No evidence of a causal relationship between miscarriage and 25-hydroxyvitamin D: a Mendelian randomization study.

STUDY QUESTION: Is there a causal relationship between 25-hydroxyvitamin D (25OHD) and miscarriage? SUMMARY ANSWER: In this study, little evidence of a causal relationship was found between low serum 25OHD concentration or vitamin D deficiency and the risk of miscarriages. WHAT IS KNOWN ALREADY: Associations between low vitamin D levels and increased risk of miscarriage have been reported, but causality is unclear. STUDY DESIGN SIZE DURATION: The latest and largest genome-wide association studies (GWAS) for serum 25OHD concentration (n = 417 580), vitamin D deficiency (426 cases and 354 812 controls), miscarriage (16 906 cases and 149 622 controls), and the number of miscarriages (n = 78 700) were used to explore the causal association between serum vitamin D levels and miscarriage by two-sample Mendelian randomization analysis. PARTICIPANTS/MATERIALS SETTING METHODS: This study was based on summary GWAS results from the FinnGen database and the UK Biobank. The random-effect inverse-variance weighted method was regarded as the primary analysis; MR-Egger, weighted median, weighted mode, simple mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were further employed as complementary methods. MR-Egger intercept analysis and MR-PRESSO were employed to test pleiotropy, and Cochran's Q statistic and leave-one-out sensitivity analysis were used to determine the heterogeneity and robustness of the overall estimates, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: There was insufficient evidence of causal associations between serum 25OHD concentration and miscarriage (odds ratio (OR) = 0.995, 95% CI: 0.888 to 1.114, P = 0.927), or the number of miscarriages (ß = -0.004, 95% CI: -0.040 to 0.032, P = 0.829). Furthermore, little evidence of causality between genetically determined vitamin D deficiency to miscarriage (OR = 0.993, 95% CI: 0.966 to 1.021, P = 0.624), or the number of miscarriages (ß = 0.001, 95% CI: -0.009 to 0.011, P = 0.828), was observed. The results of the sensitivity analysis were robust, and no significant heterogeneity or horizontal pleiotropy was found. LIMITATIONS REASONS FOR CAUTION: This study is limited by the absence of female-specific GWAS data and the limited amount of GWAS data available for this study, as well as the need for caution in generalizing the findings to non-European ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS: These findings enhance the current understanding of the intricate association between vitamin D and pregnancy outcomes, challenging prevailing beliefs regarding the strong association with miscarriage. The results provide a special perspective that may prompt further exploration and potentially offer insights for guiding future research and informing clinical guidelines pertaining to the management of miscarriage. STUDY FUNDING/COMPETING INTERESTS: This project was supported by the Hubei Provincial Natural Science Foundation Program General Surface Project (2022CFB200), the Key Research & Developmental Program of of Hubei Province (2022BCA042), the Fundamental Research Funds for the Central Universities (2042022gf0007, 2042022kf1210), and the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University (JCRCWL-2022-001, JCRCYG-2022-009). All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Fabrication of an Injectable Star-polylactide/Thiolated Hyaluronate Hydrogel as a Double Drug-Delivery System for Cancer Treatment.

Unsatisfactory solid-tumor penetration or rapid metabolism of nanomaterials limits their therapeutic efficacy. Here, we designed an injectable thiolated hyaluronate (HA-SH) hydrogel as a stable drug-releasing platform for in situ tumor treatment. Biodegradable star-shaped polylactide (S-PLLA) was first synthesized and fabricated to porous microspheres to encapsulate hydrophobic curcumin (Cur@S-PLLA), which was then blended with hydrophilic doxorubicin (Dox) and the HA-SH precursor to form composite in situ formable hydrogels [Cur@S-PLLA/(Dox)HA-SH]. The results showed that adding the microspheres improved the performance of the hydrogel, such as decreasing the gelation time from 1080 s to 960 s and also the swelling ratio. The mechanical strength increased from 27 to 45 kPa. In addition, the double drug system guaranteed a sustained release of drugs, releasing Dox at the early stage, with the continuous later release of Cur after gel swelling or S-PLLA degradation to achieve long-lasting tumor suppression, which inhibits the survival of cancer cells. The inhibitory effects of the hydrogels on MCF-7 were studied. The cell activity in the double-loaded hydrogel was significantly lower than that of the control groups, and apparent dead cells appeared in 2 days and fewer living cells with time. Flow cytometry revealed that the Cur@S-PLLA/(Dox)HA-SH group had the highest apoptosis ratio of 86.60% at 12 h, and the drugs caused the cell cycle to be blocked in phase M to reduce cell division. In summary, the innovative release platform is expected to be used in long-lasting tumor suppression and provides more ideas for the design of drug carriers.

