New Insights into the Cooperativity and Dynamics of Dimeric Enzymes.

A survey of protein databases indicates that the majority of enzymes exist in oligomeric forms, with about half of those found in the UniProt database being homodimeric. Understanding why many enzymes are in their dimeric form is imperative. Recent developments in experimental and computational techniques have allowed for a deeper comprehension of the cooperative interactions between the subunits of dimeric enzymes. This review aims to succinctly summarize these recent advancements by providing an overview of experimental and theoretical methods, as well as an understanding of cooperativity in substrate binding and the molecular mechanisms of cooperative catalysis within homodimeric enzymes. Focus is set upon the beneficial effects of dimerization and cooperative catalysis. These advancements not only provide essential case studies and theoretical support for comprehending dimeric enzyme catalysis but also serve as a foundation for designing highly efficient catalysts, such as dimeric organic catalysts. Moreover, these developments have significant implications for drug design, as exemplified by Paxlovid, which was designed for the homodimeric main protease of SARS-CoV-2.

Polymers with controlled assembly and rigidity made with click-functional peptide bundles.

The engineering of biological molecules is a key concept in the design of highly functional, sophisticated soft materials. Biomolecules exhibit a wide range of functions and structures, including chemical recognition (of enzyme substrates or adhesive ligands1, for instance), exquisite nanostructures (composed of peptides2, proteins3 or nucleic acids4), and unusual mechanical properties (such as silk-like strength3, stiffness5, viscoelasticity6 and resiliency7). Here we combine the computational design of physical (noncovalent) interactions with pathway-dependent, hierarchical 'click' covalent assembly to produce hybrid synthetic peptide-based polymers. The nanometre-scale monomeric units of these polymers are homotetrameric, α-helical bundles of low-molecular-weight peptides. These bundled monomers, or 'bundlemers', can be designed to provide complete control of the stability, size and spatial display of chemical functionalities. The protein-like structure of the bundle allows precise positioning of covalent linkages between the ends of distinct bundlemers, resulting in polymers with interesting and controllable physical characteristics, such as rigid rods, semiflexible or kinked chains, and thermally responsive hydrogel networks. Chain stiffness can be controlled by varying only the linkage. Furthermore, by controlling the amino acid sequence along the bundlemer periphery, we use specific amino acid side chains, including non-natural 'click' chemistry functionalities, to conjugate moieties into a desired pattern, enabling the creation of a wide variety of hybrid nanomaterials.

Devastating the Supply Wagons: Multifaceted Liposomes Capable of Exhausting Tumor to Death via Triple Energy Depletion.

The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.

COVID-19 vaccination affects short-term anti-coagulation levels in warfarin treatment.

Vaccines against SARS-CoV-2 have been recommended across the world, yet no study has investigated whether COVID-19 vaccination influences short-term warfarin anti-coagulation levels. Patients on stable warfarin treatment who received anti-SARS-CoV-2 vaccination were prospectively enrolled and followed up for three months. INR values less than 10 days before vaccination (baseline), 3-5 days (short-term) and 6-14 days (medium-term) after vaccination were recorded as INR0, INR1, and INR2, respectively. The variations of INR values within individuals were compared, and the linear mixed effect model was used to evaluate the variations of INR values at different time points. Logistic regression analysis was performed to determine covariates related to INR variations after COVID-19 vaccination. Vaccination safety was also monitored. There was a significant difference in INR values between INR0 and INR1 (2.15 vs. 2.26, p = 0.003), yet no marked difference was found between INR0 and INR2. The linear mixed effect model also demonstrated that INR variation was significant in short-term but not in medium-term or long-term period after vaccination. Logistic regression analysis showed that no investigated covariates, including age, vaccine dose, genetic polymorphisms of VKORC1 and CYP2C9 etc., were associated with short-term INR variations. Two patients (2.11%) reported gingival hemorrhage in the short-term due to increased INR values. The overall safety of COVID-19 vaccines for patients on warfarin was satisfying. COVID-19 vaccines may significantly influence warfarin anticoagulation levels 3-5 days after vaccination. We recommend patients on warfarin to perform at least one INR monitoring within the first week after COVID-19 vaccination.

Structure and composition of dissolved organic matters in sludge by ultrasonic treatment.

