Cost-benefit evaluation of advanced therapy lines in metastatic triple-negative breast cancer in Germany.

BACKGROUND: Triple-negative breast cancer (TNBC) is responsible for 10-20% cases of breast cancer and is resulting in rising healthcare costs. Thus, health-economic evaluations are needed to relate clinical outcomes and costs of treatment options and to provide recommendations of action from a health-economic perspective. METHODS: We investigated the cost-benefit-ratio of approved treatment options in metastatic TNBC in Germany by applying the efficiency frontier approach. These included sacituzumab-govitecan (SG), eribulin, vinorelbine, and capecitabine. Clinical benefit was measured as (i) median overall survival (mOS) and (ii) health-related quality of life (HRQoL) in terms of time to symptom worsening (TSW). To assess medical benefits, literature was systematically reviewed in PubMed for (i) and (ii), respectively. Treatment costs were calculated considering annual direct outpatient treatment costs from a statutory healthcare payer perspective. It was intended that both, (i) and (ii), yield an efficiency frontier. RESULTS: Annual direct outpatient treatment costs amounted to EUR 176,415.21 (SG), EUR 47,414.14 (eribulin), EUR 13,711.35 (vinorelbine), and EUR 3,718.84 (capecitabine). Systematic literature review of (i) and statistical analysis resulted in OS values of 14.3, 9.56, 9.44, and 7.46 months, respectively. Capecitabine, vinorelbine, and SG are part of the efficiency frontier including OS. The highest additional benefit per additional cost was determined for vinorelbine, followed by SG. Systematic review of (ii) revealed that no TSW data of TNBC patients receiving vinorelbine were available, preventing the presentation of an efficiency frontier including HRQoL. CONCLUSIONS: Vinorelbine is most cost-effective, followed by SG. Health-economic evaluations support decision-makers to assess treatment options within one indication area. In Germany, the efficiency frontier can provide decision support for the pricing of innovative interventions. Results of our analysis may thus guide reimbursement determination.

The status of forest carbon markets in Latin America.

Tropical rainforests of Latin America (LATAM) are one of the world's largest carbon sinks, with substantial future carbon sequestration potential and contributing a major proportion of the global supply of forest carbon credits. LATAM is poised to contribute predominantly towards high-quality forest carbon offset projects designed to reduce emissions from deforestation and forest degradation, halt biodiversity loss, and provide equitable conservation benefits to people. Thus, carbon markets, including compliance carbon markets and voluntary carbon markets continue to expand in LATAM. However, the extent of the growth and status of forest carbon markets, pricing initiatives, stakeholders, amongst others, are yet to be explored and extensively reviewed for the entire LATAM region. Against this backdrop, we reviewed a total of 299 articles, including peer-reviewed and non-scientific gray literature sources, from January 2010 to March 2023. Herein, based on the extensive literature review, we present the results and provide perspectives classified into five categories: (i) the status and recent trends of forest carbon markets (ii) the interested parties and their role in the forest carbon markets, (iii) the measurement, reporting and verification (MRV) approaches and role of remote sensing, (iv) the challenges, and (v) the benefits, opportunities, future directions and recommendations to enhance forest carbon markets in LATAM. Despite the substantial challenges, better governance structures for forest carbon markets can increase the number, quality and integrity of projects and support the carbon sequestration capacity of the rainforests of LATAM. Due to the complex and extensive nature of forest carbon projects in LATAM, emerging technologies like remote sensing can enable scale and reduce technical barriers to MRV, if properly benchmarked. The future directions and recommendations provided are intended to improve upon the existing infrastructure and governance mechanisms, and encourage further participation from the public and private sectors in forest carbon markets in LATAM.

Ecotourism and mangrove conservation in Southeast Asia: Current trends and perspectives.

