A meta-analysis and systematic review of photodynamic therapy for diabetic foot ulcers.

BACKGROUND: Diabetic foot ulcer (DFU) is a chronic and challenging condition, addressed through various treatments including photodynamic therapy (PDT) and standard of care (SOC), yet lacking consensus on the optimal approach. This study presents a comprehensive meta-analysis of randomized controlled trials to evaluate the efficacy and safety of PDT versus SOC in managing DFU. METHODS: An extensive literature search was conducted across PubMed, Embase, and the Cochrane Library databases to identify RCTs that compared the effectiveness of PDT with SOC in treating DFU. The primary metrics evaluated included changes in ulcer area, wound healing indices, and pain levels experienced by the patients. RESULTS: This meta-analysis incorporated data from 6 RCTs, encompassing 458 patients with 467 DFUs. The analysis indicated that while PDT led to a faster reduction in ulcer size compared to SOC, the difference was not statistically significant [mean difference (MD): 2.73cm², 95 % Confidence Interval (CI) -2.98 to 8.44; p > 0.05]. However, a notable improvement was observed in the wound healing rate in the PDT group [MD: 29.26 %, 95 % CI 7.24 to 51.28; p = 0.01]. Based on the Visual Analog Scale (VAS), pain assessment revealed no significant difference between the two treatment groups [MD: 2.35, 95 % CI -2.36 to 7.06; p = 0.33]. CONCLUSION: The study suggests that PDT might offer an enhanced healing rate for DFUs compared to SOC alone, potentially leading to improved patient outcomes. Importantly, our findings highlight the superiority of photodynamic therapy in accelerating ulcer healing without an associated increase in complications. PROSPERO: 2023 CRD42023493930.

Reconfigurable aqueous 3D printing with adaptive dual locks.

Using aqueous two-phase systems (ATPSs) for three-dimensional (3D) printed complex structures has attracted considerable attention in the field of biomedicine. In this study, we present an unusual approach to constructing reconfigurable 3D printed structures within an aqueous environment. Inspired by biological systems, we introduce both specific and nonspecific interactions to anchor functionalized nanoparticles to the water-water interface, thereby imparting adaptive dual locks of structural integrity and permeability to the 3D printed liquid structures. Using state-of-the-art in situ liquid-liquid interfacial atomic force microscopy imaging, we successfully demonstrate various morphologies of interfacial films formed at the ATPS interface. In addition, by incorporating d-glucose or sodium alginate into the systems, the dual locks can be easily manipulated. Our study paves a pathway for 3D printing multiresponsive all-aqueous systems with controllable structures and permeability, showing promising implications for the development of smart drug delivery systems and in vivo reactions.

METTL3 orchestrates glycolysis by stabilizing the c-Myc/WDR5 complex in triple-negative breast cancer.

