-being of youth in foster care who are grieving. [ABSTRACT FROM AUTHOR]

The effect of water on the modification of acidic properties of Nb2O5 and Nb1.3MnOx catalysts was investigated using the cracking of cumene as model reaction, and compared to the behavior of a HZSM-5 catalyst. Nb1.3MnOx exhibited stronger Lewis acidity than Nb2O5, which translated into a higher selectivity towards α-methylstyrene formed on Lewis acid sites (LAS) by dehydrogenation of cumene. Steam enhanced strongly the conversion of cumene over both Nb-based catalysts. The products distribution on Nb-based catalysts was also deeply modified in the presence of steam, the selectivity towards α-methylstyrene decreasing strongly in favor of benzene, which is formed on Brønsted acid sites (BAS) by dealkylation of cumene. In contrast, the performances of HZSM-5 for cumene cracking and the products distribution were only marginally modified in the presence of steam. A kinetic model based on the elementary steps of the cumene reaction pathways (dealkylation and dehydrogenation) was used to estimate the ratio of LAS to BAS in absence and presence of water over Nb1.3MnOx. The activation energy of the cracking reaction was higher than that of the dehydrogenation reaction. The model described correctly the changes in the catalyst activity induced by addition of ≈2 V% of water, which resulted in a decrease in the [LAS]/[BAS] ratio from approximatively 3 to 1. [ABSTRACT FROM AUTHOR]

Mucormycosis is a severe complication in critically ill COVID-19 patients. Throughout the pandemic, a notable prevalence of mucormycosis has been observed in the Indian population, whereas lower occurrences have been reported in Europe. However, limited data exist regarding its prevalence in Europe, which is potentially underestimated due to the low sensitivity of bronchoalveolar lavage (BAL) cultures. We aimed to evaluate the prevalence of mucormycosis in a high-risk critically ill COVID-19 population in the Netherlands, and to evaluate the potential benefit of adding Mucor PCR to BAL as part of routine follow-up. In this study, we included 1035 critically ill COVID-19 patients admitted to either one of the two ICUs at AmsterdamUMC between March 2020 and May 2022; of these, 374 had undergone at least one bronchoscopy. Following the AmsterdamUMC protocols, bronchoscopies were conducted weekly until clinical improvement was achieved. We cultured BAL fluid for fungi and used PCR and galactomannan testing to detect Aspergillus spp. Additionally, we retrospectively performed qPCR targeting Mucorales DNA in the BAL of 89 deceased patients. All cultures were negative for Mucorales, whereas 42 (11%) cultures were positive for Aspergillus. Furthermore, qPCR targeting Mucorales was negative in all 89 deceased patients. This study showed that pulmonary mucormycosis was not present in critically ill COVID-19 patients in two tertiary care ICUs. These results indicate routine Mucorales qPCR screening is not clinically necessary in a high-standard-of-care tertiary ICU in a low-endemic area. [ABSTRACT FROM AUTHOR]

Aim: The aim of this article is to present the method and results of the data quality control system and audit within the Netherlands Heart Registration (NHR) using data of patients treated with percutaneous coronary intervention (PCI) in the Netherlands as an example. Methods: The NHR is a Dutch nationwide registry of all cardiac interventions, comprising data from all 71 hospitals, of which 30 are cardiac intervention or heart centres. Each year, within the NHR, data validation and verification is performed by standard quality controls and monitoring visits (audits). For the audit in 2019, a sample of 50–100 medical records of patients treated with PCI in 2016 and 2017 were reviewed in each hospital by an independent auditor. The data received by the NHR were compared with the information in the hospitals' medical records. In total 12 patient characteristics, 5 intervention variables and 3 outcome variables were screened. The value of a variable was considered discrepant if more than 10% of the medical records reviewed regarding this variable were not consistent with the reported data received by the NHR. Results: For all variables together, the consistency was high, 97.6%. All variables, except multivessel disease (9.3% discrepancy in the 2622 medical records reviewed), had an accuracy above 95%. Conclusion: The results of the audit of the PCI medical records show that the overall quality of the data is high. For variables such as multivessel disease it is important to improve knowledge of the definitions and to train all those involved in the registration process. [ABSTRACT FROM AUTHOR]