Mangroves in Southeast Asia provide numerous supporting, provisioning, regulating, and cultural services that are crucial to the environment and local livelihoods since they support biodiversity conservation and climate change resilience. However, Southeast Asia mangroves face deforestation threats from the expansion of commercial aquaculture, agriculture, and urban development, along with climate change-related natural processes. Ecotourism has gained prominence as a financial incentive tool to support mangrove conservation and restoration. Through a systematic literature review approach, we examined the relationships between ecotourism and mangrove conservation in Southeast Asia based on scientific papers published from 2010 to 2022. Most of the studies were reported in Indonesia, Malaysia, Philippines, Thailand, and Vietnam, respectively, which were associated with the highest number of vibrant mangrove ecotourism sites and largest mangrove areas compared to the other countries of Southeast Asia. Mangrove-related ecotourism activities in the above countries mainly include boat tours, bird and wildlife watching, mangrove planting, kayaking, eating seafood, and snorkeling. The economic benefits, such as an increase in income associated with mangrove ecotourism, have stimulated infrastructural development in ecotourism destinations. Local communities benefited from increased access to social amenities such as clean water, electricity, transportation networks, schools, and health services that are intended to make destinations more attractive to tourists. Economic benefits from mangrove ecotourism motivated the implementation of several community-based mangrove conservation and restoration initiatives, which attracted international financial incentives and public-private partnerships. Since mangroves are mostly located on the land occupied by indigenous people and local communities, ensuring respect for their land rights and equity in economic benefit sharing may increase their intrinsic motivation and participation in mangrove restoration and conservation initiatives. Remote sensing tools for mangrove monitoring, evaluation, and reporting, and integrated education and awareness campaigns can ensure the long-term conservation of mangroves while sustaining ecotourism's economic infrastructure and social amenities benefits.

Effects of continuous bisphenol A exposure from early gestation on 90 day old rat testes function and sperm molecular profiles: A CLARITY-BPA consortium study.

Bisphenol A (BPA) is a ubiquitous industrial chemical that has been identified as an endocrine disrupting compound (EDC). There is growing concern that early life exposures to EDCs, such as BPA, can adversely affect the male reproductive tract and function. This study was conducted as part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) to further delineate the toxicities associated with continuous exposure to BPA from early gestation, and to comprehensively examine the elicited effects on testes and sperm. NCTR Sprague Dawley rat dams were gavaged from gestational day (GD) 6 until parturition, and their pups were directly gavaged daily from postnatal day (PND) 1 to 90 with BPA (2.5, 25, 250, 2500, 25,000, 250,000 µg/kg/d) or vehicle control. At PND 90, the testes and sperm were collected for evaluation. The testes were histologically evaluated for altered germ cell apoptosis, sperm production, and altered spermiation. RNA and DNA isolated from sperm were assessed for elicited changes in global mRNA transcript abundance and altered DNA methylation. Effects of BPA were observed in changes in body, testis and epididymis weights only at the highest administered dose of BPA of 250,000 µg/kg/d. Genome-wide transcriptomic and epigenomic analyses failed to detect robust alterations in sperm mRNA and DNA methylation levels. These data indicate that prolonged exposure starting in utero to BPA over a wide range of levels has little, if any, impact on the testes and sperm molecular profiles of 90 day old rats as assessed by the histopathologic, morphometric, and molecular endpoints evaluated.

Effects of developmental exposure to bisphenol A on spatial navigational learning and memory in rats: A CLARITY-BPA study.

Bisphenol A (BPA) is a ubiquitous industrial chemical used in the production of a wide variety of items. Previous studies suggest BPA exposure may result in neuro-disruptive effects; however, data are inconsistent across animal and human studies. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether female and male rats developmentally exposed to BPA demonstrated later spatial navigational learning and memory deficits. Pregnant NCTR Sprague-Dawley rats were orally dosed from gestational day 6 to parturition, and offspring were directly orally dosed until weaning (postnatal day 21). Treatment groups included a vehicle control, three BPA doses (2.5µg/kg body weight (bw)/day-[2.5], 25µg/kg bw/day-[25], and 2500µg/kg bw/day-[2500]) and a 0.5µg/kg/day ethinyl estradiol (EE)-reference estrogen dose. At adulthood, 1/sex/litter was tested for seven days in the Barnes maze. The 2500 BPA group sniffed more incorrect holes on day 7 than those in the control, 2.5 BPA, and EE groups. The 2500 BPA females were less likely than control females to locate the escape box in the allotted time (p value=0.04). Although 2.5 BPA females exhibited a prolonged latency, the effect did not reach significance (p value=0.06), whereas 2.5 BPA males showed improved latency compared to control males (p value=0.04), although the significance of this result is uncertain. No differences in serum testosterone concentration were detected in any male or female treatment groups. Current findings suggest developmental exposure of rats to BPA may disrupt aspects of spatial navigational learning and memory.

