Factors Affecting the Effectiveness and Safety of Polymyxin B in the Treatment of Gram-negative Bacterial Infections: A Meta-Analysis of 96 Articles.

PURPOSE: Polymyxin B, with its unique structure and mechanism of action, has emerged as a key therapeutic agent against Gram-negative bacteria. The study aims to explore potential factors to influence its effectiveness and safety. METHODS: A Model-Based Meta-Analysis (MBMA) of 96 articles was conducted, focusing on factors like dosage, bacterial species, and combined antibiotic therapy. The analysis evaluated mortality rates and incidence rate of renal dysfunction, also employing parametric survival models to assess 30-day survival rates. RESULTS: In the study involving 96 articles and 9,716 patients, polymyxin B's daily dose showed minimal effect on overall mortality, with high-dose group mortality at 33.57% (95% CI: 29.15-38.00) compared to the low-dose group at 35.44% (95% CI: 28.99-41.88), p=0.64. Mortality significantly varied by bacterial species, with Pseudomonas aeruginosa infections at 58.50% (95% CI: 55.42-63.58). Monotherapy exhibited the highest mortality at 40.25% (95% CI: 34.75-45.76), p<0.01. Renal dysfunction was more common in high-dose patients at 29.75% (95% CI: 28.52-30.98), with no significant difference across antibiotic regimens, p=0.54. The 30-day Overall Survival rate for monotherapy therapy was 63.6% (95% CI: 59.3-67.5) and 70.2% (95% CI: 64.4-76.2) for association therapy with ß-lactam drugs. CONCLUSIONS: The dosage of Polymyxin B doesn't significantly change death rates, but its effectiveness varies based on the bacterial infection. Certain bacteria like Pseudomonas aeruginosa are associated with higher mortality. Combining Polymyxin B with other antibiotics, especially ß-lactam drugs, improves survival rates. Side effects depend on the dose, with lower doses being safer. These findings emphasize the importance of customizing treatment to balance effectiveness and safety.

Analyzing the correlation between quinolone-resistant Escherichia coli resistance rates and climate factors: A comprehensive analysis across 31 Chinese provinces.

BACKGROUND: The increasing problem of bacterial resistance, particularly with quinolone-resistant Escherichia coli (QnR eco) poses a serious global health issue. METHODS: We collected data on QnR eco resistance rates and detection frequencies from 2014 to 2021 via the China Antimicrobial Resistance Surveillance System, complemented by meteorological and socioeconomic data from the China Statistical Yearbook and the China Meteorological Data Service Centre (CMDC). Comprehensive nonparametric testing and multivariate regression models were used in the analysis. RESULT: Our analysis revealed significant regional differences in QnR eco resistance and detection rates across China. Along the Hu Huanyong Line, resistance rates varied markedly: 49.35 in the northwest, 54.40 on the line, and 52.30 in the southeast (P = 0.001). Detection rates also showed significant geographical variation, with notable differences between regions (P < 0.001). Climate types influenced these rates, with significant variability observed across different climates (P < 0.001). Our predictive model for resistance rates, integrating climate and healthcare factors, explained 64.1% of the variance (adjusted R-squared = 0.641). For detection rates, the model accounted for 19.2% of the variance, highlighting the impact of environmental and healthcare influences. CONCLUSION: The study found higher resistance rates in warmer, monsoon climates and areas with more public health facilities, but lower rates in cooler, mountainous, or continental climates with more rainfall. This highlights the strong impact of climate on antibiotic resistance. Meanwhile, the predictive model effectively forecasts these resistance rates using China's diverse climate data. This is crucial for public health strategies and helps policymakers and healthcare practitioners tailor their approaches to antibiotic resistance based on local environmental conditions. These insights emphasize the importance of considering regional climates in managing antibiotic resistance.

Intravenous versus super-selected intra-arterial chemotherapy in children with advanced unilateral retinoblastoma: an open-label, multicentre, randomised trial.