The leaching of dissolved organic matter (DOM) from the sludge into the liquid phase is induced by ultrasound. However, there is limited investigation into the structure and molecular composition of sludge DOM in this process. The molecular structure and composition of sludge DOM in ultrasonic treatment were comprehensively elucidated in this study. The sludge dissolved organic carbon (DOC) and three-dimensional fluorescence spectroscopy (3D-EEM) image had most significant change at 15-min ultrasonic time and 1.2 W/mL ultrasonic density, respectively. Gas Chromatography-Mass Spectrometry (GC-MS) analysis indicated that ultrasonic treatment of sludge reduced the macromolecules to small molecules in DOM. Then, electrospray ionization Fourier-transform ion cyclotron resonance mass spectrometry (ESI FT-ICR-MS) analysis revealed that lignin, tannins, and carbohydrates were the main components of sludge DOMs after ultrasound treatment. analysis revealed that lignin, tannins, and carbohydrates were the main components of sludge DOMs after ultrasound treatment. Furthermore, through the Van Krevelen analysis, the major components were CHO (48.50%) and CHOS (23.20%) in the DOM of ultrasonicated sludge. This research provides the basis for the practical application of ultrasonic treatment of sludge and provides basic information for DOM components.

Desulfurization steel slag improves the saline-sodic soil quality by replacing sodium ions and affecting soil pore structure.

Flue gas desulfurization steel slag (DS), a solid waste produced by coal power plants and steelworks, was proposed as an amendment for the remediation of saline-sodic soil. A pot experiment including three dosages of DS alone (1%, 5%, 10% w/w) and their combination with fulvic acid (FA, 1%, w/w) was conducted to evaluate the potentials of DS as an amendment and to explore remediation mechanism of DS combined with FA on saline-sodic soil. The soil salinity, nutrition, pore structure, water retention, consistency, and desiccation cracking of DS and FA-amended soils were determined. Application of DS resulted in a significant reduction of pH, sodium adsorption ratio (SAR), and exchangeable sodium percentage (ESP) of saline-sodic soil. The DS amendment significantly increased the 6-15 µm pore volume of soil. The combination application of DS and FA showed better effect than the DS alone. The DS amendments at 5% and 10% significantly increased the field water capacity, permanent wilting point, and available water content of the soil, whereas significantly decreased the plastic limit, liquid limit, and plastic index. The DS alone and combined with FA could effectively control the development of desiccation cracking, reduced significantly the crack area density and average width of cracks of the soil. Consequently, the improvement of alkalinity and soil physical properties by DS amendment significantly increased the yield of alfalfa grown on saline-sodic soil. The remarkable improvement of physical properties of saline-sodic soil contributed to the decrease of SAR and ESP by the Ca2+ in DS replacing the Na + at soil colloid sites. Our results suggested that DS amendments alone or combined with fulvic acid have great potential as saline-alkali soil amendment.

Strontium isotope ratios in kidney stones reveal the environmental implications for humans in Beijing, China.

Kidney stones are a common disease that threatens human health on a global scale and are closely related to the contemporary environment. The strontium isotope ratio (87Sr/86Sr) has been widely used to trace the migration of ancient humans through bones and teeth, which recorded their bioavailable Sr from the environment. However, no 87Sr/86Sr data for kidney stones have been reported. Therefore, this study explored the Sr content of kidney stones and reported their 87Sr/86Sr data for the first time to reflect the environmental implications for humans; 66 calcium oxalate kidney stones collected in Beijing were measured for calcium (Ca), magnesium (Mg) and strontium (Sr) content to explore Sr distribution behavior in kidney stones, and 17 samples were tested for strontium isotopes. Ca and Mg had a joint effect on the Sr content of kidney stones, with magnesium having a stronger effect, whereas 87Sr/86Sr values were unaffected by these elements. The 87Sr/86Sr values of kidney stones ranged from 0.709662 to 0.710990, within the range of environmental soil and water in Beijing. Drinking water and surface soils (representing food sources) mainly contributed to the bioavailable Sr of kidney stones, while sea spray and dust storm did not. This study is the first to report 87Sr/86Sr values for kidney stones. Evidence of Sr isotope ratios in kidney stones reveals environmental implications for humans and bioavailable Sr sources, demonstrating a great potential of Sr isotope ratios at the intersection of life and environmental sciences.