Nurse-led shared decision-making on complementary therapy use by patients with diabetes: An participatory action research.

AIMS: The aim of this study was to develop, implement and evaluate a nurse-led shared decision-making model of care for discussing the use of complementary and alternative medicine with diabetic patients and to explore to what extent the risk-benefit assessment of using complementary and alternative medicine can provide a framework for facilitating nurse-patient dialogue and strengthening patient involvement in their disease management. DESIGN: Participatory action research with pre-post intervention. METHODS: A two-run cycle of action and spirals from participatory action research was undertaken using a purposive sampling method to involve healthcare professionals and diabetic patients from September 2021 to June 2022. The nurse-led shared decision-making model of care was designed and implemented congruent with participatory action research principles. Quantitative measures were collected about patients' perceived involvement in shared decision-making and their understanding of the risks and benefits of using complementary and alternative medicine. Patients' outcomes of disease control (fasting plasma glucose and HbA1c) were also collected. Data were analysed using IBM SPSS software (version 28). Interviews were summarized using thematic analysis. An EQUATOR Network guideline for participatory action research supported the preparation of this paper. RESULTS: Comparison of pre-post intervention outcomes showed that patients' scale scores on shared decision-making involvement and understanding of the risk-benefit of using complementary and alternative medicine improved significantly after implementing the model. Fasting plasma glucose improved only slightly after a 3-month follow-up. CONCLUSIONS: The care model strengthens patient involvement in their disease management and makes appropriate decisions about CAM use that should reduce potentially harmful side effects or interactions between CAM and conventional medicine. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: The shared decision-making model of care incorporates evidence-based CAM research into practice, facilitates the standardization of CAM management in diabetes, improves care options for patients and educates nurses about CAM use in managing diabetes. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

Colon cancer exosome-derived biomimetic nanoplatform for curcumin-mediated sonodynamic therapy and calcium overload.

Sonodynamic therapy (SDT) possesses unique properties such as being minimally invasive, exhibiting low toxicity, as well as ability to impart the treatment in the deep tissues, and hence has been extensively used. However, inherent defects such as low water-soluble sonosensitizers can limit the clinical application of SDT, and tumor microenvironment (TME) can further compromise the effect of a single SDT. To overcome these challenges, we have designed a bionic nano-system (ECaC) by coating mesoporous calcium carbonate nanoparticles (CaCO3 NPs) and sonosensitizer curcumin (Cur) into tumor-derived exosomes for developing enhanced SDT. Exosome membrane could endow CaCO3 NPs with homologous targeting abilities. In addition, compared with the bare CaCO3 NPs, ECaC showed significant accumulation in the tumor cell species. Subsequently, CaCO3 NPs upon reaching the tumor site can be degraded into Ca2+ in response to the acidic microenvironment of the tumor to destroy the cellular mitochondria. Hence, the cellular respiration could be destroyed to be a vulnerable state, causing oxidative stress, enhancing Cur-mediated chemotherapy/SDT. This synergistically dynamic therapy has demonstrated significant anti-tumor effects under in vitro and in vivo settings without exhibiting any toxic side effects. Our prepared biomimetic nano-system can effectively deliver the hydrophobic Cur to the tumor sites, which holds great promise in field of drug delivery and can broaden the application of exosomes, as this method has a certain enlightenment effect on the subsequent development of exosomes.

Novel Engineered Bacterium/Black Phosphorus Quantum Dot Hybrid System for Hypoxic Tumor Targeting and Efficient Photodynamic Therapy.

