Evaluation of polyetheretherketone composites modified by calcium silicate and carbon nanotubes for bone regeneration: mechanical properties, biomineralization and induction of osteoblasts.

Desired orthopedic implant materials must have a good biological activity and possess appropriate mechanical property that correspond to those of human bone. Although polyetheretherketone (PEEK) has displayed a promising application prospect in musculoskeletal and dentistry reconstruction thanks to its non-biodegradability and good biocompatibility in the body, the poor osseointegration and insufficient mechanical strength have significantly limited its application in the repair of load-bearing bones and surgical operations. In this study, carbon nanotubes (CNT)/calcium silicate (CS)/polyetheretherketone ternary composites were fabricated for the first time. The addition of CS was mainly aimed at improving biological activities and surface hydrophilicity, but it inevitably compromised the mechanical strength of PEEK. CNT can reinforce the composites even when brittle CS was introduced and further upgraded the biocompatibility of PEEK. The CNT/CS/PEEK composites exhibited higher mechanical strengths in tensile and bending tests, 64% and 90% higher than those of brittle CS/PEEK binary composites. Besides, after incorporation of CNT and CS into PEEK, the hydrophilicity, surface roughness and ability to induce apatite-layer deposition were significantly enhanced. More importantly, the adhesion, proliferation, and osteogenic differentiation of mouse embryo osteoblasts were effectively promoted on CNT/CS/PEEK composites. In contrast to PEEK, these composites exhibited a more satisfactory biocompatibility and osteoinductive activity. Overall, these results demonstrate that ternary CNT/CS/PEEK composites have the potential to serve as a feasible substitute to conventional metal alloys in musculoskeletal regeneration and orthopedic implantation.

The effects and predictive value of calcium and magnesium concentrations on nutritional improvement, inflammatory response and diagnosis in patients with Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a progressive inflammatory disease of the gastrointestinal tract associated with malnutrition, high levels of inflammation and calcium and magnesium deficiencies. However, the relationships between these symptoms are poorly defined. METHOD: Seventy-six adult CD patients who had not yet started treatment and 83 healthy volunteers were recruited. The dietary intakes, serum calcium and magnesium levels, nutritional indicators and biochemical markers of disease activity were measured. RESULTS: Most participants had inadequate magnesium and calcium intake. The serum magnesium and calcium levels, as well as nutritional and inflammatory indicators, differed significantly between CD patients and controls, especially in the active phase. Serum levels of magnesium and calcium correlated with both nutritional status and inflammation. The cut-off values for CD development were 0.835 mmol/L (magnesium) and 2.315 mmol/L (calcium), whereas those for the active phase were 0.785 and 2.28 mmol/L, respectively. CONCLUSION: Adequate intake of magnesium and calcium may both improve the nutritional status of CD patients and reduce inflammation, benefiting disease relief. As both magnesium and calcium reflect CD status, they may be useful markers for CD diagnosis and disease activity.

Proteins rather than mRNAs regulate nucleation and persistence of Oskar germ granules in Drosophila.

RNA granules are membraneless condensates that provide functional compartmentalization within cells. The mechanisms by which RNA granules form are under intense investigation. Here, we characterize the role of mRNAs and proteins in the formation of germ granules in Drosophila. Super-resolution microscopy reveals that the number, size, and distribution of germ granules is precisely controlled. Surprisingly, germ granule mRNAs are not required for the nucleation or the persistence of germ granules but instead control their size and composition. Using an RNAi screen, we determine that RNA regulators, helicases, and mitochondrial proteins regulate germ granule number and size, while the proteins of the endoplasmic reticulum, nuclear pore complex, and cytoskeleton control their distribution. Therefore, the protein-driven formation of Drosophila germ granules is mechanistically distinct from the RNA-dependent condensation observed for other RNA granules such as stress granules and P-bodies.

Impact of Helicobacter pylori eradication timing on the risk of thromboembolism events in patients with peptic ulcer disease: a population-based cohort study.

