To assess the feasibility of a novel hysteroscopic catheter to collect fallopian tube cytologic samples and to correlate cytologic findings with histopathology.
This was a prospective, multicenter, ...single-arm pilot study. Women undergoing salpingo-oophorectomy for a pelvic mass suspicious for malignancy or for prevention of cancer for BRCA mutation carriers were recruited from 3 gynecologic oncology centers (October 2016–August 2017). Cytologic samples were collected from the fallopian tube using a novel FDA-cleared hysteroscopic catheter and evaluated by a pathologist blinded to surgical or pathologic findings. The correlation between cytologic results and final surgical pathology was assessed.
Of the 50 patients enrolled, 42 were eligible. Hysteroscopies were completed in 40 patients with 78 fallopian tubes, of which 65 ostia (83%) were identified. Of these, 61 (72%) were successfully catheterized resulting in 44 (68%) cytology samples adequate for further evaluation: 5 were classified as positive (3 neoplastic and 2 malignant) and 39 as negative (34 benign and 5 reactive/atypical). A comparison of cytology results with fallopian tube histopathology showed a concordance rate of 95% (42/44). Of the two samples with discordant results, both had positive cytology but negative tubal pathology, and both were stage I ovarian cancers with malignant ovary histology.
Deployment of the device yielded an evaluable cytologic sample in 68% of cases with a high rate of concordance with histopathology. Further evaluation of the device's ability to detect malignancy in high risk populations is warranted.
•A novel hysteroscopic catheter can be used to collect samples from the fallopian tube for cytology evaluation.•The device can be used to identify benign versus malignant disease involving the fallopian tube.•Device use in triaging patients with a pelvic mass, or in high risk surveillance in outpatient settings needs more study.
The Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) satellite was launched in April 2006 to provide global vertically resolved measurements of clouds and aerosols. ...Correct discrimination between clouds and aerosols observed by the lidar aboard the CALIPSO satellite is critical for accurate retrievals of cloud and aerosol optical properties and the correct interpretation of measurements. This paper reviews the theoretical basis of the CALIPSO lidar cloud and aerosol discrimination (CAD) algorithm, and describes the enhancements made to the version 2 algorithm that is used in the current data release (release 2). The paper also presents a preliminary assessment of the CAD performance based on one full day (12 August 2006) of expert manual classification and on one full month (July 2006) of the CALIOP 5-km cloud and aerosol layer products. Overall, the CAD algorithm works well in most cases. The 1-day manual verification suggests that the success rate is in the neighborhood of 90% or better. Nevertheless, several specific layer types are still misclassified with some frequency. Among these, the most prevalent are dense dust and smoke close to the source regions. The analysis of the July 2006 data showed that the misclassification of dust as cloud occurs for 1% of the total tropospheric cloud and aerosol features found. Smoke layers are misclassified less frequently than are dust layers. Optically thin clouds in the polar regions can be misclassified as aerosols. While the fraction of such misclassifications is small compared with the number of aerosol features found globally, caution should be taken when studies are performed on the aerosol in the polar regions. Modifications will be made to the CAD algorithm in future data releases, and the misclassifications encountered in the current data release are expected to be reduced greatly. PUBLICATION ABSTRACT
Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as ...early drivers of tumorigenesis. We previously reported methyltransferase
, which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (αTubK40me3) during mitosis, with αTubK40me3 required for genomic stability. We now show that monoallelic,
-deficient cells retaining H3K36me3, but not αTubK40me3, exhibit a dramatic increase in mitotic defects and micronuclei count, with increased viability compared with biallelic loss. In
-inactivated human kidney cells, rescue with a pathogenic
mutant deficient for microtubule (αTubK40me3), but not histone (H3K36me3) methylation, replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show that the
tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability.
Loss of a single allele of a chromatin modifier plays a role in promoting oncogenesis, underscoring the growing relevance of tumor suppressor haploinsufficiency in tumorigenesis.
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How risky is distracted driving? Karl, J. Bradley; Nyce, Charles M.; Powell, Lawrence ...
Journal of risk and uncertainty,
06/2023, Volume:
66, Issue:
3
Journal Article
Peer reviewed
Open access
We use data on fatal crashes to quantify the risk of distracted driving. We repurpose, extend, and improve a methodology used to estimate the riskiness of drinking drivers (Levitt & Porter,
2001
). ...Our analysis suggests that distracted drivers are three times more likely to cause a fatal crash than focused drivers. We also estimate that distracted drivers represent three to four percent of drivers on the road at any given time. Further, we find that distractions associated with cellphone use are less likely to cause a fatal crash than are distractions from other sources. The externality costs between $0.02 and $0.05 per mile driven. The insurance surcharge for a distracted driving citation that could internalize the avoidable insurance losses is approximately $577 per year. Our work extends the literature on distracted driving and traffic fatalities. We believe our results can inform policymakers on the traffic-safety and economic consequences of distracted driving.