BACKGROUND: The carcinogenic transcription factor c-Myc is the most aggressive oncogene, which drive malignant transformation and dissemination of triple-negative breast cancer (TNBC). Recruitment of many cofactors, especially WDR5, a protein that nucleates H3K4me chromatin modifying complexes, play a pivotal role in regulating c-Myc-dependent gene transcription, a critical process for c-Myc signaling to function in a variety of biological and pathological contexts. For this reason, interrupting the interaction between c-Myc and the transcription cofactor WDR5 may become the most promising new strategy for treating c-Myc driven TNBC. METHODS: Immunoprecipitation and mass spectrometry (IP-MS) is used to screen proteins that bind c-Myc/WDR5 interactions. The interaction of METTL3 with c-Myc/WDR5 in breast cancer tissues and TNBC cells was detected by Co-IP and immunofluorescence. Subsequently, we further analyzed the influence of METTL3 expression on c-Myc/WDR5 protein expression and its interaction stability by Western blot and Co-IP. The correlation between METTL3 and c-Myc pathway was analyzed by ChIP-seq sequencing and METTL3 knockdown transcriptome data. The effect of METTL3 expression on c-Myc transcriptional activity was detected by ChIP-qPCR and Dual Luciferase Reporter. At the same time, the overexpression vector METTL3-MUT (m6A) was constructed, which mutated the methyltransferase active site (Aa395-398, DPPW/APPA), and further explored whether the interaction between METTL3 and c-Myc/WDR5 was independent of methyltransferase activity. In addition, we also detected the changes of METTL3 expression on TNBC's sensitivity to small molecule inhibitors such as JQ1 and OICR9429 by CCK8, Transwell and clonal formation assays. Finally, we further verified our conclusions in spontaneous tumor formation mouse MMTV-PyMT and nude mouse orthotopic transplantation tumor models. RESULTS: METTL3 was found to bind mainly to c-Myc/WDR5 protein in the nucleus. It enhances the stability of c-Myc/WDR5 interaction through its methyltransferase independent mechanism, thereby enhancing the transcriptional activity of c-Myc on downstream glucose metabolism genes. Notably, the study also confirmed that METTL3 can directly participate in the transcription of glucose metabolism genes as a transcription factor, and knockdown METTL3 enhances the drug sensitivity of breast cancer cells to small molecule inhibitors JQ1 and OICR9429. The study was further confirmed by spontaneous tumor formation mouse MMTV-PyMT and nude mouse orthotopic transplantation tumor models. CONCLUSION: METTL3 binds to the c-Myc/WDR5 protein complex and promotes glycolysis, which plays a powerful role in promoting TNBC progression. Our findings further broaden our understanding of the role and mechanism of action of METTL3, and may open up new therapeutic avenues for effective treatment of TNBC with high c-Myc expression.

Recruitment of PVT1 Enhances YTHDC1-Mediated m6A Modification of IL-33 in Hyperoxia-Induced Lung Injury During Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that specifically affects preterm infants. Oxygen therapy administered to treat BPD can lead to hyperoxia-induced lung injury, characterized by apoptosis of lung alveolar epithelial cells. Our epitranscriptomic microarray analysis of normal mice lungs and hyperoxia-stimulated mice lungs revealed elevated RNA expression levels of IL-33, as well as increased m6A RNA methylation levels of IL-33 and PVT1 in the hyperoxia-stimulated lungs. This study aimed to investigate the role of the PVT1/IL-33 axis in BPD. A mouse model of BPD was established through hyperoxia induction, and lung histological changes were assessed by hematoxylin-eosin staining. Parameters such as radial alveolar count and mean chord length were measured to assess lung function. Mouse and human lung alveolar epithelial cells (MLE12 and A549, respectively) were stimulated with hyperoxia to create an in vitro BPD model. Cell apoptosis was detected using Western blotting and flow cytometry analysis. Our results demonstrated that silencing PVT1 suppressed apoptosis in MLE12 and A549 cells and improved lung function in hyperoxia-stimulated lungs. Additionally, IL-33 reversed the effects of PVT1 both in vivo and in vitro. Through online bioinformatics analysis and RNA-binding protein immunoprecipitation assays, YTHDC1 was identified as a RNA-binding protein (RBP) for both PVT1 and IL-33. We found that PVT1 positively regulated IL-33 expression by recruiting YTHDC1 to mediate m6A modification of IL-33. In conclusion, silencing PVT1 demonstrated beneficial effects in alleviating BPD by facilitating YTHDC1-mediated m6A modification of IL-33. Inhibition of the PVT1/IL-33 axis to suppress apoptosis in lung alveolar epithelial cells may hold promise as a therapeutic approach for managing hyperoxia-induced lung injury in BPD.

Case of Congenital Hemolytic Anemia with ATP11C and ANK1 Variants.