OBJECTIVES: To evaluate the impact of Helicobacter pylori eradication on venous thromboembolism (VTE) events, and the differences between early and late treatment timing. DESIGN: A population-based cohort study. SETTING: Taiwan's National Health Insurance Research Database. PARTICIPANTS: A total of 6736 patients who received H. pylori eradication therapy from 2000 to 2010 were identified. We randomly selected 26 944 subjects matching in gender, age and baseline year as comparison cohort. PRIMARY AND SECONDARY OUTCOME MEASURES: The incidence rate ratios of VTE in the H. pylori eradication cohorts to that of the control cohort were examined. Multivariable Cox proportional hazard regression analysis was used to estimate the relative HRs and 95% CI of VTE development. RESULTS: The total incidence rate of VTE was observed in the late H. pylori eradication cohort, the early H. pylori eradication cohort and the control cohort (15.2, 3.04 and 2.91 per 1000 person-years, respectively). An age-specific trend was found in the late H. pylori eradication cohort, with a greater rate of VTE in the 50-65 years and more than 65 years age groups (adjusted HR 5.44; 95% CI 4.21 to 7.03 and 3.13; 95% CI 2.46 to 3.99). With comorbidities, the late H. pylori eradication cohort seemed to have the highest VTE incidence rate and adjusted HR (4.48, 95% CI 3.78 to 5.30). CONCLUSIONS: Late H. pylori eradication was associated with a significantly increased risk of VTE, and there was a significantly greater risk of VTE in patients with female gender, age more than 50 years and with comorbidities.

Association Between Non-Suicidal Self-Injury and Gut Microbial Characteristics in Chinese Adolescent.

Purpose: By exploring the gut-related microbiota differences of adolescents with non-suicidal self-injury (NSSI) and depression (without NSSI) and healthy volunteers, we provide a theoretical basis for the prevention and control of NSSI in adolescents through intestinal microecological regulation. Patients and Methods: A total of 99 subjects were recruited in Guangdong Province, China, including 51 adolescents with NSSI (KD), 24 healthy adolescents (NOR1), and 24 depression adolescents without NSSI (NOR2). General clinical data and fecal samples were collected from all subjects, who were assessed using the NSSI Behavioral Questionnaire and the 24-item Hamilton Depression Scale. The taxonomic composition of the gut microbiota was determined using the 16S rDNA gene sequencing method. Results: There were significant differences in diversity between the KD and NOR1, and the species uniformity index of the KD according to the Shannon and Simpson indices was significantly reduced compared with that of the NOR1 (4.81 vs 5.21, p<0.01; 0.02 vs 0.01, p<0.05). The relative abundances were different among the KD, NOR1 and NOR2, as reflected at the taxonomic levels of class, order, family, genus, and species. Bacteroides were the dominant flora of the KD and NOR2, while Mitsuokella was the dominant flora that distinguished the KD from the NOR2. Conclusion: We found that gut microbiota diversity was decreased in adolescents with NSSI, and the relative abundance was altered at different taxonomic levels. These results enrich the understanding of the relationship between NSSI and depression and the gut microbiota, Supporting that NSSI and depression are not homologous disorders. What is more, it establishes the basis for exploring the mechanisms of flora action in NSSI, providing a possible direction for NSSI to achieve a better prognosis and prevent relapse.

High-entropy-alloy nanoparticles with 21 ultra-mixed elements for efficient photothermal conversion.

Multi-metallic nanoparticles have been proven to be an efficient photothermal conversion material, for which the optical absorption can be broadened through the interband transitions (IBTs), but it remains a challenge due to the strong immiscibility among the repelling combinations. Here, assisted by an extremely high evaporation temperature, ultra-fast cooling and vapor-pressure strategy, the arc-discharged plasma method was employed to synthesize ultra-mixed multi-metallic nanoparticles composed of 21 elements (FeCoNiCrYTiVCuAlNbMoTaWZnCdPbBiAgInMnSn), in which the strongly repelling combinations were uniformly distributed. Due to the reinforced lattice distortion effect and excellent IBTs, the nanoparticles can realize an average absorption of >92% in the entire solar spectrum (250 to 2500 nm). In particular, the 21-element nanoparticles achieve a considerably high solar steam efficiency of nearly 99% under one solar irradiation, with a water evaporation rate of 2.42 kg m-2 h-1, demonstrating a highly efficient photothermal conversion performance. The present approach creates a new strategy for uniformly mixing multi-metallic elements for exploring their unknown properties and various applications.

Endothelial SIRPα signaling controls VE-cadherin endocytosis for thymic homing of progenitor cells.