The effect of black cohosh extract and risedronate coadministration on bone health in an ovariectomized rat model.

Preparations of black cohosh extract are sold as dietary supplements marketed to relieve the vasomotor symptoms of menopause, and some studies suggest it may protect against postmenopausal bone loss. Postmenopausal women are also frequently prescribed bisphosphonates, such as risedronate, to prevent osteoporotic bone loss. However, the pharmacodynamic interactions between these compounds when taken together is not known. To investigate possible interactions, 6-month-old, female Sprague-Dawley rats underwent bilateral ovariectomy or sham surgery and were treated for 24 weeks with either vehicle, ethinyl estradiol, risedronate, black cohosh extract or coadministration of risedronate and black cohosh extract, at low or high doses. Bone mineral density (BMD) of the femur, tibia, and lumbar vertebrae was then measured by dual-energy X-ray absorptiometry (DEXA) at weeks 0, 8, 16, and 24. A high dose of risedronate significantly increased BMD of the femur and vertebrae, while black cohosh extract had no significant effect on BMD individually and minimal effects upon coadministration with risedronate. Under these experimental conditions, black cohosh extract alone had no effect on BMD, nor did it negatively impact the BMD-enhancing properties of risedronate.

Validation of an ICD-code-based case definition for psychotic illness across three health systems.

Background and Hypothesis: Early detection of psychosis is critical for improving outcomes. Algorithms to predict or detect psychosis using electronic health record (EHR) data depend on the validity of the case definitions used, typically based on diagnostic codes. Data on the validity of psychosis-related diagnostic codes is limited. We evaluated the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for psychosis. Study Design: Using EHRs at three health systems, ICD codes comprising primary psychotic disorders and mood disorders with psychosis were grouped into five higher-order groups. 1,133 records were sampled for chart review using the full EHR. PPVs (the probability of chart-confirmed psychosis given ICD psychosis codes) were calculated across multiple treatment settings. Study Results: PPVs across all diagnostic groups and hospital systems exceeded 70%: Massachusetts General Brigham 0.72 [95% CI 0.68-0.77], Boston Children's Hospital 0.80 [0.75-0.84], and Boston Medical Center 0.83 [0.79-0.86]. Schizoaffective disorder PPVs were consistently the highest across sites (0.80-0.92) and major depressive disorder with psychosis were the most variable (0.57-0.79). To determine if the first documented code captured first-episode psychosis (FEP), we excluded cases with prior chart evidence of a diagnosis of or treatment for a psychotic illness, yielding substantially lower PPVs (0.08-0.62). Conclusions: We found that the first documented psychosis diagnostic code accurately captured true episodes of psychosis but was a poor index of FEP. These data have important implications for the development of risk prediction models designed to predict or detect undiagnosed psychosis.

Validation of an ICD-Code-Based Case Definition for Psychotic Illness Across Three Health Systems.

BACKGROUND AND HYPOTHESIS: Psychosis-associated diagnostic codes are increasingly being utilized as case definitions for electronic health record (EHR)-based algorithms to predict and detect psychosis. However, data on the validity of psychosis-related diagnostic codes is limited. We evaluated the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for psychosis. STUDY DESIGN: Using EHRs at 3 health systems, ICD codes comprising primary psychotic disorders and mood disorders with psychosis were grouped into 5 higher-order groups. 1133 records were sampled for chart review using the full EHR. PPVs (the probability of chart-confirmed psychosis given ICD psychosis codes) were calculated across multiple treatment settings. STUDY RESULTS: PPVs across all diagnostic groups and hospital systems exceeded 70%: Mass General Brigham 0.72 [95% CI 0.68-0.77], Boston Children's Hospital 0.80 [0.75-0.84], and Boston Medical Center 0.83 [0.79-0.86]. Schizoaffective disorder PPVs were consistently the highest across sites (0.80-0.92) and major depressive disorder with psychosis were the most variable (0.57-0.79). To determine if the first documented code captured first-episode psychosis (FEP), we excluded cases with prior chart evidence of a diagnosis of or treatment for a psychotic illness, yielding substantially lower PPVs (0.08-0.62). CONCLUSIONS: We found that the first documented psychosis diagnostic code accurately captured true episodes of psychosis but was a poor index of FEP. These data have important implications for the case definitions used in the development of risk prediction models designed to predict or detect undiagnosed psychosis.