A male infant of Han descent, with a G1P1 mother and gestational age of 40+4 weeks, was born via cesarean section owing to his mother having pregnancy complications, including premature rupture of membranes, chorioamnionitis, and gestational diabetes. On the first day after birth, routine blood examination showed that his total red blood cells count was 2.32 × 1012/L, hemoglobin count was 77 g/L, and C-reactive protein count was 48.99 mg/L. After receiving an anti-infection treatment for 10 days and two blood transfusions (100 mL in total), he was discharged from a neonatal intensive care unit (NICU). Accessory examinations showed that reticulocytes in the peripheral blood were significantly increased, the morphology of red blood cells was normal, and all hemolysis-related examinations were normal; bone marrow examinations showed that the proliferation of the red blood cell system was low and serum ferritin and vitamin B12 levels were elevated. Because of the unexplained hemolysis, a whole-exome sequencing examination was performed. The results showed a hemizygous variant of the ATP11C gene (c.3136a>t/p ile 1046phe) and a frame-shift variant of the ANK1 gene (c.937del/pala313 leufs*19). After a six-month follow-up, the serum ferritin and vitamin B12 levels had gradually decreased to normal levels, and hemoglobin and reticulocyte values were 97 g/L and 7.17%, respectively, in the peripheral blood. No splenomegaly was found in physical examination.

Using Aggregation to Chaperone Nanoparticles Across Fluid Interfaces.

Nanoparticles (NPs) transfer is usually induced by adding ligands to modify NP surfaces, but aggregation of NPs oftentimes hampers the transfer. Here, we show that aggregation during NP phase transfer does not necessarily result in transfer failure. Using a model system comprising gold NPs and amphiphilic polymers, we demonstrate an unusual mechanism by which NPs can undergo phase transfer from the aqueous phase to the organic phase via a single-aggregation-single pathway. Our discovery challenges the conventional idea that aggregation inhibits NP transfer and provides an unexpected pathway for transferring larger-sized NPs (>20 nm). The charged amphiphilic polymers effectively act as chaperons for the NP transfer and offer a unique way to manipulate the dispersion and distribution of NPs in two immiscible liquids. Moreover, by intentionally jamming the NP-polymer assembly at the liquid/liquid interface, the transfer process can be inhibited.

A feasibility study of different GSI noise indexes and concentrations of contrast medium in hepatic CT angiography of overweight patients: image quality, radiation dose, and iodine intake.

PURPOSE: To conduct a comparative study of image quality, radiation dose, and iodine intake in hepatic computed tomographic angiography (CTA) of overweight patients with different Gemstone Spectral Imaging (GSI) noise indexes combined with different concentrations of contrast medium. MATERIALS AND METHODS: Ninety patients with a body mass index of ≥ 25 kg/m2 were divided into three groups (A, B and C), each with 30 patients. The three groups underwent hepatic CTA with different NI of 7, 11 and 15, respectively, and were injected with different iodine concentrations of 370, 350 and 320 mgI/mL, respectively. Five sets of images at 40-60 keV (interval, 5 keV) were reconstructed in each group. The CT value, image noise, contrast-to-noise ratio (CNR) and subjective score of the hepatic artery and vein, and portal vein in different monochromatic image sets were analyzed to select the optimal energy level in each group. The differences in CT value, image noise, CNR and a subjective score of hepatic artery and vein, portal vein in the optimal monochromatic images among the three groups were compared, the volume CT dose index (CTDIvol) and dose-length product (DLP) were recorded, and the effective dose and iodine intake were calculated. RESULTS: The 40 keV was determined to be the optimal energy level for the monochromatic image sets in each group. No significant group differences were noted in the CT value, image noise, CNR, and subjective image scores of the hepatic artery and vein, and portal vein for the optimal monochromatic images (P > 0.05). Compared with group A, the effective dose and iodine intake in group B were reduced by 50.18% and 9.3%, and by 58.12% and 14.23% in group C, respectively. CONCLUSION: A low-concentration contrast medium combined with a high-noise GSI index in hepatic CTA of overweight patients can reduce the radiation dose and iodine intake while ensuring image quality.

Comparing feasibility of different tube voltages and different concentrations of contrast medium in coronary CT angiography of overweight patients.