Effect of access cavities on the biomechanics of mandibular molars: a finite element analysis.

INTRODUCTION: This study aimed to predict the fracture resistance of a mandibular first molar (MFM) with diverse endodontic cavities using finite element analysis (FEA). METHODS: Five experimental finite element models representing a natural tooth (NT) and 4 endodontically treated MFMs were generated. Treated MFM models were with a traditional endodontic cavity (TEC) and minimally invasive endodontic (MIE) cavities, including guided endodontic cavity (GEC), contracted endodontic cavity (CEC) and truss endodontic cavity (TREC). Three loads were applied, simulating a maximum bite force of 600 N (N) vertically and a normal masticatory force of 225 N vertically and laterally. The distributions of von Mises (VM) stress and maximum VM stress were calculated. RESULTS: The maximum VM stresses of the NT model were the lowest under normal masticatory forces. In endodontically treated models, the distribution of VM stress in GEC model was the most similar to NT model. The maximum VM stresses of the GEC and CEC models under different forces were lower than those of TREC and TEC models. Under vertical loads, the maximum VM stresses of the TREC model were the highest, while under the lateral load, the maximum VM stress of the TEC model was the highest. CONCLUSION: The stress distribution of tooth with GEC was most like NT. Compared with TECs, GECs and CECs may better maintain fracture resistance, TRECs, however, may have a limited effect on maintenance of the tooth resistance.

Promoting Co-Crystallization in Poly(butylene succinate) and Poly(butylene fumarate) Blends via End-Group Functionalization.

Co-crystallization plays a crucial role in the integration and regulation of thermal and mechanical properties in polymer blends, but the poor compatibility of the components in the crystal phase has always been a major obstacle to co-crystallization, which puts forward stricter requests for linkage and interaction between different entities. On the basis of the hydrogen-bonding interaction that can promote chain stacking and thus improve miscibility, we propose that crystalline/crystalline blends of 2-ureido-4[1H]-pyrimidinone (UPy)-functionalized poly(butylene succinate) and poly(butylene fumarate) (PBS-UPy/PBF-UPy) where UPy groups with quadruple hydrogen-bonding interaction are employed to connect different chain ends, could inhibit phase separation and improve co-crystallization. PBS-UPy/PBF-UPy blends exhibit complex component-dependent and cooling-rate-dependent co-crystallization behavior. A high level of co-crystallization occurs in the range of PBS-UPy-rich fractions, and the proportion could approach over 98% under optimized conditions with the aid of UPy quadruple hydrogen bonds interaction. This work enriches the understanding of co-crystallization in crystalline/crystalline polymer blends and provides more possibility for the design of structures and properties of polymer materials.

The effects of endodontic access cavity design on dentine removal and effectiveness of canal instrumentation in maxillary molars.

AIM: To evaluate in a laboratory setting, the impact of three designs of endodontic access cavities on dentine removal and effectiveness of canal instrumentation in extracted maxillary first molars using micro-computed tomography (micro-CT). METHODOLOGY: A total of 30 extracted intact maxillary first molars were selected and scanned by micro-CT with a voxel size of 24 µm and randomly distributed into three groups: the traditional endodontic cavity (TEC) group, the conservative endodontic cavity (CEC) group and the guided endodontic cavity (GEC) group. The pulp chambers of teeth in the groups were accessed accordingly. After root canal preparation, the teeth were rescanned. The volume of dentine removed after canal preparation, the noninstrumented canal areas, canal transportation and centring ratio were analysed. Data were analysed statistically using one-way analysis of variance. Tukey's post hoc test was used for multiple comparisons. The significance level was set at p < .05. RESULTS: The total volume of dentine removed was significantly greater in the TEC group after root canal preparation (p < .05). No significant differences in the volume of dentine removed occurred between the CEC and GEC groups (p > .05). The volume of dentine removed in the crown, pericervical dentine and coronal third of the canal was significantly lower in CEC and GEC groups when compared to that in the TEC group (p < .05), no difference was observed in the middle third of the canal and apical third of the canal amongst the three groups (p > .05). There was no significant difference in noninstrumented canal area, canal transportation and centring ratio amongst the TEC, CEC and GEC groups (p > .05). CONCLUSIONS: In extracted maxillary molars tested in a laboratory setting, CEC and GEC preserved more tooth tissue in the crown, pericervical dentine and coronal third of the canal compared with TEC after root canal preparation. The design of the endodontic access cavity did not impact on the effectiveness of canal instrumentation in terms of noninstrumented canal area, canal transportation and centring ratio.