BACKGROUND: Super-selected intra-arterial chemotherapy has increasingly been used as conservative management for retinoblastoma during the past decade. However, the absence of evidence from randomised controlled trials engendered controversy in the administration route of chemotherapy. We aimed to assess the efficacy and safety of intra-arterial chemotherapy compared with intravenous chemotherapy. METHODS: This open-label, multicentre, randomised trial was done at six hospitals in China. Patients with new-onset unilateral group D or E retinoblastoma (poorly defined, large, or very large tumours, according to the International Intraocular Retinoblastoma Classification) without high-risk clinical factors were included. Patients were randomly assigned (1:1) to receive intra-arterial chemotherapy (injections of 0·5 mg/kg [or depending on age] melphalan with 20 mg carboplatin [first and third cycles] or with 1 mg topotecan [second and fourth cycles]) or intravenous chemotherapy (0·05 mg/kg [or 1·5 mg/m2] vincristine, 5 mg/kg [or 150 mg/m2] etoposide, and 18·6 mg/kg [or 560 mg/m2] carboplatin for six cycles). After intra-arterial chemotherapy, patients received a subcutaneous injection of 0·1 mL nadroparin calcium twice at a 12 h interval. Both intra-arterial and intravenous chemotherapy cycles were completed every 4 weeks. No masking was done, except of independent statisticians, who were masked to the allocation information. The primary outcome was 2-year progression-free globe salvage rate, defined as the time from randomisation to tumour progression or enucleation, whichever occurred first, and was analysed by intention to treat. We also recorded predefined safety outcomes (myelosuppression and ophthalmic arterial stenosis or occlusion) and severe adverse events likely to be related to study treatment. The study is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-15006469, and is complete. FINDINGS: Between June 1, 2015, and June 1, 2018, 234 patients with newly diagnosed retinoblastoma were screened and 143 eligible patients (median age 23·6 months [IQR 14·0-31·9]) were enrolled and randomly assigned to the intra-arterial chemotherapy group (n=72) or the intravenous chemotherapy group (n=71). At a median follow-up of 35·8 months (IQR 28·4-43·0), the 2-year progression-free globe salvage rate was 53% (38 of 72 patients) in the intra-arterial chemotherapy group and 27% (19 of 71 patients) in the intravenous chemotherapy group (risk ratio 1·97, 95% CI 1·27-3·07, p=0·0020). Myelosuppression was less common in the intra-arterial chemotherapy group than in the intravenous chemotherapy group (37 [51%] of 72 patients vs 50 [70%] of 71 patients; 0·73, 95% CI 0·56-0·96, p=0·021) and less severe (ptrend=0·0070). In the intra-arterial chemotherapy group, two (3%) of 72 patients had ophthalmic artery occlusion and 13 (18%) patients had ophthalmic artery stenosis. INTERPRETATION: Our findings show that intra-arterial chemotherapy could significantly improve the globe salvage rate in children with advanced unilateral retinoblastoma compared with intravenous chemotherapy, with mild systemic complications and no difference in overall survival rate. Intra-arterial chemotherapy could be an acceptable first-line treatment in children with advanced unilateral retinoblastoma. FUNDING: Scientific Research Program of the National Health and Family Planning Commission of China, the Clinical Research Plan of Shanghai Hospital Development Center, the National Natural Science Foundation of China, and the Science and Technology Commission of Shanghai Municipality.

Hierarchical structure design of sea urchin Shell-Based evaporator for efficient omnidirectional Solar-Driven steam generation.

Solar-driven steam generation (SSG) is regarded as a feasible solution to the problem of fresh water scarcity. Although several attempts have been devoted to increase the efficiency of solar-to-steam conversion, it remains difficult to fabricate cost-effective, steady, and multi-angle sunlight-absorbing evaporators from readily available biomass materials. Herein, a novel hierarchical structured SSG evaporator (PDA@Shell-NaClO) is developed through a simple, low-cost, and scalable etching treatment on discarded sea urchin (SU) shells. Attributing to the dedicatedly designed microneedles array structure and porous skeleton structure of the SU shell, this PDA@Shell-NaClO evaporator shows an outstanding average light absorption performance (>90%) in a broad range of angles from 0° to 60° and exceedingly high evaporation rate of 2.81 kg m-2 h-1 under one sun condition. Furthermore, the prepared evaporator also maintains an overall stable evaporation performance and exhibits an excellent durability for a long time of up to two weeks in actual seawater. This full-ocean biomass-based SSG evaporator with plentiful raw material availability offers innovative opportunities for large-scale fresh water production.

