Patients' & Healthcare Professionals' Values Regarding True- & False-Positive Diagnosis when Colorectal Cancer Screening by CT Colonography: Discrete Choice Experiment

Purpose

To establish the relative weighting given by patients and healthcare professionals to gains in diagnostic sensitivity versus loss of specificity when using CT colonography (CTC) for colorectal cancer screening.

Materials and Methods

Following ethical approval and informed consent, 75 patients and 50 healthcare professionals undertook a discrete choice experiment in which they chose between “standard” CTC and “enhanced” CTC that raised diagnostic sensitivity 10% for either cancer or polyps in exchange for varying levels of specificity. We established the relative increase in false-positive diagnoses participants traded for an increase in true-positive diagnoses.

Results

Data from 122 participants were analysed. There were 30 (25%) non-traders for the cancer scenario and 20 (16%) for the polyp scenario. For cancer, the 10% gain in sensitivity was traded up to a median 45% (IQR 25 to >85) drop in specificity, equating to 2250 (IQR 1250 to >4250) additional false-positives per additional true-positive cancer, at 0.2% prevalence. For polyps, the figure was 15% (IQR 7.5 to 55), equating to 6 (IQR 3 to 22) additional false-positives per additional true-positive polyp, at 25% prevalence. Tipping points were significantly higher for patients than professionals for both cancer (85 vs 25, p<0.001) and polyps (55 vs 15, p<0.001). Patients were willing to pay significantly more for increased sensitivity for cancer (p = 0.021).

Conclusion

When screening for colorectal cancer, patients and professionals believe gains in true-positive diagnoses are worth much more than the negative consequences of a corresponding rise in false-positives. Evaluation of screening tests should account for this.     

Functional Nucleic Acid Nanoparticle-Based Resonance Scattering Spectral Probe

Highly sensitive and selective resonance Rayleigh scattering (RRS) and surface enhanced resonance Raman scattering (SERRS) spectral detection technique are developed by combining the functional nucleic acid including aptamer and DNAzyme, and nanoparticle such as gold/silver (NG/NS) aggregation and catalysis reaction. The recent progress of resonance scattering spectral technologies including RRS and SERRS are reviewed in this paper.     

Herbaceous layer determines the relationship between soil respiration and photosynthesis in a shrub-dominated desert plant community

Plant and Soil - Although the linkages between aboveground photosynthates production and belowground respiration processes have been well studied, doubts remain as to the extent that photosynthate...     

Defective Autophagy and mTORC1 Signaling in Myotubularin Null Mice

Autophagy is a vesicular trafficking pathway that regulates the degradation of aggregated proteins and damaged organelles. Initiation of autophagy requires several multiprotein signaling complexes, such as the ULK1 kinase complex and the Vps34 lipid kinase complex, which generates phosphatidylinositol 3-phosphate [PtdIns(3)P] on the forming autophagosomal membrane. Alterations in autophagy have been reported for various diseases, including myopathies. Here we show that skeletal muscle autophagy is compromised in mice deficient in the X-linked myotubular myopathy (XLMTM)-associated PtdIns(3)P phosphatase myotubularin (MTM1). Mtm1-deficient muscle displays several cellular abnormalities, including a profound increase in ubiquitin aggregates and abnormal mitochondria. Further, we show that Mtm1 deficiency is accompanied by activation of mTORC1 signaling, which persists even following starvation. In vivo pharmacological inhibition of mTOR is sufficient to normalize aberrant autophagy and improve muscle phenotypes in Mtm1 null mice. These results suggest that aberrant mTORC1 signaling and impaired autophagy are consequences of the loss of Mtm1 and may play a primary role in disease pathogenesis.     

Syntheses and antitumor activities of N′1,N′3-dialkyl-N′1,N′3-di-(alkylcarbonothioyl) malonohydrazide: The discovery of elesclomol

A series of N′¹,N′³-dialkyl-N′¹,N′³-di(alkylcarbonothioyl) malonohydrazides have been designed and synthesized as anticancer agents by targeting oxidative stress and Hsp70 induction. Structure–activity relationship (SAR) studies lead to the discovery of STA-4783 (elesclomol), a novel small molecule that has been evaluated in a number of clinical trials as an anticancer agent in combination with Taxol.     