Diffusion of Nanoparticles with Activated Hopping in Crowded Polymer Solutions.

A long-distance hop of diffusive nanoparticles (NPs) in crowded environments was commonly considered unlikely, and its characteristics remain unclear. In this work, we experimentally identify the occurrence of the intermittent hops of large NPs in crowded entangled poly(ethylene oxide) (PEO) solutions, which are attributed to thermally induced activated hopping. We show that the diffusion of NPs in crowded solutions is considered as a superposition of the activated hopping and the reptation of the polymer solution. Such activated hopping becomes significant when either the PEO molecular weight is large enough or the NP size is relatively small. We reveal that the time-dependent non-Gaussianity of the NP diffusion is determined by the competition of the short-time relaxation of a polymer entanglement strand, the activated hopping, and the long-time reptation. We propose an exponential scaling law τhop/τe ∼ exp(d/dt) to characterize the hopping time scale, suggesting a linear dependence of the activated hopping energy barrier on the dimensionless NP size. The activated hopping motion can only be observed between the onset time scale of the short-time relaxation of local entanglement strands and the termination time scale of the long-time relaxation. Our findings on activated hopping provide new insights into long-distance transportation of NPs in crowded biological environments, which is essential to the delivery and targeting of nanomedicines.

Risk factors for cement leakage and nomogram for predicting the intradiscal cement leakage after the vertebra augmented surgery.

BACKGROUND: Vertebral augmentation is the first-line treatment for the osteoporosis vertebral compression fractures. Bone cement leakage is the most common complication of this surgery. This study aims to assess the risk factors for different types of cement leakage and provides a nomogram for predicting the cement intradiscal leakage. METHODS: We retrospectively reviewed 268 patients who underwent vertebral augmentation procedure between January 2015 and March 2019. The cement leakage risk factors were evaluated by univariate analysis. Different types of cement leakage risk factors were identified by the stepwise logistic analysis. We provided a nomogram for predicting the cement intradiscal leakage and used the concordance index to assess the prediction ability. RESULTS: A total of 295 levels of vertebrae were included, with a leakage rate of 32.5%. Univariate analysis showed delayed surgery and lower vertebral compression ratio were the independent risk factors of cement leakage. The stepwise logistic analysis revealed percutaneous vertebroplasty was a risk factor in vein cement leakage; delayed surgery, preoperative compression ratio, and upper endplate disruption were in intradiscal cement leakage; age, preoperative fracture severity, and intravertebral vacuum cleft were in perivertebral soft tissue cement leakage; no factor was in spinal canal cement leakage. The nomogram for intradiscal cement leakage had a precise prediction ability with an original concordance index of 0.75. CONCLUSIONS: Delayed surgery and more vertebral compression increase the risk of cement leakage. Different types of cement leakage have different risk factors. We provided a nomogram for precise predicting the intradiscal cement leakage.

H2O2-responsive polymeric micelles with a benzil moiety for efficient DOX delivery and AIE imaging.

Nano drug delivery is a promising domain in biomedical theranostics and has aroused more and more attention in recent years. We report here an amphiphilic polymer TPG1, bearing a H2O2-sensitive benzil and an AIE fluorophore tetraphenylethene (TPE) unit, which is able to self-assemble into spherical nanosized micelles in aqueous solution. Doxorubicin (DOX) can be encapsulated into TPG1 micelles efficiently with the loading capability of up to 59% by weight. The benzil moiety could be cleaved via the Baeyer-Villiger type reaction in the presence of H2O2, leading to the decomposition of TPG1 micelles and release of DOX. In vitro studies indicated that DOX-loaded TPG1 micelles can be internalized by cancer cells, followed by unloading encapsulated DOX under the stimulation of H2O2. The drug release process can be monitored by the AIE fluorescence from the degradation products containing a TPE moiety. MTT assays against HeLa and HepG2 cancer cells demonstrated that DOX-loaded micelles showed good anticancer efficacy. The polymer TPG1 and the corresponding decomposed products showed great biocompatibility. Our data suggest that TPG1 has the potential to be employed for the controlled drug delivery system.