Clinical pharmacy undergraduate education in China: a comparative analysis based on ten universities' training programs.

BACKGROUND: In recent years, the scale of personnel training for clinical pharmacy professionals in China has expanded increasingly, however, the shortage of clinical pharmacists is still prominent. In 2018, the Ministry of Education of China released national standards for the teaching quality of undergraduate majors at regular colleges and universities, which has developed a core policy for undergraduate clinical pharmacy training. To explore the training methods for clinical pharmacy professionals in China and to promote the healthy and sustainable development of the clinical pharmacy education system. This study comparatively analyzed the training programs for clinical pharmacy undergraduates in China's ten universities, discussed training programs suitable for clinical pharmacy professionals in China. METHODS: The clinical pharmacy education programs in these ten universities were obtained through official school websites or by interviewing relevant people, and then compared and analyzed. RESULTS: The school with the largest number of courses and the most class hours in general courses is University A1 (34 courses, 1316 class hours), and the school with the most credits is University B1 (75.5 credits). The schools with the largest number of courses and the most class hours in the basic courses are University A1 (50 courses, 1997 class hours), and the schools with the most credits are University B3 and University B1 (105.5 credits). The schools with the largest number of courses in the core courses are University C1 (23 courses), and the school with the most credits and class hours is University B2 (51 credits, 914 class hours). The school with the most class hours in practical teaching is University B6 (1406 class hours), and the schools with the longest internship time are University A1 and University B6 (52 weeks). CONCLUSIONS: There was substantial variation in programs. There remains a gap between the existing educational model and clinical training in pharmacy in China and developed countries. China should explore the most appropriate method for undergraduate education in clinical pharmacy based on studying foreign excellent educational models and the experience of China.

Enhancing voriconazole therapy in liver dysfunction: exploring administration schemes and predictive factors for trough concentration and efficacy.

Introduction: The application of voriconazole in patients with liver dysfunction lacks pharmacokinetic data. In previous study, we proposed to develop voriconazole dosing regimens for these patients according to their total bilirubin, but the regimens are based on Monte Carlo simulation and has not been further verified in clinical practice. Besides, there are few reported factors that significantly affect the efficacy of voriconazole. Methods: We collected the information of patients with liver dysfunction hospitalized in our hospital from January 2018 to May 2022 retrospectively, including their baseline information and laboratory data. We mainly evaluated the efficacy of voriconazole and the target attainment of voriconazole trough concentration. Results: A total of 157 patients with liver dysfunction were included, from whom 145 initial and 139 final voriconazole trough concentrations were measured. 60.5% (95/157) of patients experienced the adjustment of dose or frequency. The initial voriconazole trough concentrations were significantly higher than the final (mean, 4.47 versus 3.90 µg/mL, p = 0.0297). Furthermore, daily dose, direct bilirubin, lymphocyte counts and percentage, platelet, blood urea nitrogen and creatinine seven covariates were identified as the factors significantly affect the voriconazole trough concentration. Binary logistic regression analysis revealed that the lymphocyte percentage significantly affected the efficacy of voriconazole (OR 1.138, 95% CI 1.016-1.273), which was further validated by the receiver operating characteristic curve. Conclusion: The significant variation in voriconazole trough concentrations observed in patients with liver dysfunction necessitates caution when prescribing this drug. Clinicians should consider the identified factors, particularly lymphocyte percentage, when dosing voriconazole in this population.

The Effect of Voriconazole on Tacrolimus in Kidney Transplantation Recipients: A Real-World Study.