Comparison of the global gene expression of choroid plexus and meninges and associated vasculature under control conditions and after pronounced hyperthermia or amphetamine toxicity.

BACKGROUND: The meninges (arachnoid and pial membranes) and associated vasculature (MAV) and choroid plexus are important in maintaining cerebrospinal fluid (CSF) generation and flow. MAV vasculature was previously observed to be adversely affected by environmentally-induced hyperthermia (EIH) and more so by a neurotoxic amphetamine (AMPH) exposure. Herein, microarray and RT-PCR analysis was used to compare the gene expression profiles between choroid plexus and MAV under control conditions and at 3 hours and 1 day after EIH or AMPH exposure. Since AMPH and EIH are so disruptive to vasculature, genes related to vasculature integrity and function were of interest. RESULTS: Our data shows that, under control conditions, many of the genes with relatively high expression in both the MAV and choroid plexus are also abundant in many epithelial tissues. These genes function in transport of water, ions, and solutes, and likely play a role in CSF regulation. Most genes that help form the blood-brain barrier (BBB) and tight junctions were also highly expressed in MAV but not in choroid plexus. In MAV, exposure to EIH and more so to AMPH decreased the expression of BBB-related genes such as Sox18, Ocln, and Cldn5, but they were much less affected in the choroid plexus. There was a correlation between the genes related to reactive oxidative stress and damage that were significantly altered in the MAV and choroid plexus after either EIH or AMPH. However, AMPH (at 3 hr) significantly affected about 5 times as many genes as EIH in the MAV, while in the choroid plexus EIH affected more genes than AMPH. Several unique genes that are not specifically related to vascular damage increased to a much greater extent after AMPH compared to EIH in the MAV (Lbp, Reg3a, Reg3b, Slc15a1, Sct and Fst) and choroid plexus (Bmp4, Dio2 and Lbp). CONCLUSIONS: Our study indicates that the disruption of choroid plexus function and damage produced by AMPH and EIH is significant, but the changes may not be as pronounced as they are in the MAV, particularly for AMPH. Expression profiles in the MAV and choroid plexus differed to some extent and differences were not restricted to vascular related genes.

Race, pigmentation, and the human skin barrier-considerations for dermal absorption studies.

A functional human skin barrier is critical in limiting harmful exposure to environmental agents and regulating the absorption of intentionally applied topical drug and cosmetic products. Inherent differences in the skin barrier between consumers due to extrinsic and intrinsic factors are an important consideration in the safety assessment of dermatological products. Race is a concept often used to describe a group of people who share distinct physical characteristics. The observed predisposition of specific racial groups to certain skin pathologies highlights the potential differences in skin physiology between these groups. In the context of the human skin barrier, however, the current data correlating function to race often conflict, likely as a consequence of the range of experimental approaches and controls used in the existing works. To date, a variety of methods have been developed for evaluating compound permeation through the human skin, both in vivo and in vitro. Additionally, great strides have been made in the development of reconstructed human pigmented skin models, with the flexibility to incorporate melanocytes from donors of different race and pigmentation levels. Together, the advances in the production of reconstructed human skin models and the increased adoption of in vitro methodologies show potential to aid in the standardization of dermal absorption studies for discerning racial- and skin pigmentation-dependent differences in the human skin barrier. This review analyzes the existing data on skin permeation, focusing on its interaction with race and skin pigmentation, and highlights the tools and research opportunities to better represent the diversity of the human populations in dermal absorption assessments.

Cannabis use among patients presenting to the emergency department for psychosis: Associations with restraint use, medication administration, psychiatric hospitalization, and repeat visits.

Cannabis use is associated with increased severity of psychotic symptoms and the risk of acute agitation and aggressive behavior in inpatient (IP) and outpatient settings. Whether or not cannabis use is associated with increased acuity of psychosis-related ED presentations and risk of repeat ED visits for psychosis is unclear. In this retrospective study of 2,134 ED visits for acute psychosis, we investigated the risk of physical restraint, parenteral medication administration, psychiatric hospitalization, and recurrent ED visits. We examined ED visits between March 1, 2019 and February 28, 2021 based on urinary Tetrahydrocannabinol (THC) screen status (positive vs negative vs no screen). The risk of physical restraint, parenteral antipsychotic, and benzodiazepine administration was significantly greater in ED visits with a positive THC screen compared to those with a negative or no THC screen. We did not find an association between a positive urinary THC screen and IP hospitalization or the risk of recurrent ED presentation for psychosis within 90 days. These findings suggest that positive urinary THC may predict acute agitation or acuity of symptoms in ED settings and underscores the importance of screening for THC during ED presentations for psychosis.

