ABSTRACT
Connexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore-a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.
Subject(s)
Connexins , Humans , Connexins/metabolism , Connexins/genetics , Ion Transport , Animals , Mutation , Ions/metabolism , Gap Junctions/metabolism , Ion Channels/metabolism , Ion Channels/geneticsABSTRACT
Cutibacterium acnes is a commensal bacterium on the skin that is generally well-tolerated, but different strain types have been hypothesized to contribute to the disease acne vulgaris. To understand how some strain types might contribute to skin inflammation, we generated a repository of C. acnes isolates from skin swabs of healthy subjects and subjects with acne and assessed their strain-level identity and capacity to stimulate cytokine release. Phylotype II K-type strains were more frequent on healthy and nonlesional skin of subjects with acne than those isolated from lesions. Phylotype IA-1 C-type strains were increased on lesional skin compared with those on healthy skin. The capacity to induce cytokines from cultured monocyte-derived dendritic cells was opposite to this action on sebocytes and keratinocytes and did not correlate with the strain types associated with the disease. Whole-genome sequencing revealed a linear plasmid in high-inflammatory isolates within similar strain types that had different proinflammatory responses. Single-cell RNA sequencing of mouse skin after intradermal injection showed that strains containing this plasmid induced a higher inflammatory response in dermal fibroblasts. These findings revealed that C. acnes strain type is insufficient to predict inflammation and that carriage of a plasmid could contribute to disease.
Subject(s)
Acne Vulgaris , Dermatitis , Animals , Mice , Humans , Skin/microbiology , Acne Vulgaris/microbiology , Propionibacterium acnes/genetics , Plasmids/genetics , Inflammation , Cytokines/geneticsABSTRACT
AIM: To establish an artificial neural network (ANN) model to predict subsolid nodules (SSNs) before percutaneous core-needle biopsy (PCNB). The results of the two methods were compared to provide guidance on the treatment of SSNs. MATERIALS AND METHODS: This was a single-centre retrospective study using data from 1,459 SSNs between 2013 and 2021. The ANN was developed using data from patients who underwent surgery following computed tomography (CT) (SFC) and validated using data from patients who underwent surgery following biopsy (SFB). The prediction results of the ANN for the PCNB group and the histopathological results obtained after biopsy were compared with the histopathological results of lung nodules in the same group after surgery. Additionally, the choice of predictors for PCNB was analysed using multivariate analysis. RESULTS: There was no significant difference between the accuracies of the ANN and PCNB in the SFB group (p=0.086). The sensitivity of PCNB was lower than that of the ANN (p=0.000), but the specificity was higher (p=0.001). PCNB had better diagnostic ability than the ANN. The incidence of precursor lesions and non-neoplastic lesions in the SFB group was lower than that in the SFC group (p=0.000). A history of malignant tumours, size (2-3 cm), volume (>400 cm3) and mean CT value (≥-450 HU) are important factors for selecting PCNB. CONCLUSIONS: Both ANN and PCNB have comparable accuracy in diagnosing SSNs; however, PCNB has a slightly higher diagnostic ability than ANN. Selecting appropriate patients for PCNB is important for maximising the benefit to SSN patients.
Subject(s)
Lung Neoplasms , Nitrobenzenes , Tomography, X-Ray Computed , Humans , Retrospective Studies , Biopsy , Biopsy, Large-Core Needle , Tomography, X-Ray Computed/methods , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathologyABSTRACT
Mechanosensitive PIEZO channels constitute potential pharmacological targets for multiple clinical conditions, spurring the search for potent chemical PIEZO modulators. Among them is Yoda1, a widely used synthetic small molecule PIEZO1 activator discovered through cell-based high-throughput screening. Yoda1 is thought to bind to PIEZO1's mechanosensory arm domain, sandwiched between two transmembrane regions near the channel pore. However, how the binding of Yoda1 to this region promotes channel activation remains elusive. Here, we first demonstrate that cross-linking PIEZO1 repeats A and B with disulfide bridges reduces the effects of Yoda1 in a redox-dependent manner, suggesting that Yoda1 acts by perturbing the contact between these repeats. Using molecular dynamics-based absolute binding free energy simulations, we next show that Yoda1 preferentially occupies a deeper, amphipathic binding site with higher affinity in PIEZO1 open state. Using Yoda1's binding poses in open and closed states, relative binding free energy simulations were conducted in the membrane environment, recapitulating structure-activity relationships of known Yoda1 analogs. Through virtual screening of an 8 million-compound library using computed fragment maps of the Yoda1 binding site, we subsequently identified two chemical scaffolds with agonist activity toward PIEZO1. This study supports a pharmacological model in which Yoda1 activates PIEZO1 by wedging repeats A and B, providing a structural and thermodynamic framework for the rational design of PIEZO1 modulators. Beyond PIEZO channels, the three orthogonal computational approaches employed here represent a promising path toward drug discovery in highly heterogeneous membrane protein systems.