A study published in the European Journal of Clinical Microbiology & Infectious Diseases compared the diagnostic sensitivity of lower and upper respiratory tract specimens for detecting Mycoplasma pneumoniae (Mp) infections. The study found that Mp diagnostics were most sensitive using specimens from the lower respiratory tract (LRT), based on the detection of Mp in paired patient specimens and the evaluation of Ct-values. However, testing for Mp in upper respiratory tract (URT) specimens still resulted in few missed diagnoses and can be used as a primary diagnostic specimen. It is important to interpret positive results from URT specimens with caution, as Mp carriage has been reported in asymptomatic children. [Extracted from the article]

Purpose: It is unknown if future fertility is compromised by the administration of chemotherapy during pregnancy. The aim of this study was to identify if chemotherapy affects the maternal ovaries during pregnancy and whether these effects depend on type of chemotherapy and duration of exposure. Methods: Pregnant 8-week-old female BL6 mice were exposed to 6 different single chemotherapeutic agents (carboplatin, cisplatin, paclitaxel, epirubicin, doxorubicin, or cyclophosphamide) or saline at gestational day (GD) 13.5. The mice were sacrificed at GD 15.5 or GD 18.5. Ovaries were assessed by histopathology and immunohistochemistry. Follicle count was determined per follicle stage and per treatment modality. Results: Maternal ovarian damage was demonstrated by the presence of apoptosis and necrosis in preantral follicles. The extent of this damage depends upon type of chemotherapy and duration of exposure (2 or 5 days). After short exposure, 81% of ovaries showed histopathologic signs of damage compared to 36% after long exposure, which might suggest a transient effect. Loss of primordial follicles (PMFs) was observed after both short and long exposure, with a reduction of more than 70%. Evidence of DNA damage, as demonstrated by phospho-H2AX expression, was present in 23% (range 0–89%) of PMFs exposed to chemotherapy, but only in the short exposure group. Overall, the least damage was seen after administration of paclitaxel. Conclusion: Despite physiological ovarian function suppression during gestation, chemotherapy-induced damage of the ovaries occurs in pregnant mouse models, potentially affecting future fertility. [ABSTRACT FROM AUTHOR]

With billions of active users, social media platforms now generate spatial data on a massive scale, which presents researchers with opportunities to use this data in new and innovative ways. There is a body of literature within which location-based social media data have been used as a means to spatially analyze certain phenomenon. Due to the low cost, high availability, and extreme ranges of content and geographic coverage, location-based social media data have the potential to play a major role in GIS research. To this end, our review maps the field of evidence as it relates to the methods used by GIS researchers to collect, spatially analyze, and cartographically visualize location-based social media data. The results are informed by 222 articles that utilize spatial social media for a wide variety of purposes and GIS-based analyses. Findings were organized according to a typical GIS workflow and are presented to give the reader an operationalized understanding of each step in the workflow. Collection strongly favoured platforms like Twitter and Flickr, and similar to methods analysis were dictated either by content or locational data attributes. Data visualization was achieved through discrete, continuous, and transmission surfaces. [ABSTRACT FROM AUTHOR]

The use of therapeutic monoclonal antibodies is constrained because single antigen targets often do not provide sufficient selectivity to distinguish diseased from healthy tissues. We present HexElect®, an approach to enhance the functional selectivity of therapeutic antibodies by making their activity dependent on clustering after binding to two different antigens expressed on the same target cell. lmmunoglobulin G (lgG)-mediated clustering of membrane receptors naturally occurs on cell surfaces to trigger complement- or cell-mediated effector functions or to initiate intracellular signaling. We engineer the Fc domains of two different lgG antibodies to suppress their individual homo-oligomerization while promoting their pairwise hetero-oligomerization after binding co-expressed antigens. We show that recruitment of complement component C1q to these hetero-oligomers leads to clustering-dependent activation of effector functions such as complement mediated killing of target cells or activation of cell surface receptors. HexElect allows selective antibody activity on target cells expressing unique, potentially unexplored combinations of surface antigens. Antibody pairs are made to act selectively on cells co-expressing two targets by engineering their Fc domains. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) of the central thalamus is an experimental treatment for restoration of impaired consciousness in patients with severe acquired brain injury. Previous results of experimental DBS are heterogeneous, but significant improvements in consciousness have been reported. However, the mechanism of action of DBS remains unknown. We used magnetoencephalography to study the direct effects of DBS of the central thalamus on oscillatory activity and functional connectivity throughout the brain in a patient with a prolonged minimally conscious state. Different DBS settings were used to improve consciousness, including two different stimulation frequencies (50 Hz and 130 Hz) with different effective volumes of tissue activation within the central thalamus. While both types of DBS resulted in a direct increase in arousal, we found that DBS with a lower frequency (50 Hz) and larger volume of tissue activation was associated with a stronger increase in functional connectivity and neural variability throughout the brain. Moreover, this form of DBS was associated with improvements in visual pursuit, a reduction in spasticity, and improvement of swallowing, eight years after loss of consciousness. However, after DBS, all neurophysiological markers remained significantly lower than in healthy controls and objective increases in consciousness remained limited. Our findings provide new insights on the mechanistic understanding of neuromodulatory effects of DBS of the central thalamus in humans and suggest that DBS can re-activate dormant functional brain networks, but that the severely injured stimulated brain still lacks the ability to serve cognitive demands. [ABSTRACT FROM AUTHOR]