Parallel evaluation of alternative skin barrier models and excised human skin for dermal absorption studies in vitro.

Skin permeation is a primary consideration in the safety assessment of cosmetic ingredients, topical drugs, and human users handling veterinary medicinal products. While excised human skin (EHS) remains the 'gold standard' for in vitro permeation testing (IVPT) studies, unreliable supply and high cost motivate the search for alternative skin barrier models. In this study, a standardized dermal absorption testing protocol was developed to evaluate the suitability of alternative skin barrier models to predict skin absorption in humans. Under this protocol, side-by-side assessments of a commercially available reconstructed human epidermis (RhE) model (EpiDerm-200-X, MatTek), a synthetic barrier membrane (Strat-M, Sigma-Aldrich), and EHS were performed. The skin barrier models were mounted on Franz diffusion cells and the permeation of caffeine, salicylic acid, and testosterone was quantified. Transepidermal water loss (TEWL) and histology of the biological models were also compared. EpiDerm-200-X exhibited native human epidermis-like morphology, including a characteristic stratum corneum, but had an elevated TEWL as compared to EHS. The mean 6 h cumulative permeation of a finite dose (6 nmol/cm2) of caffeine and testosterone was highest in EpiDerm-200-X, followed by EHS and Strat-M. Salicylic acid permeated most in EHS, followed by EpiDerm-200-X and Strat-M. Overall, evaluating novel alternative skin barrier models in the manner outlined herein has the potential to reduce the time from basic science discovery to regulatory impact.

Influence of urban forests on residential property values: A systematic review of remote sensing-based studies.

Urban forests provide direct and indirect benefits to human well-being that are increasingly captured in residential property values. Remote Sensing (RS) can be used to measure a wide range of forest and vegetation parameters that allows for a more detailed and better understanding of their specific influences on housing prices. Herein, through a systematic literature review approach, we reviewed 89 papers (from 2010 to 2022) from 21 different countries that used RS data to quantify vegetation indices, forest and tree parameters of urban forests and estimated their influence on residential property values. The main aim of this study was to understand and provide insights into how urban forests influence residential property values based on RS studies. Although more studies were conducted in developed (n = 55, 61.7%) than developing countries (n = 34, 38.3%), the results indicated for the most part that increasing tree canopy cover on property and neighborhood level, forest size, type, greenness, and proximity to urban forests increased housing prices. RS studies benefited from spatially explicit repetitive data that offer superior efficiency to quantify vegetation, forest, and tree parameters of urban forests over large areas and longer periods compared to studies that used field inventory data. Through this work, we identify and underscore that urban forest benefits outweigh management costs and have a mostly positive influence on housing prices. Thus, we encourage further discussions about prioritizing reforestation and conservation of urban forests during the urban planning of cities and suburbs, which could support UN Sustainable Development Goals (SDGs) and urban policy reforms.

A robust biostatistical method leverages informative but uncertainly determined qPCR data for biomarker detection, early diagnosis, and treatment.

As a common medium-throughput technique, qPCR (quantitative real-time polymerase chain reaction) is widely used to measure levels of nucleic acids. In addition to accurate and complete data, experimenters have unavoidably observed some incomplete and uncertainly determined qPCR data because of intrinsically low overall amounts of biological materials, such as nucleic acids present in biofluids. When there are samples with uncertainly determined qPCR data, some investigators apply the statistical complete-case method by excluding the subset of samples with uncertainly determined data from analysis (CO), while others simply choose not to analyze (CNA) these datasets altogether. To include as many observations as possible in analysis for interesting differential changes between groups, some investigators set incomplete observations equal to the maximum quality qPCR cycle (MC), such as 32 and 40. Although straightforward, these methods may decrease the sample size, skew the data distribution, and compromise statistical power and research reproducibility across replicate qPCR studies. To overcome the shortcomings of the existing, commonly-used qPCR data analysis methods and to join the efforts in advancing statistical analysis in rigorous preclinical research, we propose a robust nonparametric statistical cycle-to-threshold method (CTOT) to analyze incomplete qPCR data for two-group comparisons. CTOT incorporates important characteristics of qPCR data and time-to-event statistical methodology, resulting in a novel analytical method for qPCR data that is built around good quality data from all subjects, certainly determined or not. Considering the benchmark full data (BFD), we compared the abilities of CTOT, CO, MC, and CNA statistical methods to detect interesting differential changes between groups with informative but uncertainly determined qPCR data. Our simulations and applications show that CTOT improves the power of detecting and confirming differential changes in many situations over the three commonly used methods without excess type I errors. The robust nonparametric statistical method of CTOT helps leverage qPCR technology and increase the power to detect differential changes that may assist decision making with respect to biomarker detection and early diagnosis, with the goal of improving the management of patient healthcare.

