Policymakers are increasingly using norm-based messages to influence individual decision making. We partner with a metropolitan water utility to implement a natural field experiment to examine the ...effect of such messages on residential water demand. The data, drawn from more than 100,000 households, indicate that social comparison messages had a greater influence on behavior than simple prosocial messages or technical information alone. Moreover, our data suggest that social comparison messages are most effective among households identified as the least price sensitive: high users. Yet the effectiveness of such messages wanes over time. Our results thus highlight important complementarities between pecuniary and nonpecuniary strategies.
Objective
To characterise the bladder microbiota of continent adult women.
Design
Cross‐sectional study of adult women who contributed catheterised urine samples, completed validated symptom ...questionnaires, and provided demographic data.
Setting
US academic medical centre.
Population
Well‐characterised continent adult women.
Methods
Participants contributed symptoms questionnaires, demographic data, and catheterised urine samples that were analysed by enhanced urine culture methodology and 16S rRNA gene sequencing.
Main outcome measures
Associations between demographics and microbial community state structures (urotypes, defined by the dominant taxon of each specimen).
Results
The bladder microbiota (urobiome) of a control group of 224 continent women were characterised, demonstrating variability in terms of urotype. The most common urotype was Lactobacillus (19%), which did not differ with any demographic. In contrast, the Gardnerella (P < 0.001) and Escherichia (P = 0.005) urotypes were more common in younger and older women, respectively.
Conclusions
For urobiome research, enhanced culture methods and/or DNA sequencing are the preferred techniques for bacterial detection. The interpretation of clinical tests, such as the standard urine culture, should incorporate the knowledge that some women have Gardnerella or Escherichia urotypes without evidence of any clinical disorder. Clinical care strategies should preserve or restore the beneficial effects of the native urobiome, as disruption of that microbial community could result in unintended vulnerability to uropathogen invasion or opportunistic pathogen overgrowth. Longitudinal studies of urobiome responses to therapies should be encouraged.
Tweetable
In continent adult women bladder microbiome composition differs by age, with relevance for clinical practice.
Tweetable
In continent adult women bladder microbiome composition differs by age, with relevance for clinical practice.
Metagenomic analyses have indicated that the female bladder harbors an indigenous microbiota. However, there are few cultured reference strains with sequenced genomes available for functional and ...experimental analyses. Here we isolate and genome-sequence 149 bacterial strains from catheterized urine of 77 women. This culture collection spans 78 species, representing approximately two thirds of the bacterial diversity within the sampled bladders, including Proteobacteria, Actinobacteria, and Firmicutes. Detailed genomic and functional comparison of the bladder microbiota to the gastrointestinal and vaginal microbiotas demonstrates similar vaginal and bladder microbiota, with functional capacities that are distinct from those observed in the gastrointestinal microbiota. Whole-genome phylogenetic analysis of bacterial strains isolated from the vagina and bladder in the same women identifies highly similar Escherichia coli, Streptococcus anginosus, Lactobacillus iners, and Lactobacillus crispatus, suggesting an interlinked female urogenital microbiota that is not only limited to pathogens but is also characteristic of health-associated commensals.
Testing for crowd out in social nudges Brandon, Alec; List, John A.; Metcalfe, Robert D. ...
Proceedings of the National Academy of Sciences - PNAS,
03/2019, Letnik:
116, Številka:
12
Journal Article
Recenzirano
Odprti dostop
This study considers the response of household electricity consumption to social nudges during peak load events. Our investigation considers two social nudges. The first targets conservation during ...peak load events, while the second promotes aggregate conservation. Using data from a natural field experiment with 42,100 households, we find that both social nudges reduce peak load electricity consumption by 2 to 4% when implemented in isolation and by nearly 7% when implemented in combination. These findings suggest an important role for social nudges in the regulation of electricity markets and a limited role for crowd out effects.
Hyaluronan (HA), a glycosaminoglycan located in the extracellular matrix, is important in embryo development, inflammation, wound healing and cancer. There is an extensive body of research ...demonstrating the role of HA in all stages of cancer, from initiation to relapse and therapy resistance. HA interacts with multiple cell surface receptors, including CD44, receptor for hyaluronan mediated motility (RHAMM) and intracellular signaling pathways, including receptor tyrosine kinase pathways, to promote the survival and proliferation of cancer cells. Additionally, HA promotes the formation of cancer stem cell (CSC) populations, which are hypothesized to be responsible for the initiation of tumors and therapy resistance. Recent studies have identified that the molecular weight of HA plays differing roles on both normal and cancer cell behavior. This review explores the role of HA in cancer progression and therapy resistance and how its molecular weight is important in regulating CSC populations, epithelial to mesenchymal transition (EMT), ATP binding cassette (ABC) transporter expression and receptor tyrosine kinase pathways.