Greenspace and socioeconomic status are known correlates of diabetes prevalence, but their combined effects at the sub-neighborhood scale are not yet known. This study derives, maps, and validates a combined socioeconomic/greenspace index of individual-level diabetes risk at the sub-neighborhood scale, without the need for clinical measurements. In two Canadian cities (Vancouver and Hamilton), we computed 4 greenspace variables from satellite imagery and extracted 11 socioeconomic variables from the Canadian census. We mapped 5125 participants from the Prospective Urban and Rural Epidemiology Study by their residential address and used age- and sex-dependent walking speeds to estimate individual exposure zones to local greenspace and socioeconomic characteristics, which were then entered into a principal component analysis to derive a novel diabetes risk index (DRI-GLUCoSE). We mapped index scores in both study areas and validated the index using fully adjusted logistic regression models to predict individual diabetes status. Model performance was then compared to other non-clinical diabetes risk indices from the literature. Diabetes prevalence among participants was 9.9%. The DRI-GLUCoSE index was a significant predictor of diabetes status, exhibiting a small non-significant attenuation with the inclusion of dietary and physical activity variables. The final models achieved a predictive accuracy of 75%, the highest among environmental risk models to date. Our combined index of local greenspace and socioeconomic factors demonstrates that the environmental component of diabetes risk is not sufficiently explained by diet and physical activity, and that increasing urban greenspace may be a suitable means of reducing the burden of diabetes at the community scale. [ABSTRACT FROM AUTHOR]

Purpose: It remains unclear whether the long-term results of RCTs regarding the outcome of microdiscectomy for lumbosacral radicular syndrome (LSRS) are generalizable. The purpose of this study was to determine the external validity of the outcome preseneted in RCTs after microdicectomy for LSRS in a patient cohort from a high-volume spine center. Methods: Between 2007 and 2010, 539 patients had a single level microdiscectomy for MRI disk-related LSRS of whom 246 agreed to participate. Questionnaires included visual analogue scores (VAS) for leg pain, RDQ, OLBD, RAND-36 and Likert scores for recovery, leg and back pain. Lumbar re-operation(s) were registered. Results: Mean age was 51.3, and median time of follow-up was 8.0 years. Re-operation occurred in 64 (26%) patients. Unfavorable perceived recovery was noted in 85 (35%) patients, and they had worse leg and back pain than the 161 (65%) patients with a favorable recovery: median VAS for leg pain 28/100 mm versus 2/100 mm and median VAS for back pain 9/100 mm versus 3/100 mm, respectively. In addition, the median RDQ and OLBD scores differed significantly: 9 vs 3 for RDQ and 26 vs 4 for OLBD, respectively (p < 0.001). Conclusion: In this cohort study, the long-term results after microdiscectomy for LSRS were less favorable than those obtained in RCTs, possibly caused by less strict patient selection than in RCTs. Our findings emphasize that patients, who do not meet the same inclusion criteria for surgery as in RCTs, should be informed about the chances of a less favorable result. [ABSTRACT FROM AUTHOR]

However, re-examination of disease origins, in part aided by rapid advances in genetic and other classification techniques, led to the realization that observed diseases were in many cases a result of exotic pathogens or anthropogenic impacts (Meager and Meyer, [32]; NPS, [35], [36]; Wobeser, [54]). Although research has shown that a decrease in biodiversity often results in increased disease risk (Civitello et al., [6]; Keesing et al., [27]; Orrock et al., 2011; Johnson et al., [22]; Johnson and Thieltges, [23]; Johnson et al., [24],[25]), climate change could also decrease the prevalence and geographic extent of some diseases. Historically, disease in free-ranging animals was considered a natural process inherent to the functioning of a park ecosystem, and the NPS did not routinely intervene or attempt to manage disease impacts unless overt public health impacts existed (Sellars, [44]). [Extracted from the article]