Effectiveness of steam inhalation and nasal irrigation for chronic or recurrent sinus symptoms in primary care: a pragmatic randomized controlled trial

Background:Systematic reviews support nasal saline irrigation for chronic or recurrent sinus symptoms, but trials have been small and few in primary care settings. Steam inhalation has also been proposed, but supporting evidence is lacking. We investigated whether brief pragmatic interventions to encourage use of nasal irrigation or steam inhalation would be effective in relieving sinus symptoms.Methods:We conducted a pragmatic randomized controlled trial involving adults (age 18–65 yr) from 72 primary care practices in the United Kingdom who had a history of chronic or recurrent sinusitis and reported a “moderate to severe” impact of sinus symptoms on their quality of life. Participants were recruited between Feb. 11, 2009, and June 30, 2014, and randomly assigned to 1 of 4 advice strategies: usual care, daily nasal saline irrigation supported by a demonstration video, daily steam inhalation, or combined treatment with both interventions. The primary outcome measure was the Rhinosinusitis Disability Index (RSDI). Patients were followed up at 3 and 6 months. We imputed missing data using multiple imputation methods.Results:Of the 961 patients who consented, 871 returned baseline questionnaires (210 usual care, 219 nasal irrigation, 232 steam inhalation and 210 combined treatment). A total of 671 (77.0%) of the 871 participants reported RSDI scores at 3 months. Patients’ RSDI scores improved more with nasal irrigation than without nasal irrigation by 3 months (crude change −7.42 v. −5.23; estimated adjusted mean difference between groups −2.51, 95% confidence interval −4.65 to −0.37). By 6 months, significantly more patients maintained a 10-point clinically important improvement in the RSDI score with nasal irrigation (44.1% v. 36.6%); fewer used over-the-counter medications (59.4% v. 68.0%) or intended to consult a doctor in future episodes. Steam inhalation reduced headache but had no significant effect on other outcomes. The proportion of participants who had adverse effects was the same in both intervention groups.Interpretation:Advice to use steam inhalation for chronic or recurrent sinus symptoms in primary care was not effective. A similar strategy to use nasal irrigation was less effective than prior evidence suggested, but it provided some symptomatic benefit. Trial registration: ISRCTN, no. 88204146.Rhinosinusitis probably affects more than 25 million Americans and 2.5 million Canadians.¹ Quality of life of patients with chronic or recurrent sinusitis has been reported to be similar to congestive heart disease and chronic pulmonary disease.² Antibiotics are prescribed for nearly all patients with sinusitis,³ but the evidence is modest⁴ and an international priority is to contain antibiotic resistance.⁵ Steam inhalation is widely advocated in rhinosinusitis, but a Cochrane review of steam for the “common cold” found equivocal evidence,⁶ and a recent primary care trial found no benefit and some harm (mild thermal injury) for pragmatic advice to inhale steam twice daily for a range of respiratory tract infections.⁷ The Cochrane review of nasal saline irrigation reported benefit.⁸ However, most of the trials were small, mainly from secondary care settings, and the review documented symptom data from only 129 participants, with high heterogeneity. Two small randomized controlled trials included some participants from primary care settings.^9,10 One of the studies compared a gravity-based nasal irrigation device with routine care among 76 participants mainly from primary care settings; it found that symptoms improved very little in the control group (by 1 point on the Rhinosinusitis Disability Index [RSDI] converted to a 100-point scale), as compared with a 14-point improvement in the irrigation group.⁹ The other (published since the Cochrane review) compared a positive-pressure squeeze bottle with saline nasal spray among 121 volunteers from various sources and found an 8.5-point improvement in the control group, as compared with a 15-point improvement in the irrigation group.¹⁰We conducted a large pragmatic randomized controlled trial of the effectiveness of brief advice to use nasal irrigation or steam inhalation in routine primary care for chronic or recurrent sinus symptoms.     