Temporal dynamics of SARS-CoV-2 genome and detection of variants of concern in wastewater influent from two metropolitan areas in Arkansas.

Although SARS-CoV-2 can cause severe illness and death, a percentage of the infected population is asymptomatic. This, along with other factors, such as insufficient diagnostic testing and underreporting due to self-testing, contributes to the silent transmission of SARS-CoV-2 and highlights the importance of implementing additional surveillance tools. The fecal shedding of the virus from infected individuals enables its detection in community wastewater, and this has become a valuable public health tool worldwide as it allows the monitoring of the disease on a populational scale. Here, we monitored the presence of SARS-CoV-2 and its dynamic genomic changes in wastewater sampled from two metropolitan areas in Arkansas during major surges of COVID-19 cases and assessed how the viral titers in these samples related to the clinical case counts between late April 2020 and January 2022. The levels of SARS-CoV-2 RNA were quantified by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) using a set of TaqMan assays targeting three different viral genes (encoding ORF1ab polyprotein, surface glycoprotein, and nucleocapsid phosphoprotein). An allele-specific RT-qPCR approach was used to screen the samples for SARS-CoV-2 mutations. The identity and genetic diversity of the virus were further investigated through amplicon-based RNA sequencing, and SARS-CoV-2 variants of concern were detected in wastewater samples throughout the duration of this study. Our data show how changes in the virus genome can affect the sensitivity of specific RT-qPCR assays used in COVID-19 testing with the surge of new variants. A significant association was observed between viral titers in wastewater and recorded number of COVID-19 cases in the areas studied, except when assays failed to detect targets due to the presence of particular variants. These findings support the use of wastewater surveillance as a reliable complementary tool for monitoring SARS-CoV-2 and its genetic variants at the community level.

Current Trends and Perspectives on Predictive Models for Mildew Diseases in Vineyards.

Environmental and economic costs demand a rapid transition to more sustainable farming systems, which are still heavily dependent on chemicals for crop protection. Despite their widespread application, powdery mildew (PM) and downy mildew (DM) continue to generate serious economic penalties for grape and wine production. To reduce these losses and minimize environmental impacts, it is important to predict infections with high confidence and accuracy, allowing timely and efficient intervention. This review provides an appraisal of the predictive tools for PM and DM in a vineyard, a specialized farming system characterized by high crop protection cost and increasing adoption of precision agriculture techniques. Different methodological approaches, from traditional mechanistic or statistic models to machine and deep learning, are outlined with their main features, potential, and constraints. Our analysis indicated that strategies are being continuously developed to achieve the required goals of ease of monitoring and timely prediction of diseases. We also discuss that scientific and technological advances (e.g., in weather data, omics, digital solutions, sensing devices, data science) still need to be fully harnessed, not only for modelling plant-pathogen interaction but also to develop novel, integrated, and robust predictive systems and related applied technologies. We conclude by identifying key challenges and perspectives for predictive modelling of phytopathogenic disease in vineyards.

Arabidopsis Rab-E GTPases exhibit a novel interaction with a plasma-membrane phosphatidylinositol-4-phosphate 5-kinase.