Tissue-derived adenosine, acting via the adenosine A2A receptor (A2AR), is emerging as an important negative regulator of T-cell function. In this report, we demonstrate that A2AR stimulation not ...only inhibits the generation of adaptive effector T cells but also promotes the induction of adaptive regulatory T cells. In vitro, antigen recognition in the setting of A2AR engagement induces T-cell anergy, even in the presence of costimulation. T cells initially stimulated in the presence of an A2AR agonist fail to proliferate and produce interleukin-2 and interferon (IFN)-γ when rechallenged in the absence of A2AR stimulation. Likewise, in an in vivo model of autoimmunity, tissue-derived adenosine promotes anergy and abrogates tissue destruction. Indeed, A2AR stimulation inhibits interleukin-6 expression while enhancing the production of transforming growth factor-β. Accordingly, treating mice with A2AR agonists not only inhibits Th1 and Th17 effector cell generation but also promotes the generation of Foxp3+ and LAG-3+ regulatory T cells. In this regard, A2AR agonists fail to prevent autoimmunity by LAG-3−/− clonotypic T cells, implicating an important role for LAG-3 in adenosine-mediated peripheral tolerance. Overall, our findings demonstrate that extracellular adenosine stimulates the A2AR to promote long-term T-cell anergy and the generation of adaptive regulatory T cells.
Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns ("RNA biosignatures") ...in response to infections may provide an alternative diagnostic approach.
To assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections.
Prospective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature >38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type.
RNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections.
Bacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores.
Of 1883 febrile infants (median age, 37 days; 55.7% boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections-including 32 with bacteremia and 15 with urinary tract infections-and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87% (95% CI, 73%-95%) sensitivity and 89% (95% CI, 81%-93%) specificity. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set with 94% (95% CI, 70%-100%) sensitivity and 95% (95% CI, 88%-98%) specificity. The incremental C statistic for the RNA biosignatures over the YOS score was 0.37 (95% CI, 0.30-0.43).
In this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with vs without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice.
Regulatory T cells (T(regs)) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25(+) FoxP3(+) T(regs) in vivo may promote T cell cancer immunosurveillance, but ...no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration-approved CD25-blocking monoclonal antibody daclizumab with regard to human T(reg) survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25(high) CD45RA(neg) T(regs). Moreover, daclizumab-treated CD45RA(neg) T(regs) lost suppressive function and regained the ability to produce interferon-γ, consistent with reprogramming. To understand the impact of daclizumab on T(regs) in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in T(regs) in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms T(regs) in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated T(regs) while avoiding autoimmunity.
Diabetes is highly prevalent worldwide, with an estimated 536 million living with diabetes in 2021, and that number projected to increase to 783 million by 2045. Diabetic bladder dysfunction is ...thought to affect up to 60%-90% of individuals with diabetes and can significantly impact quality of life. Despite the prevalence of diabetic bladder dysfunction, the exact pathophysiological mechanism, and resulting clinical presentation, remains debated. Our objective was to compare urodynamic parameters between diabetic and nondiabetic women, assessing the impact of various markers of diabetes severity on bladder function.
A retrospective chart review was conducted on female patients aged 18 and above who underwent urodynamic studies at a single tertiary care university hospital system from 2014 to 2020. Patients were categorized based on diabetes status, and diabetes severity including duration of disease, hemoglobin A1c levels, insulin dependence, and markers of end-organ dysfunction. Urodynamic variables, including compliance, bladder voided efficiency, bladder contractility index, postvoid residual, maximum flow rate, capacity, voided volume, and detrusor overactivity, were assessed by two independent reviewers. Statistical analyses were performed to assess the impact of diabetes and diabetic severity on urodynamic parameters.
A total of 652 female patients were included in the study, of which, 152 (23.3%) had diabetes, with an average duration of diagnosis of 82.3 months. Diabetic women were older and had higher body mass index compared to nondiabetic women. Diabetic retinopathy and neuropathy were present in 18% and 54.6% of diabetic patients, respectively. Significant differences in urodynamic parameters were observed between diabetic and nondiabetic women, with diabetic women showing higher rates of detrusor overactivity (p = 0.01), particularly associated with increasing BMI (p = 0.03). However, classic markers of diabetes severity including duration, as well as markers of end-organ damage, showed mixed associations with urodynamic changes.
Despite the prevalence of diabetic bladder dysfunction and its impact on patient quality of life, the exact mechanisms and clinical presentation remain elusive. Our study highlights the significant differences in urodynamic parameters between diabetic and nondiabetic women, emphasizing the need for further research into the relationship between diabetes and diabetic bladder dysfunction.
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