Redox-Responsive Nanogel with Intracellular Reconstruction and Programmable Drug Release for Targeted Tumor Therapy.

A tumor-selective drug delivery nanogel with redox-responsive size swelling and co-instantaneous drug release is developed. The nanogel is formed by poly(ethylene glycol) diglycidyl ether and cystamine double crosslinked hyaluronic acid (HA). The disulfide bond in cystamine (Cys) is in charge of the responsiveness, while the compact polymer network turns the nanogel a capsule for effective drug loading. The tumor targeting is achieved by the known HA-receptor mediated endocytosis. The responsive swelling of this nanogel and co-instantaneous drug releases happen with the cleavage of the disulfide bond following tumor targeting and cell endocytosis, which is triggered by massive glutathione (GSH) in the cytoplasm of tumor cells. The highly selective nanogel uptake by tumor cells is directly demonstrated by fluorescence microscopy and flow cytometry. The dynamic light scattering and fluorescent spectrum reveal the GSH-triggered size change and simultaneous drug release, which results in higher tumor cytotoxicity and over fourfold efficacy against tumor cells compared with normal cells. These results indicate that these HA-PEG-Cys-DOX nanogels, with performance of selective drug delivery, intracellular reconstruction, and responsive drug release, are promising platforms for better therapeutic effects in cancer treatment.

Unconventional Facial Entry Points Confirmed Using a 3D CT Reconstruction-Guided Stereotactic Approach to Radiofrequency Thermocoagulation for the Treatment of Trigeminal Neuralgia: A Series of Case Reports.

OBJECTIVES: Patients with trigeminal neuralgia who are refractory to medical therapy may choose to undergo Gasserian ganglion percutaneous radiofrequency thermocoagulation. However, in cases where the foramen ovale is difficult to access due to various anatomical anomalies, the typical estimation of the facial entry point is suboptimal. METHODS: Three-dimensional computed tomography reconstruction imaging performed before surgery revealed anatomical variations in each of the four adult patient cases that made it more difficult to successfully access the foramen ovale (FO) for percutaneous radiofrequency thermocoagulation. Using measurements collected from preoperative imaging that showed each specific anatomical variation in the FO, researchers marked alternate facial entry points that would allow successful probe placement into the FO and recorded the arc angle data in the stereotactic instrument. RESULTS: Patients were evaluated during follow-up visits ranging from seven to 26 months after surgery and asked to rate postoperative pain using a visual analog scale. These scores decreased from 10 to 3 in all four patients by the third day after the procedure. There were no permanent complications or morbidities from the surgery. One patient experienced mild facial numbness; however, this side effect subsided within three months after surgery. During the follow-up period, no patient reported pain recurrence. CONCLUSIONS: The expectation for clinicians approaching trigeminal nerve block using a peri-oral approach should be to expect a great degree of potential variability in terms of both distances from the corner of the mouth and needle angle taken to successfully navigate the anatomy and access the foramen ovale.

Polydopamine-coated cotton fibers as the adsorbent for in-tube solid-phase microextraction.

Polydopamine was coated onto cotton fibers as the adsorbent to improve the extraction efficiency. Polydopamine-coated cotton fibers were placed into a polyetheretherketone tube for in-tube solid-phase microextraction. To develop an online analysis system, the extraction tube was connected with high-performance liquid chromatography. The tube was evaluated with five estrogenic analytes, and the extraction and desorption conditions were optimized to get high extraction efficiency. Under the optimum conditions, the enrichment factors of five analytes were 143-1745. An online analysis method was established, it had large linear ranges (0.10-40 and 0.16-40 µg/L), low limits of detection (0.03, 0.05 µg/L) and satisfactory repeatability (≤3.2%). The analysis method was applied to detect targets in the real samples like as hot water in new plastic cup and tap water. The relative recoveries spiked at 1 and 5 µg/L in these samples were investigated and the results were in the range of 83.7-109%.

Bare polyprolylene hollow fiber as extractive phase for in-tube solid-phase microextraction to determine estrogens in water samples.