Subject(s)
High-Throughput Screening Assays , Ion Channels , Ion Channels/metabolism , Drug Discovery , Binding Sites , Thermodynamics , Mechanotransduction, Cellular/physiologyABSTRACT
The frequency and severity of extreme weather events are increasing and expected to increase more in the future, together with global change. However, how extreme events and global change factors interactively influence community structures and ecosystem processes is largely unknown. Here, we investigated the responses of the temporal stability and resilience of aboveground net primary productivity (ANPP) of an alpine meadow to an extreme flooding event under different treatments of experimental drought and clipping. We found that ecosystems that were exposed to drought treatments for 3 years significantly decreased the temporal stability of community productivity but increased resilience to flooding, whereas their resistance to or recovery from flooding did not change. Neither clipping nor its interaction with drought altered the responses of these community stability metrics to flooding. Drought treatments significantly decreased plant species richness and asynchrony and dominant species stability, leading to a decrease in temporal stability and an increase in resilience in response to the extreme flooding event. The study also revealed that the change in species asynchrony was the dominant impact pathway determining the responses of resilience and temporal stability to flooding. Our results highlight that alpine grassland that experiences a multiyear drought may aggravate the instability of community productivity to extreme climatic events by reducing species asynchrony.
Subject(s)
Droughts , Ecosystem , Grassland , Plants , FloodsABSTRACT
The Indian subcontinent has an origin geologically different from Eurasia, but many terrestrial animal and plant species on it have congeneric or sister species in other parts of Asia, especially in the Southeast. This faunal and floral similarity between India and Southeast Asia is explained by either of the two biogeographic scenarios, 'into-India' or 'out-of-India'. Phylogenies based on complete mitochondrial genomes and five nuclear genes were undertaken for ricefishes (Adrianichthyidae) to examine which of these two biogeographic scenarios fits better. We found that Oryzias setnai, the only adrianichthyid distributed in and endemic to the Western Ghats, a mountain range running parallel to the western coast of the Indian subcontinent, is sister to all other adrianichthyids from eastern India and Southeast-East Asia. Divergence time estimates and ancestral area reconstructions reveal that this western Indian species diverged in the late Mesozoic during the northward drift of the Indian subcontinent. These findings indicate that adrianichthyids dispersed eastward 'out-of-India' after the collision of the Indian subcontinent with Eurasia, and subsequently diversified in Southeast-East Asia. A review of geographic distributions of 'out-of-India' taxa reveals that they may have largely fuelled or modified the biodiversity of Eurasia.
Subject(s)
Oryzias , Animals , Asia, Southeastern , Biodiversity , India , PhylogenyABSTRACT
Cell-surface polysaccharides are essential to many aspects of physiology, serving as a highly conserved evolutionary feature of life and as an important part of the innate immune system in mammals. Here, as simplified biophysical models of these sugar coatings, we present results of molecular dynamics simulations of hyaluronic acid and heparin brushes that show important effects of ion pairing, water dielectric decrease, and coion exclusion. As in prior studies of macromolecular crowding under physiologically relevant salt concentrations, our results show equilibria with electroneutrality attained through screening and pairing of brush anionic charges by monovalent cations at the atomistic detail. Most surprising is the reversal of the Donnan potential obtained from both nonpolarizable and Drude polarizable force fields, in contrast to what would be expected based on electrostatic Boltzmann partitioning alone. Water dielectric decrement within the brush domain is also associated with Born hydration-driven cation exclusion from the brush. We observe that the primary partition energy attracting cations to attain brush electroneutrality is the ion pairing or salt-bridge energy. Potassium and sodium pairings to glycosaminoglycan carboxylates and sulfates show similar abundance of contact-pairing and solvent-separated pairing. We conclude that in these crowded macromolecular brushes, ion-pairing, Born-hydration, and electrostatic potential energies all contribute to attain electroneutrality and should therefore contribute in mean-field models to accurately represent brush electrostatics.