Scenario planning has emerged as a widely used planning process for resource management in situations of consequential, irreducible uncertainty. Because it explicitly incorporates uncertainty, scenario planning is regularly employed in climate change adaptation. An early and essential step in developing scenarios is identifying “climate futures”—descriptions of the physical attributes of plausible future climates that could occur at a specific place and time. Divergent climate futures that describe the broadest possible range of plausible conditions support information needs of decision makers, including understanding the spectrum of potential resource responses to climate change, developing strategies robust to that range, avoiding highly consequential surprises, and averting maladaptation. Here, we discuss three approaches for generating climate futures: a Representative Concentration Pathway (RCP)-ensemble, a quadrant-average, and an individual-projection approach. All are designed to capture relevant uncertainty, but they differ in utility for different applications, complexity, and effort required to implement. Using an application from Big Bend National Park as an example of numerous similar efforts to develop climate futures for National Park Service applications over the past decade, we compare these approaches, focusing on their ability to capture among-projection divergence during early-, mid-, and late-twenty-first century periods to align with near-, mid-, and long-term planning efforts. The quadrant-average approach and especially the individual-projection approach captured a broader range of plausible future conditions than the RCP-ensemble approach, particularly in the near term. Therefore, the individual-projection approach supports decision makers seeking to understand the broadest potential characterization of future conditions. We discuss tradeoffs associated with different climate future approaches and highlight suitable applications. [ABSTRACT FROM AUTHOR]

The glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation is frequently used to alleviate therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung cancer. We show that GR activation induces reversible cancer cell dormancy characterised by anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anticancer therapy related side-effects. Glucocorticoids (GC) are reported to block cancer cell proliferation, but the mode of action is unclear. Here the authors show that glucocorticoid receptor activation induces cancer cell dormancy in lung cancer by regulating CDKN1C expression through a distal enhancer, and these dormant cells are addicted to IGF-1R signalling pathway. [ABSTRACT FROM AUTHOR]

The pathophysiology of sepsis is multi-facetted and highly complex. As sepsis is a leading cause of global mortality that still lacks targeted therapies, increased understanding of its pathogenesis is vital for improving clinical care and outcomes. An increasing number of investigations seeks to unravel the complexity of sepsis through high-dimensional data analysis, enabled by advances in -omics technologies. Here, we summarize progress in the following major -omics fields: genomics, epigenomics, transcriptomics, proteomics, lipidomics, and microbiomics. We describe what these fields can teach us about sepsis, and highlight current trends and future challenges. Finally, we focus on multi-omics integration, and discuss the challenges in deriving biological meaning and clinical applications from these types of data. [ABSTRACT FROM AUTHOR]

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GIS-based multicriteria evaluation (MCE) provides a framework for analysing complex decision problems by quantifying variables of interest to score potential locations according to their suitability. In the context of earthquake preparedness and post-disaster response, MCE has relied mainly on uninformed or non-expert stakeholders to identify high-risk zones, prioritise areas for response, or highlight vulnerable populations. In this study, we compare uninformed, informed non-expert, and expert stakeholders' responses in MCE modelling for earthquake response planning in Vancouver, Canada. Using medium- to low-complexity MCE models, we highlight similarities and differences in the importance of infrastructural and socioeconomic variables, emergency services, and liquefaction potential between a non-weighted MCE, a medium-complexity informed non-expert MCE, and a low-complexity MCE informed by 35 local earthquake planning and response experts from governmental and non-governmental organisations. Differences in the observed results underscore the importance of accessible, expert-informed approaches for prioritising locations for earthquake response planning and for the efficient and geographically precise allocation of resources. [ABSTRACT FROM AUTHOR]