Intratumoral hypoxia significantly constrains the susceptibility of solid tumors to oxygen-dependent photodynamic therapy (PDT), and effort to reverse such hypoxia has achieved limited success to date. Herein, we developed a novel engineered bacterial system capable of targeting hypoxic tumor tissues and efficiently mediating the photodynamic treatment of these tumors. For this system, we genetically engineered Escherichia coli to express catalase, after which we explored an electrostatic adsorption approach to link black phosphorus quantum dots (BPQDs) to the surface of these bacteria, thereby generating an engineered E. coli/BPQDs (EB) system. Following intravenous injection, EB was able to target hypoxic tumor tissues. Subsequent 660 nm laser irradiation drove EB to generate reactive oxygen species (ROS) and destroy the membranes of these bacteria, leading to the release of catalase that subsequently degrades hydrogen peroxide to yield oxygen. Increased oxygen levels alleviate intratumoral hypoxia, thereby enhancing BPQD-mediated photodynamic therapy. This system was able to efficiently kill tumor cells in vivo, exhibiting good therapeutic efficacy. In summary, this study is the first to report the utilization of engineered bacteria to facilitate PDT, and our results highlight new avenues for BPQD-mediated cancer treatment.

Injectable Hydrogel for NIR-II Photo-Thermal Tumor Therapy and Dihydroartemisinin-Mediated Chemodynamic Therapy.

In traditional Chinese medicine, dihydroartemisinin (DHA) is the focus of extensive attention because of its unique activity with Fe2+ to produce reactive oxygen species (ROS) and promote apoptosis. In this work, we designed a newfangled ink@hydrogel containing FeCl3, traditional Chinese ink (Hu Kaiwen ink), and agarose hydrogel to create a synergistic activity with DHA in the treatment of cancer. When the system is irradiated under 1,064 nm for a few minutes, the ink in the ink@hydrogel converts the light to heat and hyperthermia causes the reversible hydrolysis of hydrogel. Then, Fe3+ quickly diffuses from the hydrogel to the tumor microenvironment and is reduced to Fe2+ to break the endoperoxide bridge in pre-injected DHA, which results in the release of free radicals for a potent anticancer action. To our knowledge, this is the first report of a hydrogel tumor therapy system that induces a photo-thermal response in the second near infrared window (NIR-II). in vivo experiments also showed a significant effect of DHA-Fe2+ in chemodynamic therapy (CDT) and in photo-thermal therapy. This hydrogel platform provided an encouraging idea for synergistic tumor therapy.

Enhanced Tumor Targeting and Radiotherapy by Quercetin Loaded Biomimetic Nanoparticles.

In Chinese traditional medicine, quercetin (QT) plays a fundamental role in the treatment of asthma, as an anti-allergen and to lower blood pressure. Recent evidence suggests that QT can improve tumor radiosensitivity through multiple mechanisms. However, poor tumor tissue targeting ability and low water solubility of QT limit its usefulness in the treatment of cancers. Herein, we designed a novel drug delivery system (CQM) consisting of inner QT loaded mesoporous silica nanoparticles (MSNs) and outer cancer cell membranes (CM). The developed nanoplatform had strong anti-cancer effects under X-ray irradiation and good QT loading characteristics. In addition, CQM effectively targeted tumor tissues. Results of in vitro and in vivo experiments demonstrated that the developed CQM drug delivery system has excellent tumor targeting ability and effectively inhibited tumor growth. Therefore, the CQM platform realized targeted drug delivery and radiotherapy sensitization, which provided a newfangled idea of cancer treatment.

Modulatory effects of vitamin D on peripheral cellular immunity in patients with recurrent miscarriage.

PROBLEM: We aimed to investigate the modulatory effects of vitamin D on peripheral blood cellular immune response in patients with recurrent miscarriage (RM). METHOD OF STUDY: The effect of vitamin D on the number of peripheral blood cells, T helper 1 (Th1) cytokines, and NK cytotoxicity was measured in 99 women with RM. RESULTS: The percentage of CD19+ B cells and NK cytotoxicity at an effector-to-target cell (E:T) ratio of 50:1, 25:1, and 12.5:1 were significantly higher in the vitamin D insufficiency group (VDI) than in the vitamin D normal group (VDN) (P<.05 each). The proportion of TNF-α-expressing Th cells was significantly higher in the vitamin D deficiency group (VDD) than in VDN (P<.05). However, there were no significant differences between VDI and VDD. This dysregulation was significantly reduced with 1,25(OH)2 D supplementation. CONCLUSION: The data suggest that the abnormalities of cellular immune response were observed in RM patients with a low vitamin D level, which could be regulated to some extent with 1,25(OH)2 D supplementation.