OBJECTIVES: To compare image quality, radiation dose, and iodine intake of coronary computed tomography angiography (CCTA) acquired by wide-detector using different tube voltages and different concentrations of contrast medium (CM) for overweight patients. MATERIALS AND METHODS: A total of 150 overweight patients (body mass index≥25 kg/m2) who underwent CCTA are enrolled and divided into three groups according to scan protocols namely, group A (120 kVp, 370 mgI/ml CM); group B (100 kVp, 350 mgI/ml CM); and group C (80 kVp, 320 mgI/ml CM). The CT values, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and figure-of-merit (FOM) of all images are calculated. Images are subjectively assessed using a 5-point scale. In addition, the CT dose index volume (CTDIvol) and dose length product (DLP) of each patient are recorded. The effective radiation dose (ED) is also calculated. Above data are then statistically analyzed. RESULTS: The mean CT values, SNR, CNR, and subjective image quality of group A are significantly lower than those of groups B and C (P < 0.001), but there is no significant difference between groups B and C (P > 0.05). FOMs show a significantly increase trend from group A to C (P < 0.001). The ED values and total iodine intake in groups B and C are 30.34% and 68.53% and 10.22% and 16.85% lower than those in group A, respectively (P < 0.001). CONCLUSION: The lower tube voltage and lower concentration of CM based on wide-detector allows for significant reduction in iodine load and radiation dose in CCTA for overweight patients comparing to routine scan protocols. It also enhances signal intensity of CCTA and maintains image quality.

Risk factors for POD24 in patients with previously untreated follicular lymphoma: a systematic review and meta-analysis.

Progression of disease within 24 months (POD24) is strongly associated with a poor outcome in patients with follicular lymphoma (FL). Our study aimed to identify the potential risk factors for POD24 in patients with FL. Medline, EMBASE and the Cochrane Library were systematically searched from the earliest record to September 2020. Studies investigating the prognostic factors for POD24 in patients with newly diagnosed grade 1-3a FL were included. Among 10,014 pieces of literature, a total of 90 studies investigating 82 risk factors were included for qualitative analysis. Meta-analyses were performed in 31 studies with 11 factors. Results showed that elevated sIL-2R, ß2m and LDH, total metabolic tumour volume > 510 cm3, vitamin D < 20 ng/mL, grade 3a and lymphoma-associated macrophages/high-power field ≥ 15 were significantly associated with an increased risk of POD24. No significant association was found between POD24 and the ALC/AMC ratio, sex, T effector signature or EZH2 genetic alteration. Additionally, minimal residual disease, Ki-67, PD-1 and TP53 were analysed narratively. Overall, this is the first study that comprehensively analysed the prognostic factors associated with POD24 in FL patients. We have confirmed the significance value of several common prognostic factors as well as others not commonly included in clinical study, helping to construct an integrated and more efficient model.

Aquabots.

Soft robots, made from elastomers, easily bend and flex, but deformability constraints severely limit navigation through and within narrow, confined spaces. Using aqueous two-phase systems we print water-in-water constructs that, by aqueous phase-separation-induced self-assembly, produce ultrasoft liquid robots, termed aquabots, comprised of hierarchical structures that span in length scale from the nanoscopic to microsciopic, that are beyond the resolution limits of printing and overcome the deformability barrier. The exterior of the compartmentalized membranes is easily functionalized, for example, by binding enzymes, catalytic nanoparticles, and magnetic nanoparticles that impart sensitive magnetic responsiveness. These ultrasoft aquabots can adapt their shape for gripping and transporting objects and can be used for targeted photocatalysis, delivery, and release in confined and tortuous spaces. These biocompatible, multicompartmental, and multifunctional aquabots can be readily applied to medical micromanipulation, targeted cargo delivery, tissue engineering, and biomimetics.

Shape-Reconfigurable Ferrofluids.

Ferrofluids (FFs) can adapt their shape to a magnetic field. However, they cannot maintain their shape when the magnetic field is removed. Here, with a magneto-responsive and reconfigurable interfacial self-assembly (MRRIS) process, we show that FFs can be structured by a magnetic field and maintain their shape, like solids, after removing the magnetic field. The competing self-assembly of magnetic and nonmagnetic nanoparticles at the liquid interface endow FFs with both reconfigurability and structural stability. By manipulating the external magnetic field, we show that it is possible to "write" and "erase" the shape of the FFs remotely and repeatedly. To gain an in-depth understanding of the effect of MRRIS on the structure of FFs, we systematically study the shape variation of these liquids under both the static and dynamic magnetic fields. Our study provides a simple yet novel way of manipulating FFs and opens opportunities for the fabrication of all-liquid devices.