Tetraspanin CD37 has recently received renewed interest as a therapeutic target for B-cell malignancies. Although complement-dependent cytotoxicity (CDC) is a powerful Fc-mediated effector function for killing hematological cancer cells, CD37-specific antibodies are generally poor inducers of CDC. To enhance CDC, the E430G mutation was introduced into humanized CD37 monoclonal IgG1 antibodies to drive more efficient IgG hexamer formation through intermolecular Fc-Fc interactions after cell surface antigen binding. DuoHexaBody-CD37, a bispecific CD37 antibody with the E430G hexamerization-enhancing mutation targeting two non-overlapping epitopes on CD37 (biparatopic), demonstrated potent and superior CDC activity compared to other CD37 antibody variants evaluated, in particular ex vivo in patient-derived chronic lymphocytic leukemia cells. The superior CDC potency was attributed to enhanced IgG hexamerization mediated by the E430G mutation in combination with dual epitope targeting. The mechanism of action of DuoHexaBody-CD37 was shown to be multifaceted, as it was additionally capable of inducing efficient antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro. Finally, potent anti-tumor activity in vivo was observed in cell line- and patient-derived xenograft models from different B-cell malignancy subtypes. These encouraging preclinical results suggest that DuoHexaBody-CD37 (GEN3009) may serve as a potential therapeutic antibody for the treatment of human B-cell malignancies. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer is the most common malignancy among young women of reproductive age. Adjuvant treatment with tamoxifen reduces the risk of recurrence in hormone-sensitive breast cancer. However, the use of tamoxifen is considered contraindicated during pregnancy, because of a limited number of case reports demonstrating potential adverse effects on the fetus. The objective of this report is to give a more broad overview of the available data on the effect of tamoxifen exposure during pregnancy. Methods: A literature review was performed using PubMed and the databases of the Netherlands Pharmacovigilance Centre Lareb and of the International Network on Cancer, Infertility, and Pregnancy. Results: A total of 238 cases of tamoxifen use during pregnancy were found. Of the 167 pregnancies with known outcome, 21 were complicated by an abnormal fetal development. The malformations described were non-specific and the majority of cases concerned healthy infants despite exposure to tamoxifen. Conclusion: There seems to be an increased risk of fetal abnormalities when taking tamoxifen during pregnancy (12.6% in contrast to 3.9% in the general population), but the evidence is limited and no causal relationship could be established. The possible disadvantage of postponing or discontinuing tamoxifen for the maternal prognosis is unclear. Patients should be counseled about the use of tamoxifen during pregnancy instead of presenting it as being absolutely contraindicated. [ABSTRACT FROM AUTHOR]

Recently in the journal, Legrand and colleagues identified three distinct clinical sub-phenotypes of COVID-19, which may help recognize patients at high risk of deterioration [[2]]. The retrospective cohort study of Legrand et al. consisted of 893 patients of which 608 were used for cluster analysis, after excluding patients with missing data. [Extracted from the article]

Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but relapse after hormonal treatment is also noted. The panhormonal action of steroid hormonal receptors, including estrogen receptor alpha (ERα), androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (GR) in this understudied tumor type remains wholly unexamined. This study reveals genomic cross-talk of steroid hormone receptor action and interplay in human tumors, here in the context of MBC, in relation to the female disease and patient outcome. Here we report the characterization of human breast tumors of both genders for cistromic make-up of hormonal regulation in human tumors, revealing genome-wide chromatin binding landscapes of ERα, AR, PR, GR, FOXA1, and GATA3 and enhancer-enriched histone mark H3K4me1. We integrate these data with transcriptomics to reveal gender-selective and genomic location-specific hormone receptor actions, which associate with survival in MBC patients. [ABSTRACT FROM AUTHOR]

A combined temporal analysis of products (TAP) and steady-state kinetic study was achieved to characterize the surface reactivity of fresh and aged bimetallic Pd-Rh/AlO Natural-Gas Vehicle catalysts. Single NO pulse TAP experiments were performed on a stabilized surface after exposure to successive NO pulses until to get a steady-state NO conversion. Outlet flow curves recorded during such experiments show fast reaction steps taking place on noble metal particles and a slow process during NO desorption ascribed to the involvement of spill-over effect of chemisorbed NO molecules from the metal to the support. This slow process attenuates on the aged sample likely due to an alteration of the metal/support interface induced by particle sintering at high temperature. Thermal aging also alters the surface composition of bimetallic Pd-Rh particles which leads to changes in the products distribution from NO dissociation. A similar selectivity behavior is observed from steady-state kinetic measurements during the NO/H reaction. Interestingly, a weak partial pressure dependency of the selectivity reflects a surface Rh enrichment of Pd-Rh particles during aging. [ABSTRACT FROM AUTHOR]