Disabled-2 (
), a key adaptor protein in clathrin mediated endocytosis, is implicated in the regulation of key signalling pathways involved in homeostasis, cell positioning and epithelial to ...mesenchymal transition (EMT). It was initially identified as a tumour suppressor implicated in the initiation of ovarian cancer, but was subsequently linked to many other cancer types.
contains key functional domains which allow it to negatively regulate key signalling pathways including the mitogen activated protein kinase (MAPK), wingless/integrated (Wnt) and transforming growth factor beta (TGFβ) pathways. Loss of
is primarily associated with activation of these pathways and tumour progression, however this review also explores studies which demonstrate the complex nature of
function with pro-tumorigenic effects. A recent strong interest in microRNAs (miRNA) in cancer has identified
as a common target. This has reignited an interest in
research in cancer. Transcriptomics of tumour associated macrophages (TAMs) has also identified a pro-metastatic role of
in the tumour microenvironment. This review will cover the broad depth literature on the tumour suppressor role of
, highlighting its complex relationships with different pathways. Furthermore, it will explore recent findings which suggest
has a more complex role in cancer than initially thought.
Open-Source Automated Insulin Delivery in Type 1 Diabetes Burnside, Mercedes J; Lewis, Dana M; Crocket, Hamish R ...
New England journal of medicine/The New England journal of medicine,
09/2022, Letnik:
387, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Open-source automated insulin delivery (AID) systems are used by many patients with type 1 diabetes. Data are needed on the efficacy and safety of an open-source AID system.
In this multicenter, ...open-label, randomized, controlled trial, we assigned patients with type 1 diabetes in a 1:1 ratio to use an open-source AID system or a sensor-augmented insulin pump (control). The patients included both children (defined as 7 to 15 years of age) and adults (defined as 16 to 70 years of age). The AID system was a modified version of AndroidAPS 2.8 (with a standard OpenAPS 0.7.0 algorithm) paired with a preproduction DANA-i insulin pump and Dexcom G6 CGM, which has an Android smartphone application as the user interface. The primary outcome was the percentage of time in the target glucose range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter) between days 155 and 168 (the final 2 weeks of the trial).
A total of 97 patients (48 children and 49 adults) underwent randomization (44 to open-source AID and 53 to the control group). At 24 weeks, the mean (±SD) time in the target range increased from 61.2±12.3% to 71.2±12.1% in the AID group and decreased from 57.7±14.3% to 54.5±16.0% in the control group (adjusted difference, 14 percentage points; 95% confidence interval, 9.2 to 18.8; P<0.001), with no treatment effect according to age (P = 0.56). Patients in the AID group spent 3 hours 21 minutes more in the target range per day than those in the control group. No severe hypoglycemia or diabetic ketoacidosis occurred in either group. Two patients in the AID group withdrew from the trial owing to connectivity issues.
In children and adults with type 1 diabetes, the use of an open-source AID system resulted in a significantly higher percentage of time in the target glucose range than the use of a sensor-augmented insulin pump at 24 weeks. (Supported by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12620000034932.).
Precision medicine in oncology is the result of an increasing awareness of patient‐specific clinical features coupled with the development of genomic‐based diagnostics and targeted therapeutics. ...Companion diagnostics designed for specific drug‐target pairs were the first to widely utilize clinically applicable tumor biomarkers (eg, HER2, EGFR), directing treatment for patients whose tumors exhibit a mutation susceptible to an FDA‐approved targeted therapy (eg, trastuzumab, erlotinib). Clinically relevant germline mutations in drug‐metabolizing enzymes and transporters (eg, TPMT, DPYD) have been shown to impact drug response, providing a rationale for individualized dosing to optimize treatment. The use of multigene expression‐based assays to analyze an array of prognostic biomarkers has been shown to help direct treatment decisions, especially in breast cancer (eg, Oncotype DX). More recently, the use of next‐generation sequencing to detect many potential “actionable” cancer molecular alterations is further shifting the 1 gene–1 drug paradigm toward a more comprehensive, multigene approach. Currently, many clinical trials (eg, NCI‐MATCH, NCI‐MPACT) are assessing novel diagnostic tools with a combination of different targeted therapeutics while also examining tumor biomarkers that were previously unexplored in a variety of cancer histologies. Results from ongoing trials such as the NCI‐MATCH will help determine the clinical utility and future development of the precision‐medicine approach.