Comparison of two different GSI scanning protocols in head and neck CT angiography: Image quality and radiation dose.

OBJECTIVES: To compare image quality and radiation dose of computed tomography angiography (CTA) of the head and neck in patients using two Gemstone Spectral Imaging (GSI) scanning protocols. METHODS: A total of 100 patients who underwent head-neck CTA were divided into two groups (A and B) according to the scanning protocols, with 50 patients in each group. The patients in group A underwent GSI scanning protocol 1 (GSI profile: head and neck CTA), while those in group B underwent GSI scanning protocol 2 (GSI profile: chest 80 mm). All images were reconstructed using 40% and 70% pre- and post-adaptive level statistical iterative reconstruction V (pre-ASiR-V and post-ASiR-V) algorithms, respectively. The CT dose index (CTDIvol) and dose-length (DLP) product were recorded and the mean value was calculated and converted to the effective dose. CT values, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) of all images were calculated. Additionally, subjective image evaluation was conducted by two independent radiologists using a five-point scoring method. All data were statistically analyzed. RESULTS: There were no significant differences in the CT values, SNR, CNR, and subjective score between groups A and B (p > 0.05); however, the mean effective dose (1.2±0.1 mSv) in group B was 45.5% lower than that in group A (2.2±0.2 mSv) (p < 0.05). CONCLUSIONS: GSI scanning protocol 2 could more effectively reduce the radiation dose in head-neck CT angiography while maintaining image quality compared to GSI scanning protocol 1.

Altered Phenotype and Enhanced Antibody-Producing Ability of Peripheral B Cells in Mice with Cd19-Driven Cre Expression.

Given the importance of B lymphocytes in inflammation and immune defense against pathogens, mice transgenic for Cre under the control of Cd19 promoter (Cd19Cre/+ mice) have been widely used to specifically investigate the role of loxP-flanked genes in B cell development/function. However, impacts of expression/insertion of the Cre transgene on the phenotype and function of B cells have not been carefully studied. Here, we show that the number of marginal zone B and B1a cells was selectively reduced in Cd19Cre/+ mice, while B cell development in the bone marrow and total numbers of peripheral B cells were comparable between Cd19Cre/+ and wild type C57BL/6 mice. Notably, humoral responses to both T cell-dependent and independent antigens were significantly increased in Cd19Cre/+ mice. We speculate that these differences are mainly attributable to reduced surface CD19 levels caused by integration of the Cre-expressing cassette that inactivates one Cd19 allele. Moreover, our literature survey showed that expression of Cd19Cre/+ alone may affect the development/progression of inflammatory and anti-infectious responses. Thus, our results have important implications for the design and interpretation of results on gene functions specifically targeted in B cells in the Cd19Cre/+ mouse strain, for instance, in the context of (auto) inflammatory/infectious diseases.

A cascaded copper-based nanocatalyst by modulating glutathione and cyclooxygenase-2 for hepatocellular carcinoma therapy.