Subject(s)
Glycosaminoglycans , Molecular Dynamics Simulation , Solvents , Static Electricity , WaterABSTRACT
In order to study the transcriptional differences of Citrus medica var. sarcodactylis at different developmental stages, we explored the genes regulating the biosynthesis of the effective components. In this study, Illumina Hiseq 4 000 high-throughput sequencing technology was used to sequence the transcriptome of C. medica var. sarcodactylis at different developmental stages, 121 235 unigenes were obtained with an average length of 2 434 bp, 3 379 different genes were obtained using DESeq screening, which mainly connected to biological processes such as signal transmission, biological regulation, and metabolic processes, and enriched in metabolic pathways such as starch, sucrose metabolism, phenylpropanoid biosynthesis, and flavonoid biosynthesis. Further dynamic comparison of biosynthesis related genes of active ingredients: the expression levels of PAL, CHI, CYP75B1, ZDS, 4CL and FLS gradually increased as the fruit turned from green to yellow; the expressions of COMT, F3H and CYP73A increased at first and then decreased; CCR, HCT and HRP were down-regulated whereas up-regulated. This study provides references for further excavation of key genes in the biosynthesis of active components, as well as biopathway analysis of active components for C. medica var. sarcodactylis.
Subject(s)
Citrus , Citrus/genetics , Computational Biology , Fruit/genetics , Gene Expression Profiling , Gene Expression Regulation, Plant , High-Throughput Nucleotide Sequencing , TranscriptomeABSTRACT
To explore the mechanism of Scutellaria barbata-Hedyotis diffusa against breast cancer based on network pharmacological methods. The active components and corresponding target proteins of S. barbata and H. diffusa were screened by using Traditional Chinese Medicine Systems Pharmacology Database(TCMSP), and the targets of breast cancer were screened through the Genecards and OMIM databases. Venn online software was used to obtain the common targets of drugs and the disease, and then the "compound-target-disease" network diagram was constructed by using Cytoscape 3.7.2 software. The STRING database was used to draw the protein-protein interaction(PPI) network, and the David database was used to perform GO function and KEGG pathway enrichment analysis on effective targets. The results showed that 29 S. barbata compounds, 7 H. diffusa compounds, and 109 effective targets were screened. The 59 common targets for drugs and disease were obtained through Venn diagrams. The PPI network showed that MYC, CCND1, EGFR, ESR1, CASP3, VEGFA, etc. might be the key targets for "S. barbata-H. diffusa" in the treatment of breast cancer. In the GO function analysis, 88 entries were found, involving the regulation of transcription factor activity, receptor activity, cytokine activity, enzyme activity, and biosynthetic processes. In KEGG pathway analysis, 37 entries related to cancer, cell cycle, apoptosis, angioge-nesis and other pathways were found, including p53 signaling pathway, ErbB signaling pathway, nod like receptor signaling pathway, MAPK signaling pathway, VEGF signaling pathway, Wnt signaling pathway and mTOR signaling pathway and other classic signaling pathways. This study preliminarily revealed the key targets, biological processes and signal pathway of "S. barbata-H. diffusa" against breast cancer. It was found that its function was in a multi-target and multi-channel manner, which laid a foundation for future molecular biological experiments.