The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental ...models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti‐CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti‐human CD154 domain antibody (dAb, BMS‐986004). The anti‐CD154 dAb effectively blocked CD40‐CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti‐CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti‐CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti‐CD154 dAb treatment increased the frequency of CD4+CD25+Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti‐CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti‐CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.
An Fc‐silent anti‐CD154 domain antibody safely and effectively promotes long‐term kidney transplant survival in nonhuman primates without the risk of thromboembolism when combined with a clinically relevant conventional immunosuppression regimen. See the editorial from Thomson and Ezzelarab on page 1156.
Epithelial ovarian cancer is the most lethal gynaecological cancer worldwide. Chemotherapy resistance represents a significant clinical challenge and is the main reason for poor ovarian cancer ...prognosis. We identified novel expression of markers related to epithelial mesenchymal transitions (EMT) in a carboplatin resistant ovarian cancer cell line by proteomics. This was validated in the platinum resistant versus sensitive parental cell lines, as well as platinum resistant versus sensitive human ovarian cancer patient samples. The prognostic significance of the different proteomics-identified marker proteins in prognosis prediction on survival as well as their correlative association and influence on immune cell infiltration was determined by public domain data bases.
We explored the proteomic differences between carboplatin-sensitive OVCAR5 cells (parental) and their carboplatin-resistant counterpart, OVCAR5 CBPR cells. qPCR and western blots were performed to validate differentially expressed proteins at the mRNA and protein levels, respectively. Association of the identified proteins with epithelial-mesenchymal transition (EMT) prompted the investigation of cell motility. Cellular bioenergetics and proliferation were studied to delineate any biological adaptations that facilitate cancer progression. Expression of differentially expressed proteins was assessed in ovarian tumors obtained from platinum-sensitive (n = 15) versus platinum-resistant patients (n = 10), as well as matching tumors from patients at initial diagnosis and following relapse (n = 4). Kaplan-Meier plotter and Tumor Immune Estimation Resource (TIMER) databases were used to determine the prognostic significance and influence of the different proteomics-identified proteins on immune cell infiltration in the tumor microenvironment (TME).
Our proteomics study identified 2422 proteins in both cell lines. Of these, 18 proteins were upregulated and 14 were downregulated by ≥ twofold (p < 0.05) in OVCAR5 CBPR cells. Gene ontology enrichment analysis amongst upregulated proteins revealed an overrepresentation of biological processes consistent with EMT in the resistant cell line. Enhanced mRNA and/or protein expression of the identified EMT modulators including ITGA2, TGFBI, AKR1B1, ITGAV, ITGA1, GFPT2, FLNA and G6PD were confirmed in OVCAR5 CBPR cells compared to parental OVCAR5 cell line. Consistent with the altered EMT profile, the OVCAR5 CBPR cells demonstrated enhanced migration and reduced proliferation, glycolysis, and oxidative phosphorylation. The upregulation of G6PD, AKR1B1, ITGAV, and TGFβ1 in OVCAR5 CBPR cells was also identified in the tumors of platinum-resistant compared to platinum-sensitive high grade serous ovarian cancer (HGSOC) patients. Matching tumors of relapsed versus newly diagnosed HGSOC patients also showed enhanced expression of AKR1B1, ITGAV, TGFβ1 and G6PD protein in relapsed tumors. Among the identified proteins, significant enhanced expression of GFPT2, FLNA, TGFBI (CDGG1), ITGA2 predicted unfavorable prognosis in ovarian cancer patients. Further analysis suggested that the expression of TGFBI to correlate positively with the expression of identified and validated proteins such as GFPT2, FLNA, G6PD, ITGAV, ITGA1 and ITGA2; and with the infiltration of CD8
T cells, macrophages, neutrophils, and dendritic cells in the TME.
Our research demonstrates proteomic-based discovery of novel EMT-related markers with an altered metabolic profile in platinum-resistant versus sensitive ovarian cancer cell lines. The study also confirms the expression of selected identified markers in the tumors of platinum-resistant versus sensitive, and in matching relapsed versus newly diagnosed HGSOC patients. The study provides insights into the metabolic adaptation of EMT-induced carboplatin resistant cells that confers on them reduced proliferation to provide effective migratory advantage; and the role of some of these identified proteins in ovarian cancer prognosis. These observations warrant further investigation of these novel target proteins in platinum-resistant patients.
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