Thymic homing of hematopoietic progenitor cells (HPCs) is tightly regulated for proper T cell development. Previously we have identified a subset of specialized thymic portal endothelial cells (TPECs), which is important for thymic HPC homing. However, the underlying molecular mechanism still remains unknown. Here, we found that signal regulatory protein alpha (SIRPα) is preferentially expressed on TPECs. Disruption of CD47-SIRPα signaling in mice resulted in reduced number of thymic early T cell progenitors (ETPs), impaired thymic HPC homing, and altered early development of thymocytes. Mechanistically, Sirpa-deficient ECs and Cd47-deficient bone marrow progenitor cells or T lymphocytes demonstrated impaired transendothelial migration (TEM). Specifically, SIRPα intracellular ITIM motif-initiated downstream signaling in ECs was found to be required for TEM in an SHP2- and Src-dependent manner. Furthermore, CD47 signaling from migrating cells and SIRPα intracellular signaling were found to be required for VE-cadherin endocytosis in ECs. Thus, our study reveals a novel role of endothelial SIRPα signaling for thymic HPC homing for T cell development.

Critically-Ill Patients with Biliary Obstruction and Cholangitis: Bedside Fluoroscopic-Free Endoscopic Drainage versus Percutaneous Drainage.

Severe acute cholangitis is a life-threatening medical emergency. Endoscopic biliary drainage (EBD) or percutaneous transhepatic biliary drainage (PTBD) is usually used for biliary decompression. However, it can be risky to transport a critical patient to the radiology unit. We aimed to compare clinical outcomes between bedside, radiation-free EBD and fluoroscopic-guided PTBD in patients under critical care. METHODS: A retrospective study was conducted on critically ill patients admitted to the intensive care unit with biliary obstruction and cholangitis from January 2011 to April 2020. RESULTS: A total of 16 patients receiving EBD and 31 patients receiving PTBD due to severe acute cholangitis were analyzed. In the EBD group, biliary drainage was successfully conducted in 15 (93.8%) patients. Only one patient (6.25%) encountered post-procedure pancreatitis. The 30-day mortality rate was no difference between the 2 groups (32.72% vs. 31.25%, p = 0.96). Based on multivariate analysis, independent prognostic factors for the 30-day mortality were a medical history of malignancy other than pancreatobiliary origin (HR: 5.27, 95% confidence interval [CI]: 1.01-27.57) and emergent dialysis (HR: 7.30, 95% CI: 2.20-24.24). CONCLUSIONS: Bedside EBD is safe and as effective as percutaneous drainage in critically ill patients. It provides lower risks in patient transportation but does require experienced endoscopists to perform the procedure.

Quinary High-Entropy-Alloy@Graphite Nanocapsules with Tunable Interfacial Impedance Matching for Optimizing Microwave Absorption.

Designing heterogeneous interfaces and components at the nanoscale is proven effective for optimizing electromagnetic wave absorption and shielding properties, which can achieve desirable dielectric polarization and ferromagnetic resonances. However, it remains a challenge for the precise control of components and microstructures via an efficient synthesis approach. Here, the arc-discharged plasma method is proposed to synthesize core@shell structural high-entropy-alloy@graphite nanocapsules (HEA@C-NPs), in which the HEA nanoparticles are in situ encapsulated within a few layers of graphite through the decomposition of methane. In particular, the HEA cores can be designed via combinations of various transition elements, presenting the optimized interfacial impedance matching. As an example, the FeCoNiTiMn HEA@C-NPs obtain the minimum reflection loss (RLmin ) of -33.4 dB at 7.0 GHz (3.34 mm) and the efficient absorption bandwidth (≤-10 dB) of 5.45 GHz ranging from 12.55 to 18.00 GHz with an absorber thickness of 1.9 mm. The present approach can be extended to other carbon-coated complex components systems for various applications.

High-Entropy-Alloy Nanoparticles with Enhanced Interband Transitions for Efficient Photothermal Conversion.