Subject(s)
Breast Neoplasms , Drugs, Chinese Herbal , Hedyotis , Scutellaria , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Drugs, Chinese Herbal/pharmacology , Humans , Medicine, Chinese TraditionalABSTRACT
Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are among the most prescribed drugs. However, ARB effectiveness varies widely, which may be due to non-synonymous single nucleotide polymorphisms (nsSNPs) within the AT1R gene. The AT1R coding sequence contains over 100 nsSNPs; therefore, this study embarked on determining which nsSNPs may abrogate the binding of selective ARBs. The crystal structure of olmesartan-bound human AT1R (PDB:4ZUD) served as a template to create an inactive apo-AT1R via molecular dynamics simulation (n = 3). All simulations resulted in a water accessible ligand-binding pocket that lacked sodium ions. The model remained inactive displaying little movement in the receptor core; however, helix 8 showed considerable flexibility. A single frame representing the average stable AT1R was used as a template to dock Olmesartan via AutoDock 4.2, MOE, and AutoDock Vina to obtain predicted binding poses and mean Boltzmann weighted average affinity. The docking results did not match the known pose and affinity of Olmesartan. Thus, an optimization protocol was initiated using AutoDock 4.2 that provided more accurate poses and affinity for Olmesartan (n = 6). Atomic models of 103 of the known human AT1R polymorphisms were constructed using the molecular dynamics equilibrated apo-AT1R. Each of the eight ARBs was then docked, using ARB-optimized parameters, to each polymorphic AT1R (n = 6). Although each nsSNP has a negligible effect on the global AT1R structure, most nsSNPs drastically alter a sub-set of ARBs affinity to the AT1R. Alterations within N298 -L314 strongly effected predicted ARB affinity, which aligns with early mutagenesis studies. The current study demonstrates the potential of utilizing in silico approaches towards personalized ARB therapy. The results presented here will guide further biochemical studies and refinement of the model to increase the accuracy of the prediction of ARB resistance in order to increase overall ARB effectiveness.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Imidazoles/therapeutic use , Precision Medicine , Tetrazoles/therapeutic use , Angiotensin II Type 1 Receptor Blockers/chemistry , Humans , Imidazoles/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Polymorphism, Single Nucleotide , Receptor, Angiotensin, Type 1/genetics , Reproducibility of Results , Tetrazoles/chemistrySubject(s)
Analgesics, Opioid/pharmacokinetics , Fentanyl/pharmacokinetics , Heroin/pharmacokinetics , Maternal-Fetal Exchange , Methadone/pharmacokinetics , Morphine/pharmacokinetics , Naloxone/pharmacokinetics , Oxycodone/pharmacokinetics , Placenta/metabolism , Trophoblasts/metabolism , Female , Gas Chromatography-Mass Spectrometry , Humans , PregnancyABSTRACT
OBJECTIVES: MET amplification or MET exon 14 skipping site mutation can be treated with crizotinib in non-small cell lung cancer patients. Y1003 is a binding site for E3 ubiquitin ligase, which is critical for MET degradation. Here we show an adenocarcinoma patient with Y1003S mutation and she got tumor remission after crizotinib treatment. MATERIALS AND METHODS: A 61-year-old never-smoking female was admitted to our hospital due to increased carcino-embryonicantigen. Positron emission tomography (PET)-CT showed enlargement of bilateral cervical, left supraclavicular and multiple mediastinal lymph nodes. PET-CT also showed stripe in the left upper lobe. Adenocarcinoma cells were found from biopsy on her left supraclavicular lymph nodes. We detected cell-free circulating tumor DNA (ctDNA) from peripheral blood and identified a MET Y1003S mutation by next generation sequencing technology. Y1003 mutations predicted to be similar to MET exon 14 skipping in functionality based on the literature. After an extensive discussion of treatment options, the patient opted to treatment with crizotinib, a small-molecule dual inhibitor of the MET and ALK. RESULTS AND CONCLUSION: Dramatic response was observed within 1 months of treatment, which lasted more than 10 months. Chest CT scans revealed significant improvement of the lung focus and decrease in size of the lymph nodes lesions, meeting RECIST partial response criteria (-30%). Y1003 alterations may be diverse mutations and sensitive to MET inhibitors.
Subject(s)
Adenocarcinoma of Lung/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Crizotinib/therapeutic use , Lung Neoplasms/genetics , Point Mutation/genetics , Proto-Oncogene Proteins c-met/genetics , Adenocarcinoma of Lung/drug therapy , Drug Resistance, Neoplasm/genetics , High-Throughput Nucleotide Sequencing , Humans , Lung Neoplasms/drug therapy , Male , Middle AgedABSTRACT
Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph-a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies.