Sorafenib-mediated chemotherapy is currently the first choice for hepatocellular carcinoma (HCC) that cannot be surgically excised, and can significantly improve the survival of patients. However, its poor water solubility restricts its bioavailability, and long-term single use of it does not achieve satisfactory HCC therapy effects. Herein, we report a novel cascaded copper-based metal-organic framework (MOF) therapeutic nanocatalyst using HKUST-1 by integrating cyclooxygenase-2 (COX-2) inhibitor meloxicam (Mel) and chemotherapeutic agent sorafenib (Sol) to amplify HCC therapy. This HKUST-1 nanocatalyst can be degraded by glutathione (GSH) into a Fenton-like agent to trigger chemodynamic therapy (CDT). CDT-mediated cytotoxic reactive oxygen species (ROS) can activate ferroptosis by accumulating lipid peroxides (LPO). Alternatively, GSH depletion not only deactivates glutathione peroxidase 4 (GPX4) to trigger ferroptosis, but also leads to oxidative stress amplification. Moreover, Sol can also activate ferroptosis by inhibiting system XC-, resulting in cascade-amplified ferroptosis mediated HCC therapy. Furthermore, the down-regulation of COX-2 can induce PINK1/Parkin-mediated mitophagy to further act synergistically with Sol-mediated chemotherapy. Therefore, this HKUST-1 nanocatalyst provides a novel strategy to regulate GSH and COX-2 levels for amplified chemo/chemodynamic and ferroptosis-mediated HCC therapy.

Multifunctional Ti3C2Tx MXene/Low-Density Polyethylene Soft Robots with Programmable Configuration for Amphibious Motions.

To diversify the motion modes of multifunctional soft robots capable of shape programming, we fabricate a biomimetic and programmable Ti3C2Tx MXene/low-density polyethylene (LDPE) bilayer actuator by spraying an aqueous dispersion of MXenes onto a plasma-activated LDPE film, followed by optimal thermal regulations. Because of the eminent light absorption and photothermal/electrothermal features of MXenes and the extremely mismatched thermal expansion coefficients between the two layers, the MXene/LDPE actuator can be sensitively driven by many stimuli of near-infrared light, electricity, and heat. The initial configuration of the bilayer actuator can be programmed by tuning the thermal regulation temperature, thereby assembling multiple actuation units to achieve biomimetic functions, such as artificial iris, mechanical arms, and flying birds. More importantly, in virtue of free shape cutting and programmable configuration, the MXene/LDPE bilayer actuator can perform untethered locomotion including crawling, rolling, and sailing. The soft robots can not only move on the ground in different forms but also sail on water along any designated routes and complete the surface cargo transportation driven by a near-infrared laser via the photothermal Marangoni effect. The shape-programmable methodology for the three amphibious motion modes lays foundations for wide applications of the MXene-based soft robots.

Hydromorphone for cancer pain.