Photothermal materials with broadband optical absorption and high conversion efficiency are intensively pursued to date. Here, proposing by the d-d interband transitions, we report an unprecedented high-entropy alloy FeCoNiTiVCrCu nanoparticles that the energy regions below and above the Fermi level (±4 eV) have been fully filled by the 3d transition metals, which realizes an average absorbance greater than 96 % in the entire solar spectrum (wavelength of 250 to 2500 nm). Furthermore, we also calculated the photothermal conversion efficiency and the evaporation rate towards the steam generation. Due to its pronounced full light capture and ultrafast local heating, our high-entropy-alloy nanoparticle-based solar steam generator has over 98 % efficiency under one sun irradiation, meanwhile enabling a high evaporation rate of 2.26 kg m-2 h-1 .

Product Inhibition and the Catalytic Destruction of a Nerve Agent Simulant by Zirconium-Based Metal-Organic Frameworks.

Rapid degradation/destruction of chemical warfare agents, especially ones containing a phosphorous-fluorine bond, is of notable interest due to their extreme toxicity and typically rapid rate of human incapacitation. Recent studies of the hydrolytic destruction of a key nerve agent simulant, dimethyl 4-nitrophenylphosphate (DMNP), catalyzed by Zr6-based metal-organic frameworks (MOFs), have suggested deactivation of the active sites due to inhibition by the products as the reaction progresses. In this study, the interactions of two MOFs, NU-1000 and MOF-808, and two hydrolysis products, dimethyl phosphate (DMP) and ethyl methyl phosphonate (EMP), from the hydrolysis of the simulant (DMNP) and nerve agent ethyl methylphosphonofluoridate (EMPF), resembling the hydrolysis degradation product of the G-series nerve agent, Sarin (GB), have been investigated to deconvolute the effect of product inhibition from other effects on catalytic activity. Kinetic studies via in situ nuclear magnetic resonance spectroscopy indicated substantial product inhibition upon catalyst activity after several tens to several thousand turnovers, depending on specific conditions. Apparent product binding constants were obtained by fitting initial reaction rates at pH 7.0 and pH 10.5 to a Langmuir-Freundlich binding/adsorption model. For the fits, varying amounts/concentrations of candidate inhibitors were introduced before the start of catalytic hydrolysis. The derived binding constants proved suitable for quantitatively describing product inhibition effects upon reaction rates over the extended time course of simulant hydrolysis by aqua-ligand-bearing hexa-zirconium(IV) nodes.

Isomer of linker for NU-1000 yields a new she-type, catalytic, and hierarchically porous, Zr-based metal-organic framework.

The well-known MOF (metal-organic framework) linker tetrakis(p-benzoate)pyrene (TBAPy4-) lacks steric hindrance between its benzoates. Changing the 1,3,6,8-siting of benzoates in TBAPy4- to 4,5,9,10-siting introduces substantial steric hindrance and, in turn, enables the synthesis of a new hierarchically porous, she-type MOF Zr6(µ3-O)4(µ3-OH)4(C6H5COO)3(COO)3(TBAPy-2)3/2 (NU-601), where TBAPy-24- is the 4,5,9,10 isomer of TBAPy4-. NU-601 shows high catalytic activity for degradative hydrolysis of a simulant for G-type fluoro-phosphorus nerve agents.

Geographical traceability and multielement analysis of edible and medicinal fungi: Taking Wolfiporia cocos (F.A. Wolf) Ryvarden and Gilb. as an example.

Different geographical environment has a certain influence on the accumulation of fungi elements and chemical components. However, our knowledge is limited to elucidate the fungi elements in response to heterogeneous environmental and the quality differences among different habitats. Here, multielement analysis, FTIR spectrum, and feature-level fusion technique combined with chemometrics were used to study Wolfiporia cocos from different geographical areas, different sampling sites and different altitude sources. From the results, (1) there is significant difference in element content of samples from different sampling sites and no positive correlation with geographical ranges. (2) There is a correlation between elevation and elements, and relatively low elevation (<1,800 m) is conducive to the enrichment of elements. (3) From the perspective of elements, the W. cocos in Yuxi have relatively better quality. (4) FTIR and feature-level models can well realize origin identification. The SVM models are better than the PLS-DA models, and the feature-level model is better than the single FTIR models. In summary, this study demonstrated that the developed method was reliable and could realize the genuineness evaluation and origin identification of W. cocos. The results have implications for the establishment of the technology system of geographical traceability and the development of high-quality geographical indication products of W. cocos.

Node-Accessible Zirconium MOFs.