Subject(s)
Algorithms , Narcolepsy/physiopathology , Neural Networks, Computer , Sleep Stages/physiology , Adolescent , Adult , Aged , Cohort Studies , Female , HLA-DQ beta-Chains/analysis , Humans , Male , Middle Aged , Narcolepsy/diagnosis , Narcolepsy/immunology , Polysomnography , Sensitivity and Specificity , Sleep Stages/immunology , Young AdultABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disorder that affects approximately 35 million people worldwide, and diet has been reported to influence the prevalence/incidence of AD. Colorectal cancer is among the most common cancers in Western populations, and the correlation between constipation and the occurrence of colorectal cancer has been identified in a number of studies, which show that a Westernized diet is a mutual risk factor. Constipation is a growing health problem, particularly in middle-aged and older adults. As the most common gastrointestinal disorder in adults, constipation affects 2-20% of the world population, and it is associated with several diseases, such as diabetes, Parkinson's disease, and others. Comparing the epidemiological data on colorectal cancer and AD, we find that colorectal cancer and AD have similar epidemiologic feature, which is both disease correlate with high prevalence of constipation. Therefore, we hypothesized that constipation may influence Alzheimer's disease in a similar way that it contributes to colorectal cancer. This review aimed to systemically elucidate the evidence that constipation contributes to Alzheimer's disease progression.
ABSTRACT
Long noncoding RNAs (lncRNAs) are a novel class of eukaryotic transcripts. They are thought to act as a critical regulator of protein-coding gene expression. Herein, we identified and characterized 13 putative lncRNAs from the expressed sequence tags from secondary hair follicle of Cashmere goat. Furthermore, we investigated their transcriptional pattern in secondary hair follicle of Liaoning Cashmere goat during telogen and anagen phases. Also, we generated intracellular regulatory networks of upregulated lncRNAs at anagen in Wnt signaling pathway based on bioinformatics analysis. The relative expression of six putative lncRNAs (lncRNA-599618, -599556, -599554, -599547, -599531, and -599509) at the anagen phase is significantly higher than that at telogen. Compared with anagen, the relative expression of four putative lncRNAs (lncRNA-599528, -599518, -599511, and -599497) was found to be significantly upregulated at telogen phase. The network generated showed that a rich and complex regulatory relationship of the putative lncRNAs and related miRNAs with their target genes in Wnt signaling pathway. Our results from the present study provided a foundation for further elucidating the functional and regulatory mechanisms of these putative lncRNAs in the development of secondary hair follicle and cashmere fiber growth of Cashmere goat.
Subject(s)
Goats/genetics , Hair Follicle/metabolism , RNA, Long Noncoding/genetics , Wnt Signaling Pathway/genetics , Animals , Female , Gene Regulatory Networks/genetics , Goats/metabolism , RNA, Long Noncoding/analysis , RNA, Long Noncoding/metabolismABSTRACT
A novel photoelectric integration process (MPEC) was developed to degrade Amaranth. In the MPEC, the output voltage of the microbial fuel cells (MFCs) was used to assist the dual slant-placed electrodes thin-film photocatalytic (PC). With two MFCs connected in series, the MPEC process realized the highest decolorization efficiency. It is close to that of the external bias photoelectrocatalytic (PEC), and 7% higher than that of the self-generated electric field-assisted photoelectrocatalytic (SPEC). The feasibility of MPEC pre-treatment and MFC post-treatment of Amaranth was investigated. The results demonstrated that MPEC pre-treatment of Amaranth could improve its biodegradability. The higher MPEC decolorization efficiency indicated the stronger biodegradability of the obtained intermediates and the higher MFC output voltage. When the MPEC decolorization efficiency was gradually increased to 50%, the removal efficiencies of total Chemical Oxygen Demand (COD) by the MPEC and MFC increased; when the decolorization efficiency was increased above 50%, the removal efficiencies became stable. MPEC enhanced the biodegradability efficiently and was applicable to pre-treat textile wastewater.