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

The Keap1‐Nrf2/ARE signaling pathway is an important defense system against exogenous and endogenous oxidative stress injury. The dysregulation of the signaling pathway is associated with many diseases, such as cancer, diabetes, and respiratory diseases. Over the years, a wide range of natural products has provided sufficient resources for the discovery of potential therapeutic drugs. Among them, polyphenols possess Nrf2 activation, not only inhibit the production of ROS, inhibit Keap1‐Nrf2 protein–protein interaction, but also degrade Keap1 and regulate the Nrf2 related pathway. In fact, with the continuous improvement of natural polyphenols separation and purification technology and further studies on the Keap1‐Nrf2 molecular mechanism, more and more natural polyphenols monomer components of Nrf2 activators have been gradually discovered. In this view, we summarize the research status of natural polyphenols that have been found with apparent Nrf2 activation and their action modes. On the whole, this review may guide the design of novel Keap1‐Nrf2 activator.     

Impaired host defense to infection and Toll-like receptor 2-independent killing of Borrelia burgdorferi clinical isolates in TLR2-deficient C3H/HeJ mice

To investigate the role of Toll-like receptor 2 (TLR2)-mediated signaling in host innate defense and development of Lyme disease, the pathogenicity of Borrelia burgdorferi sensu stricto clinical isolates representing two distinct genotypes (RST1 and RST3A) was assessed in TLR2(-/-) C3H/HeJ mice. All TLR2(-/-) mice infected with a B. burgdorferi RST1 isolate developed severe arthritis. The numbers of spirochetes in heart, joint and ear biopsy specimens were significantly higher in TLR2(-/-) mice than in wild-type mice similarly infected as determined by real-time quantitative polymerase chain reaction. Interestingly, despite the higher spirochete levels in heart tissues, milder carditis was observed in TLR2(-/-) than in wild-type mice infected with this RST1 isolate (P=0.02). By contrast, no positive cultures were obtained from any of the blood and tissue specimens from TLR2(-/-) mice inoculated with two RST3A clinical isolates. The data suggest that there is impaired host innate defense against infection and TLR2-independent killing of B. burgdorferi clinical isolates in TLR2-deficient C3H/HeJ mice.     

Real-time PCR for simultaneous detection and quantification of Borrelia burgdorferi in field-collected Ixodes scapularis ticks from the Northeastern United States

The density of spirochetes in field-collected or experimentally infected ticks is estimated mainly by assays based on microscopy. In this study, a real-time quantitative PCR (qPCR) protocol targeting the Borrelia burgdorferi-specific recA gene was adapted for use with a Lightcycler for rapid detection and quantification of the Lyme disease spirochete, B. burgdorferi, in field-collected Ixodes scapularis ticks. The sensitivity of qPCR for detection of B. burgdorferi DNA in infected ticks was comparable to that of a well-established nested PCR targeting the 16S-23S rRNA spacer. Of the 498 I. scapularis ticks collected from four northeastern states (Rhode Island, Connecticut, New York, and New Jersey), 91 of 438 (20.7%) nymphal ticks and 15 of 60 (25.0%) adult ticks were positive by qPCR assay. The number of spirochetes in individual ticks varied from 25 to 197,200 with a mean of 1,964 spirochetes per nymphal tick and a mean of 5,351 spirochetes per adult tick. No significant differences were found in the mean numbers of spirochetes counted either in nymphal ticks collected at different locations in these four states (P = 0.23 by one-way analysis of variance test) or in ticks infected with the three distinct ribosomal spacer restriction fragment length polymorphism types of B. burgdorferi (P = 0.39). A high degree of spirochete aggregation among infected ticks (variance-to-mean ratio of 24,877; moment estimate of k = 0.279) was observed. From the frequency distribution data and previously published transmission studies, we estimated that a minimum of 300 organisms may be required in a host-seeking nymphal tick to be able to transmit infection to mice while feeding on mice. These data indicate that real-time qPCR is a reliable approach for simultaneous detection and quantification of B. burgdorferi infection in field-collected ticks and can be used for ecological and epidemiological surveillance of Lyme disease spirochetes.