High-stability, zirconium-based metal-organic frameworks are attractive as heterogeneous catalysts and as model supports for uniform arrays of subsequently constructed heterogeneous catalysts-for example, MOF-node-grafted metal-oxy and metal-sulfur clusters. For hexa-Zr(IV)-MOFs characterized by nodes that are less than 12-connected, sites not used for linkers are ideally occupied by reactive and displaceable OH/H2O pairs. The desired pairs are ideal for grafting the aforementioned catalytic clusters, while aqua-ligand lability renders them effective for exposing highly Lewis-acidic Zr(IV) sites (catalytic sites) to candidate reactants. New single-crystal X-ray studies of an eight-connected Zr-MOF, NU-1000, reveal that conventional activation fully removes modulator ligands, but replaces them with three node-blocking formate ligands (from solvent decomposition) and only one OH/H2O pair, not four-a largely overlooked complication that now appears to be general for Zr-MOFs. Here we describe an alternative activation protocol that effectively removes modulators, avoids formate, and installs the full complement of terminal OH/H2O pairs. It does so via an unusual isolatable intermediate featuring eight aqua ligands and four non-ligated chlorides-again as supported by single-crystal X-ray data. We find that complete replacement of node-blocking modulators/formate with the originally envisioned OH/OH2 pairs has striking consequences; here we touch upon just three. First, elimination of unrecognized formate renders aqua ligands much more thermally labile, enabling open Zr(IV) sites to be obtained at lower temperature. Second, in the absence of formate, which otherwise links and locks pairs of node Zr(IV) ions, reversible removal of aqua ligands engenders reversible contraction of MOF meso- and micropores, as evidenced by X-ray diffraction. Third, formate replacement with OH/OH2 pairs renders NU-1000 ca.10× more active for catalytic hydrolytic degradation of a representative simulant of G-type chemical warfare agents.

Biodegradable poly (lactic acid-co-trimethylene carbonate)/chitosan microsphere scaffold with shape-memory effect for bone tissue engineering.

Poly (lactic acid) (PLA), although extensively used as biomedical materials, has the distinct disadvantage of producing acidic byproducts which can lead to tissue inflammatory reactions and clinic failure. Here we presented a combination of Poly (lactic acid-co-trimethylene carbonate) and natural polymer chitosan, improving its compression resilience and reducing its acidic byproducts. In this case, we developed 3D scaffolds using solvent/nonsolvent technique sintered PLA-TMC and PLA-TMC/Chitosan microspheres with selected particle size (355-500 µm). By controlling the preparation methods and parameters, the porosity, pore size and mechanical properties of microsphere scaffolds can be designed and controlled. Strikingly, PLA-TMC/15 % Chitosan microsphere scaffolds possess shape-memory effect and rapidly recovered to initial shape when heated to 37℃ within 300 s. The microsphere scaffolds had a 3D porous architecture with pore size ranging from 105.67 ± 12.51 µm to 129.69 ± 11.39 µm. The mechanical and physicochemical properties of microspheres and scaffolds were characterized in details. Moreover, all microsphere scaffolds were qualified as their compressive modulus (120.36 MPa -195.32 MPa) matched the cancellous bone during 16 weeks degradation. Furthermore, CCK8 cell proliferation assay and ALP activity assay verified that the scaffolds were non-toxic and conductive to cell adhesion. The scaffolds are expected to be used in bone regeneration and bone repair field.

Metal-Organic-Framework-Supported and -Isolated Ceria Clusters with Mixed Oxidation States.