Rab GTPases of the Arabidopsis Rab-E subclass are related to mammalian Rab8 and are implicated in membrane trafficking from the Golgi to the plasma membrane. Using a yeast two-hybrid assay, Arabidopsis phosphatidylinositol-4-phosphate 5-kinase 2 (PtdIns(4)P 5-kinase 2; also known as PIP5K2), was shown to interact with all five members of the Rab-E subclass but not with other Rab subclasses residing at the Golgi or trans-Golgi network. Interactions in yeast and in vitro were strongest with RAB-E1d[Q74L] and weakest with the RAB-E1d[S29N] suggesting that PIP5K2 interacts with the GTP-bound form. PIP5K2 exhibited kinase activity towards phosphatidylinositol phosphates with a free 5-hydroxyl group, consistent with PtdIns(4)P 5-kinase activity and this activity was stimulated by Rab binding. Rab-E proteins interacted with PIP5K2 via its membrane occupancy and recognition nexus (MORN) domain which is missing from animal and fungal PtdIns(4)P 5-kinases. In plant cells, GFP:PIP5K2 accumulated at the plasma membrane and caused YFP:RAB-E1d to relocate there from its usual position at the Golgi. GFP:PIP5K2 was rapidly turned over by proteasomal activity in planta, and overexpression of YFP:PIP5K2 caused pleiotropic growth abnormalities in transgenic Arabidopsis. We propose that plant cells exhibit a novel interaction in which PIP5K2 binds GTP-bound Rab-E proteins, which may stimulate temporally or spatially localized PtdIns(4,5)P(2) production at the plasma membrane.

Characterizing Typologies of Polytraumatization: A Replication and Extension Study Examining Internalizing and Externalizing Psychopathology in an Urban Population.

A person-centered approach to examining trauma has uncovered typologies of polytraumatization that are differentially associated with psychopathology. However, previous research is limited by narrow conceptualizations of trauma, limited distal outcomes, and underrepresentation of minorities. To address these gaps, we used latent profile analyses to uncover distinct polytraumatization typologies and examine four symptom-based (PTSD, depression, aggression, and substance abuse) and two behavior-based (self-harm, jail counts) outcomes in a sample of low-income adults (n = 7,426, 94% African American). The models were indicated by 19 traumatic experiences (e.g., accident, sexual assault, witnessing/experiencing violence). The best fitting model uncovered five classes: minimal trauma, physical abuse, violence exposure, sexual abuse, and polytrauma. Classes characterized by significant and varied trauma were higher on both internalizing and externalizing psychopathology, while those characterized by specific types of trauma were only higher on one type of psychopathology. Implications for the assessment and treatment of trauma-related disorders are discussed.

Reproducibility challenges for biomarker detection with uncertain but informative experimental data.

Recent studies have revealed that circulating microRNAs are promising biomarkers for detecting toxicity or disease. Quantitative real-time polymerase chain reaction (qPCR) is often used to measure the levels of microRNAs. Besides complete and certain data, investigators inevitably have observed technically incomplete or uncertain qPCR data. Investigators usually set incomplete observations equal to the maximum quality number of qPCR cycles, apply the complete-observation method, or choose not to analyze targets with incomplete observations. Using biostatistical knowledge and published studies, we show that three commonly applied methods tend to cause biased inference and decrease reproducibility in biomarker detection. More efforts are needed to address the challenges to identify and detect reliable, novel circulating biomarkers in liquid biopsies.

Effects of intravenous and oral di(2-ethylhexyl) phthalate (DEHP) and 20% Intralipid vehicle on neonatal rat testis, lung, liver, and kidney.

The highest human exposures to the plasticizer di(2-ethylhexyl) phthalate (DEHP) occur through intravenous (iv) exposure from medical procedures. Rodent toxicity studies, mainly using oral exposures, have identified male reproductive toxicity after developmental exposure to DEHP as the primary concern. Other organs are also affected by DEHP and route may influence the degree of target organ involvement. Cammack et al. (2003) reported a critical study focused on testicular toxicity using oral and iv exposures of neonatal Sprague-Dawley rats to 60, 300, or 600 mg/kg body weight/day DEHP in Intralipid vehicle. The present study followed the same dosing paradigm and included assessment of additional organs to evaluate the potential utility of this design for DEHP alternatives. Reduction of testis weight was observed in all DEHP treatment groups and germ cell and Sertoli cell toxicity was observed at the two highest doses with both routes. Lung granulomas occurred in all iv DEHP groups, possibly related to increased fat particle size in DEHP lipid emulsions. Lung alveolar development was inhibited after both oral and iv high dose DEHP. Toxicity of oral Intralipid vehicle was observed in germ and Sertoli cells. The lack of such effects after iv vehicle exposure suggested that this may be a gut-mediated effect.