Polypropylene hollow fibers as the adsorbent were directly filled into a polyetheretherketone tube for in-tube solid-phase microextraction. The surface properties of hollow fibers were characterized by a scanning electron microscope. Combined with high performance liquid chromatography, the extraction tube showed good extraction performance for five environmental estrogen hormones. To achieve high analytical sensitivity, four important factors containing sampling volume, sampling rate, content of organic solvent in sample, and desorption time were investigated. Under the optimum conditions, an online analysis method was established with wide linear range (0.03-20 µg/L), good correlation coefficients (≥0.9998), low limits of detection (0.01-0.05 µg/L), low limits of quantitation (0.03-0.16 µg/L), and high enrichment factors (1087-2738). Relative standard deviations (n = 3) for intraday (≤3.6%) and interday (≤5.1%) tests proved the stable extraction performance of the material. Durability and chemical stability of the extraction tube were also investigated, relative standard deviations of all analytes were less than 5.8% (n = 3), demonstrating the satisfactory stability. Finally, the method was successfully applied to detect estrogens in real samples.

A green extraction material - natural cotton fiber for in-tube solid-phase microextraction.

Natural cotton fiber was applied as a green extraction material for in-tube solid-phase microextraction. Cotton fibers were characterized by scanning electron microscope. A bundle of cotton fibers (685 mg, 20 cm) was directly packed into a polyetheretherketone tube (i.d. 0.75 mm) to get the extraction device. It was connected into high performance liquid chromatography, building an online extraction and dectection system. Through the online analysis system, several polycyclic aromatic hydrocarbons were used as the targets to evaluate the extraction performace of the device. In order to get high extraction efficiency and sensitivity, the extraction and desorption conditions were optimized. Under the optimum conditions, the sensitive analysis method was established, and provided low limits of detection of 0.02 and 0.05 µg/L, good linearity ranges of 0.06-15 and 0.16-15 µg/L, as well as high enrichment factors of 176-1868. The method was applied to the online determination of trace polycyclic aromatic hydrocarbons in snow water and river water, and the relative recoveries corresponding to 2 and 5 µg/L were in the range of 80-116%. The repeatability of extraction and preparation of the device was investigated and the relative standard deviations (n = 3) were less than 3.6 and 5.2%.

Study on mitigating membrane fouling based on precursor and flocculant Alb matching in EC/O-UF system.

One of the effective ways to remove halogenated disinfection by-products (DBPs) from drinking water is the application of ultrafiltration technology. However, membrane fouling is an important factor affecting the service life and treatment effect. In this study, the electrocoagulation/oxidation-ultrafiltration (EC/O-UF) process was used to remove the precursor substance that produced DBPs, i.e. dissolved organic matters (DOMs). Operating parameters were optimized from the matching of different flocculant morphology to low concentration DOM. The degree of membrane fouling was characterized by analyzing DOMs concentration and membrane flux. The results showed that the optimal conditions for the production of Alb were: current density 10 A/m2, hydraulic retention time 10 min, and initial pH 5.0-7.0. Under these conditions, the production of flocculant Alb could reach 58-61%, 94-97% DOMs were removed by EC/O-UF.

Risk of colorectal cancer in patients with periodontal disease severity: a nationwide, population-based cohort study.

BACKGROUND: Periodontal disease (PD) and colorectal cancer (CRC) were associated with chronic inflammation. This retrospective cohort study examined the association between PD severity and CRC in a large-scale, population-based Chinese cohort. METHODS: A total of approximately 106,487 individuals with newly diagnosed PD and 106,487 age-matched and sex-matched patients without PD from 2000 to 2002 were identified from Taiwan's National Health Insurance Research Database (NHIRD). RESULTS: The Kaplan-Meier analysis revealed that the cumulative incidence of CRC was significantly higher in patients with PD than in those without PD (log-rank test, P < 0.001). After adjustment for age, sex, and comorbidities, patients with PD were associated with a significantly higher risk of CRC compared with those without PD (adjusted HR = 1.64, 95% CI = 1.50-1.80). Further, the risk of CRC appeared to increase with increasing frequency of PD medical visits [adjusted HR (95% CI) was 1.78 (1.58-2.02) and 1.53 (1.35-1.74) for annual visits > 10 and < 4, respectively]. CONCLUSION: Based on our study, PD severity was associated with an increase in the risk of CRC. Further mechanistic research is needed.