The formation of oxygen vacancies via reversible transitions between Ce(IV) and Ce(III) plays a crucial role in the propensity of cerium oxide to act as a supporting promoter in oxidative heterogeneous catalysis. An open challenge is, however, preparation of high-porosity, supported arrays of isolated ceria(IV, III) clusters with high porosity. Herein, we report two examples of oxy-Ce(IV, III) clusters supported and spatially isolated on an oxy-zirconium MOF, NU-1000. The clusters are introduced using either of two Ce complexes (precursors): CeIV(tmhd)4 (tmhd = 2,2,6,6-tetramethyl-3,5-heptanedionate) or CeIII(iPrCp)3 (iPrCp = tris(isopropyl-cyclopenta-dienyl), via SIM (solvothermal installation in MOFs). The prepared materials are named Ce-l-SIM-NU-1000 and Ce-n-SIM-NU-1000, respectively. X-ray photoelectron spectroscopy characterization shows that the ratio of Ce(III) to Ce(IV) oxidation states can be modulated. Difference envelope density analyses of X-ray scattering show that CexOyHz clusters in Ce-n-SIM-NU-1000 are located between pairs of Zr6 nodes, whereas in Ce-l-SIM-NU-1000, they are sited on MOF linkers throughout the micropores of NU-1000. Cluster size differences were further evaluated by pair function distribution (PDF) analyses of total X-ray scattering reveal that the node sited clusters contain of only a few cerium ions, whereas the linker-sited clusters each contain ∼90 cerium ions. The observed size appears to be defined by the size of NU-1000s triangular pores, that is, cluster formation appears to be pore templated. The Ce-SIM functionalized materials are catalytically active for hydrolysis of DMNP (dimethyl 4-nitrophenyl phosphate), a nerve-agent simulant. Conversion of a small fraction of the Ce(IV) ions in which the presence of small fractions of the cerium(IV) ions in Ce-l-SIM-NU-1000 to cerium(III) significantly enhances catalytic activity-perhaps by labilizing aqua ligands and facilitating simulant binding to the clusters Lewis-basic metal ions. While not explored here, the larger clusters, when partially reduced, are, we believe, candidate catalysts for O2 activation and subsequent selective oxidation of organic substrates.

Enhancing the mechanical and thermal properties of polypropylene composite by encapsulating styrene acrylonitrile with ammonium polyphosphate.

BACKGROUNDS: In recent decades, incorporating polypropylene (PP) within flame retardants has proved to be an effective method of improving the thermal stabilities of PP, but too much adversely affects the mechanical properties of this polymer materials. Herein we report a novel multifunctional flame retardant, (styrene acrylonitrile)-(titanate-modified ammonium polyphosphate) (SAN-TAPP), to simultaneously improve the mechanical properties and thermal stability of PP composites. METHODS: SAN-TAPP was synthesized by encapsulating SAN resins with functional titanate-modified APP (TAPP) and subsequently was incorporated into PP by a melt-blending process. The phase characteristics and morphology of SAN-TAPP were investigated, and the mechanical properties and thermal stability of different content of PP/SAN-TAPP composites were studied. RESULTS: The results showed that the TAPP was almost entirely wrapped in the SAN resins and PP/SAN-TAPP composites exhibited the sea-island morphology. For the mechanical properties, the impact strength of PP/SAN-TAPP composite was significantly improved, especially 15 wt% SAN-TAPP filled PP/SAN-TAPP composite exhibiting 2.17 times higher than that of pure PP. And the tensile strength and modulus also increased by addition of SAN-TAPP. For the thermal stabilities, melting temperatures (Tm) and residual char yield were improved. Furthermore, the LOI value of PP/SAN-TAPP composites increased from 19.8 to 27.5%; The 15 and 20 wt% SAN-TAPP filled in PP/SAN-TAPP composites passed the V-2 test of UL-94, and exerted the similar effect on the flame retardancy to TAPP with the same loading. CONCLUSIONS: These results revealed that a novel PP/SAN-TAPP composites with synthetically enhancement on the mechanical properties, thermal stabilities and flame retardancy, suggesting a strong correlation between the phase structure, mechanical and thermal properties.

A Systematic Review of the Medicinal Potential of Mulberry in Treating Diabetes Mellitus.

Diabetes mellitus (DM) is a serious metabolic disorder which has reached epidemic proportions all over the world. Despite tremendous developments in medicinal chemistry, traditional medicine is still commonly used for the prevention and treatment of DM. Traditional herbal medicines have played a major role in the management of DM in Asian countries. In particular, mulberry has commonly been utilized in China for the treatment of DM for thousands of years. In the last decade, numerous preclinical findings have suggested that mulberry is a promising therapeutic agent for the treatment of DM, and the polyhydroxylated alkaloids, flavonoids and polysaccharides from mulberry may be the potential active components. The present review systematically summarizes the chemical composition of mulberry and the pharmacological effects of different medicinal parts on DM; these effects include influences on glucose absorption, insulin (INS) production/secretion, anti-oxidation and anti-inflammation processes. After summarizing our research findings, we will discuss the challenges and opportunities and explore the direction of future research and the potential for developing mulberry into pharmaceuticals for the widespread treatment of DM.