Subject(s)
Amaranth Dye/metabolism , Bacteria/metabolism , Bioelectric Energy Sources/microbiology , Wastewater/microbiology , Water Pollutants, Chemical/metabolism , Water Purification/methods , Amaranth Dye/chemistry , Bacteria/chemistry , Biodegradation, Environmental , Biological Oxygen Demand Analysis , Electricity , Electrodes , Light , Photolysis/radiation effects , Wastewater/chemistry , Water Pollutants, Chemical/chemistry , Water Purification/instrumentationABSTRACT
BACKGROUND: Smad4 is a critical effector of TGF-ß signaling that regulates a variety of cellular functions. However, its role in the brain has rarely been studied. Here, we examined the molecular mechanisms underlying the post-translational regulation of Smad4 function by SUMOylation, and its role in spatial memory formation. RESULTS: In the hippocampus, Smad4 is SUMOylated by the E3 ligase PIAS1 at Lys-113 and Lys-159. Both spatial training and NMDA injection enhanced Smad4 SUMOylation. Inhibition of Smad4 SUMOylation impaired spatial learning and memory in rats by downregulating TPM2, a gene associated with skeletal myopathies. Similarly, knockdown of TPM2 expression impaired spatial learning and memory, while TPM2 mRNA and protein expression increased after spatial training. Among the TPM2 mutations associated with skeletal myopathies, the TPM2E122K mutation was found to reduce TPM2 expression and impair spatial learning and memory in rats. CONCLUSIONS: We have identified a novel role of Smad4 SUMOylation and TPM2 in learning and memory formation. These results suggest that patients with skeletal myopathies who carry the TPM2E122K mutation may also have deficits in learning and memory functions.
Subject(s)
Smad4 Protein/genetics , Spatial Memory , Sumoylation , Tropomyosin/genetics , Up-Regulation , Animals , Male , Rats , Rats, Sprague-Dawley , Smad4 Protein/metabolism , Tropomyosin/metabolismABSTRACT
BACKGROUND: We used administrative health data to explore the impact of primary care physician (pcp) visits on acute-care service utilization by women receiving adjuvant chemotherapy for early-stage breast cancer (ebc). METHODS: Our population-based retrospective cohort study examined pcp visits and acute-care use [defined as an emergency room (er) visit or hospitalization] by women diagnosed with ebc between 2007 and 2009 and treated with adjuvant chemotherapy. Multivariate regression analysis was used to identify the effect of pcp visits on the likelihood of experiencing an acute-care visit. RESULTS: Patients receiving chemotherapy visited a pcp significantly more frequently than they had before their diagnosis [relative risk (rr): 1.48; 95% confidence interval (ci): 1.44 to 1.53; p < 0.001] and significantly more frequently than control subjects without cancer (rr: 1.51; 95% ci: 1.46 to 1.57; p < 0.001). More than one third of pcp visits by chemotherapy patients were related to breast cancer or chemotherapy-related side effects. In adjusted multivariate analyses, the likelihood of experiencing an er visit or hospitalization increased in the days immediately after a pcp visit (rr: 1.92; 95% ci: 1.76 to 2.10; p < 0.001). CONCLUSIONS: During chemotherapy treatment, patients visited their pcp more frequently than control subjects did, and they visited for reasons related to their breast cancer or to chemotherapy-related side effects. Visits to a pcp by patients receiving chemotherapy were associated with an increased frequency of er visits or hospitalizations in the days immediately after the pcp visit. Those results suggest an opportunity to institute measures for early detection and intervention in chemotherapy side effects.
ABSTRACT
BACKGROUND: Timely follow-up of fecal occult blood screening with colonoscopy is essential for achieving colorectal cancer mortality reduction. In the present study, we evaluated the effectiveness of centrally generated, physician-targeted audit and feedback to improve colonoscopy uptake after a positive fecal occult blood test (fobt) result within Ontario's population-wide ColonCancerCheck Program. METHODS: This prospective cohort study used data sets from Ontario's ColonCancerCheck Program (2008-2011) that were linked to provincial administrative health databases. Cox proportional hazards regression was used to estimate the effect of centralized, physician-targeted audit and feedback on colonoscopy uptake in an Ontario-wide fobt-positive cohort. RESULTS: A mailed physician audit and feedback report identifying individuals outstanding for colonoscopy for 3 or more months after a positive fobt result did not increase the likelihood of colonoscopy uptake (hazard ratio: 0.95; 95% confidence interval: 0.79 to 1.13). Duration of positive fobt status was strongly inversely associated with the hazard of follow-up colonoscopy (p for linear trend: <0.001). CONCLUSIONS: In a large population-wide setting, centralized tracking in the form of physician-targeted mailed audit and feedback reports does not improve colonoscopy uptake for screening participants with a positive fobt result outstanding for 3 or more months. Mailed physician-targeted screening audit and feedback reports alone are unlikely to improve compliance with follow-up colonoscopy in Ontario. Other interventions such as physician audits or automatic referrals, demonstrated to be effective in other jurisdictions, might be warranted.