BACKGROUND: This is an update of the original Cochrane Review first published in Issue 10, 2016. For people with advanced cancer, the prevalence of pain can be as high as 90%. Cancer pain is a distressing symptom that tends to worsen as the disease progresses. Evidence suggests that opioid pharmacotherapy is the most effective of these therapies. Hydromorphone appears to be an alternative opioid analgesic which may help relieve these symptoms. OBJECTIVES: To determine the analgesic efficacy of hydromorphone in relieving cancer pain, as well as the incidence and severity of any adverse events. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and clinical trials registers in November 2020. We applied no language, document type or publication status limitations to the search. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared hydromorphone with placebo, an alternative opioid or another active control, for cancer pain in adults and children. Primary outcomes were participant-reported pain intensity and pain relief; secondary outcomes were specific adverse events, serious adverse events, quality of life, leaving the study early and death. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We calculated risk ratio (RR) and 95% confidence intervals (CI) for binary outcomes on an intention-to-treat (ITT) basis. We estimated mean difference (MD) between groups and 95% CI for continuous data. We used a random-effects model and assessed risk of bias for all included studies. We assessed the evidence using GRADE and created three summary of findings tables. MAIN RESULTS: With four new identified studies, the review includes a total of eight studies (1283 participants, with data for 1181 participants available for analysis), which compared hydromorphone with oxycodone (four studies), morphine (three studies) or fentanyl (one study). All studies included adults with cancer pain, mean age ranged around 53 to 59 years and the proportion of men ranged from 42% to 67.4%. We judged all the studies at high risk of bias overall because they had at least one domain with high risk of bias. We found no studies including children. We did not complete a meta-analysis for the primary outcome of pain intensity due to skewed data and different comparators investigated across the studies (oxycodone, morphine and fentanyl). Comparison 1: hydromorphone compared with placebo We identified no studies comparing hydromorphone with placebo. Comparison 2: hydromorphone compared with oxycodone Participant-reported pain intensity We found no clear evidence of a difference in pain intensity (measured using a visual analogue scale (VAS)) in people treated with hydromorphone compared with those treated with oxycodone, but the evidence is very uncertain (3 RCTs, 381 participants, very low-certainty evidence). Participant-reported pain relief We found no studies reporting participant-reported pain relief. Specific adverse events We found no clear evidence of a difference in nausea (RR 1.13 95% CI 0.74 to 1.73; 3 RCTs, 622 participants), vomiting (RR 1.18, 95% CI 0.72 to 1.94; 3 RCTs, 622 participants), dizziness (RR 0.91, 95% CI 0.58 to 1.44; 2 RCTs, 441 participants) and constipation (RR 0.92, 95% CI 0.72 to 1.19; 622 participants) (all very low-certainty evidence) in people treated with hydromorphone compared with those treated with oxycodone, but the evidence is very uncertain. Quality of life We found no studies reporting quality of life. Comparison 3: hydromorphone compared with morphine Participant-reported pain intensity We found no clear evidence of a difference in pain intensity (measured using the Brief Pain Inventory (BPI) or VAS)) in people treated with hydromorphone compared with those treated with morphine, but the evidence is very uncertain (2 RCTs, 433 participants; very low-certainty evidence). Participant-reported pain relief We found no clear evidence of a difference in the number of clinically improved participants, defined by 50% or greater pain relief rate, in the hydromorphone group compared with the morphine group, but the evidence is very uncertain (RR 0.99, 95% CI 0.84 to 1.18; 1 RCT, 233 participants; very low-certainty evidence). Specific adverse events At 24 days of treatment, morphine may reduce constipation compared with hydromorphone, but the evidence is very uncertain (RR 1.56, 95% CI 1.12 to 2.17; 1 RCT, 200 participants; very low-certainty evidence). We found no clear evidence of a difference in nausea (RR 0.94, 95% CI 0.66 to 1.30; 1 RCT, 200 participants), vomiting (RR 0.87, 95% CI 0.58 to 1.31; 1 RCT, 200 participants) and dizziness (RR 1.15, 95% CI 0.71 to 1.88; 1 RCT, 200 participants) (all very low-certainty evidence) in people treated with hydromorphone compared with those treated with morphine, but the evidence is very uncertain. Quality of life We found no studies reporting quality of life. Comparison 4: hydromorphone compared with fentanyl Participant-reported pain intensity We found no clear evidence of a difference in pain intensity (measured by numerical rating scale (NRS)) at 60 minutes in people treated with hydromorphone compared with those treated with fentanyl, but the evidence is very uncertain (1 RCT, 82 participants; very low-certainty evidence). Participant-reported pain relief We found no studies reporting participant-reported pain relief. Specific adverse events We found no studies reporting specific adverse events. Quality of life We found no studies reporting quality of life. AUTHORS' CONCLUSIONS: The evidence of the benefits and harms of hydromorphone compared with other analgesics is very uncertain. The studies reported some adverse events, such as nausea, vomiting, dizziness and constipation, but generally there was no clear evidence of a difference between hydromorphone and morphine, oxycodone or fentanyl for this outcome. There is insufficient evidence to support or refute the use of hydromorphone for cancer pain in comparison with other analgesics on the reported outcomes. Further research with larger sample sizes and more comprehensive outcome data collection is required.

Influence of angiotensin converting enzyme inhibitors/angiotensin receptor blockers on the risk of all-cause mortality and other clinical outcomes in patients with confirmed COVID-19: A systemic review and meta-analysis.