In this paper we report on a two-stage evaluation of unsupervised labeling of audiovisual content using collateral text data sources to investigate how such an approach can provide acceptable results for given requirements with respect to archival quality, authority and service levels to external users. We conclude that with parameter settings that are optimized using a rigorous evaluation of precision and accuracy, the quality of automatic term-suggestion is sufficiently high. We furthermore provide an analysis of the term extraction after being taken into production, where we focus on performance variation with respect to term types and television programs. Having implemented the procedure in our production work-flow allows us to gradually develop the system further and to also assess the effect of the transformation from manual to automatic annotation from an end-user perspective. Additional future work will be on deploying different information sources including annotations based on multimodal video analysis such as speaker recognition and computer vision. [ABSTRACT FROM AUTHOR]

Climate change adaptation is a rapidly evolving field in conservation biology and includes a range of strategies from resisting to actively directing change on the landscape. The term 'climate change resilience,' frequently used to characterize adaptation strategies, deserves closer scrutiny because it is ambiguous, often misunderstood, and difficult to apply consistently across disciplines and spatial and temporal scales to support conservation efforts. Current definitions of resilience encompass all aspects of adaptation from resisting and absorbing change to reorganizing and transforming in response to climate change. However, many stakeholders are unfamiliar with this spectrum of definitions and assume the more common meaning of returning to a previous state after a disturbance. Climate change, however, is unrelenting and intensifying, characterized by both directional shifts in baseline conditions and increasing variability in extreme events. This ongoing change means that scientific understanding and management responses must develop concurrently, iteratively, and collaboratively, in a science-management partnership. Divergent concepts of climate change resilience impede cross-jurisdictional adaptation efforts and complicate use of adaptive management frameworks. Climate change adaptation practitioners require clear terminology to articulate management strategies and the inherent tradeoffs involved in adaptation. Language that distinguishes among strategies that seek to resist change, accommodate change, and direct change (i.e., persistence, autonomous change, and directed change) is prerequisite to clear communication about climate change adaptation goals and management intentions in conservation areas. [ABSTRACT FROM AUTHOR]

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The exponential adoption of smartphones affords the general public access to tools (sensors) that were once only available to highly trained scientists and geospatial technicians. This provides more people with opportunities to contribute and consume information relevant to their current location. Geographers have been applying critical theory to examine privacy implications associated with constant locational aware smartphone usage while applied researchers are measuring spatial cognitive abilities using empirically bound approaches. What remains unknown is how smartphone users perceive implications associated with privacy and spatial cognitive abilities as a result of smartphone use for location based queries. An online survey was administered to collect perceptions related to these issues from the general smartphone-using public. It was found that while participants were mindful of privacy concerns associated with smartphone use, they reported that perceived benefits of smartphone use outweigh associated costs. Additionally, the majority of the participants found that their smartphones provided them with confidence in wayfinding tasks rather than hindering them as some literature suggests. Through this study we aim to describe how a lack of understanding of the general publics' perceptions of smartphone usage may be limiting contemporary theory and practice within volunteered geographic information and location based services related research associated with geography. [ABSTRACT FROM AUTHOR]

We explored the dilemma between patients' right not to know their genetic status and the efficient use of health-care resources in the form of clinical cancer screening programmes. Currently, in the Netherlands, 50% risk carriers of heritable cancer syndromes who choose not to know their genetic status have access to the same screening programmes as proven mutation carriers. This implies an inefficient use of health-care resources, because half of this group will not carry the familial mutation. At the moment, only a small number of patients are involved; however, the expanding possibilities for genetic risk profiling means this issue must be addressed because of potentially adverse societal and financial impact. The trade-off between patients' right not to know their genetic status and efficient use of health-care resources was discussed in six focus groups with health-care professionals and patients from three Dutch university hospitals. Professionals prefer patients to undergo a predictive DNA test as a prerequisite for entering cancer screening programmes. Professionals prioritise treating sick patients or proven mutation carriers over screening untested individuals. Participation in cancer screening programmes without prior DNA testing is, however, supported by most professionals, as testing is usually delayed and relatively few patients are involved at present. Reducing the number of 50% risk carriers undergoing screening is expected to be achieved by: offering more psychosocial support, explaining the iatrogenic risks of cancer screening, increasing out-of-pocket costs, and offering a less stringent screening programme for 50% risk carriers. [ABSTRACT FROM AUTHOR]