Since the COVID-19 pandemic, physicians concerned about the potential adverse effects of angiotensin converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs). To explore the relationship between ACEIs/ARBs and the risk of mortality and other clinical outcomes in COVID-19 patients, the authors conducted a systemic review and meta-analysis. An electronic search was performed from inception to November 12, 2020 in PubMed, Medline, EMBASE, ClinicalTrials, TRIP, the Cochrane Library, CNKI, Wanfang, and CBM database. Risk of bias was assessed using the Risk Of Bias In Non-randomized Studies of Interventions tool. The primary outcome was in-hospital all-cause mortality. Secondary outcomes included all-cause mortality measured at 30-day or longer term, mechanical ventilation, length of hospital stay, readmission, and cardiac adverse events. A total of 28 studies with 73 465 patients was included. Twenty-two studies with 19 871 patients reported the incidence of all-cause mortality. Results showed no association between using ACEIs/ARBs and risk of mortality crude odds ratio （OR） of 1.02, 95% CI 0.71-1.46, p = .90, I2  = 88%, adjusted OR in 6260 patients of 0.96, 95% CI 0.77-1.18, p = .68, I2  = 0%. While six studies with 10 030 patients reported a lower risk of mortality in ACEIs/ARBs group hazard ratio (HR) of 0.53, 95% CI 0.34-0.84, p = .007, I2  = 68%. Similar association (for HR) was found in hypertension subgroup. There was no significant association for the secondary outcomes. Based on the available data, we concluded that ACEIs/ARBs is not associated with the risk of in-hospital all-cause mortality in COVID-19 patients, but may be associated with a decreased risk of 30-day all-cause mortality. Patients with hypertension may benefit from using ACEIs/ARBs.

Pharmacological Activation of Estrogen Receptor Beta Overcomes Tumor Resistance to Immune Checkpoint Blockade Therapy.

The emerging immune checkpoint blockade (ICB) therapy has ushered the cancer therapeutics field into an era of immunotherapy. Although ICB treatment provides remarkable clinical responses in a subset of patients with cancer, this regimen fails to extend survival in a large proportion of patients. Here, we found that a combined treatment of estrogen receptor beta (ERß) agonist and PD-1 antibody treatment improved therapeutic efficacy in mouse tumor models, compared with monotherapies, by reducing infiltration of myeloid-derived suppressor cells (MDSCs) and increasing CD8+ T cells in tumors. Mechanistically, LY500307 treatment reduced tumor-derived CSF1 and decreased infiltration of CSF1R+ MDSCs in the tumor bed. CSF1 released by tumor cells induced CSF1R+ MDSC chemotaxis in vitro and blockade of CSF1R demonstrated similar therapeutic effects as ERß activation in vivo. Collectively, our study proved combined treatment of ERß agonist and PD-1 antibody reduced MDSC infiltration in the tumor and enhanced tumor response to ICB therapy.

Antibiotic resistance genes in sediments of the Yangtze Estuary: From 2007 to 2019.

To better understand the occurrence and succession of antibiotic resistance genes (ARGs) in the environment, the investigation of ARGs in sediment for a long time scale is urgently needed. In this study, sediment samples were taken in the Yangtze Estuarine area from 2007 to 2019, and the interannual variations in ARGs and their possible physicochemical and socioeconomic influencing factors were analyzed. The results showed that the abundance of ARGs, including sul1, sul2, tetM, tetW, aac(6')-Ib and qnrS, was higher in recent years (from 2015 to 2019) than that in earlier years (from 2007 to 2011), and heavier ARG pollution was found in Wusongkou (WSK) samples than in Liuhekou (LHK) samples. According to the redundancy discriminant analysis (RDA) and correlation analysis, the antibiotics (especially individual antibiotic categories, including oxytetracycline, doxycycline hyclate and norfloxacin), metals and a metal resistance gene (zntA) and total organic carbon (TOC) showed significant correlations to ARGs. In addition, antibiotics, metals, TOC and ARGs were also significantly correlated with several socioeconomic indices. Furthermore, the extended STIRPAT model analysis revealed that the second industry product and the first industry product were the major socioeconomic driver factors for the ARG distribution at WSK and LHK, respectively. Overall, with socioeconomic development, antibiotics, metals, TOC and ARGs increased in sediment. In addition, antibiotics, metals and TOC may participate in the regulation of the occurrence and distribution of ARGs in the Yangtze Estuary for the long time scale.