Tacrolimus is an immunosuppressant with a narrow therapeutic window. Tacrolimus exposure increased significantly during voriconazole co-therapy. The magnitude of this interaction is highly variable, but it is hard to predict quantitatively. We conducted a study on 91 kidney transplantation recipients with voriconazole co-therapy. Furthermore, 1701 tacrolimus concentration data were collected. Standard concentration adjusted by tacrolimus daily dose (C/D) and weight-adjusted standard concentration (CDW) increased to 6 times higher during voriconazole co-therapy. C/D and CDW increased with voriconazole concentration. Patients with the genotype of CYP3A5 *3/*3 and CYP2C19 *2/*2 or *2/*3 were more variable at the same voriconazole concentration level. The final prediction model could explain 54.27% of the variation in C/D and 51.11% of the variation in CDW. In conclusion, voriconazole was the main factor causing C/D and CDW variation, and the effect intensity should be quantitative by its concentration. Kidney transplant recipients with CYP3A5 genotype of *3/*3 and CYP2C19 genotype of *2/*2 and *2/*3 should be given more attention during voriconazole co-therapy. The prediction model established in this study may help to reduce the occurrence of rejection.

Staged lensectomy and vitrectomy in the management of stage 5C retinopathy of prematurity with corneal opacification: long-term follow up.

AIM: To verify the feasibility and safety of staged lensectomy and vitrectomy in stage 5C retinopathy of prematurity (ROP) with corneal opacification. METHODS: This was a retrospective, interventional, consecutive case series. Twenty-two eyes of 18 stage 5C ROP patients with corneal opacification were included. Regular combined lensectomy and vitrectomy were not prescribed due to the invisible fundus. Staged lensectomy and posterior vitrectomy were performed. The anatomical and visual outcomes were reviewed at the final follow-up visit. RESULTS: The mean gestational age of ROP patients was 29.3±1.6wk (range: 27-32wk), comprising 8 males and 10 females. The average birth weight was 1363.0±300.0 g. All the eyes had corneal opacity and flat or disappeared anterior chambers pre-operatively. Two eyes had complicated cataract and 7 eyes had retrolental fibroplasia. Six eyes had posterior pupillary synechiae or membranes. Seven (31.8%) eyes had vascularly active retinas. The average interval between two procedures was 6.8±4.6mo (2.5-18.5mo). After surgeries, all the patients had normal anterior chambers. Fourteen eyes had clear corneas. The intraocular pressure of 3 eyes with glaucoma was controlled by medication. Two eyes had ocular phthisis. The retina was reattached in 3 eyes and partially attached in 11 eyes. Visual acuity ranged from no light perception to hand motion. CONCLUSION: Staged lensectomy and vitrectomy are procedures that can halt progression to further complications and preserve some useful eyesight in stage 5C ROP patients with corneal opacification. The earlier the lensectomy is performed, the better the prognosis is.

Long-term clinical prognosis of 335 infant single-gene positive FEVR cases.

PURPOSE: To describe and analyze the clinical prognosis of infants diagnosed of familial exudative vitreoretinopathy (FEVR) with single gene mutation in long-term follow-up. METHODS: A retrospective case study was conducted on 355 FEVR infants with single positive gene. RESULT: Of the 335 single-gene positive infant FEVR cases (under 3 years old), 20% (n = 67) was diagnosed of strabismus at first visit. Staging of various genotypes was different (P < 0.001). Patients with NDP mutations presented the most severe clinical phenotypes and patients with ZNF408 mutations presented the mildest clinical phenotypes. Most infants underwent surgery under 1 year old (5th stage 75 of 108 [69.44%]). The axial length of different genotypes showed no significant difference (P = 0.2891). The 1st to 3rd stage cases were given intravitreal injection and/or retina photocoagulation with the last follow-up vision above 20/67. The 4th to 5th stage cases received the transcorneal vitrectomy with lensectomy or lens sparing vitrectomy (LSV), whose lens maintained transparent after LSV (11/14[78.58%]). After 2 to 10 years of follow-up, 37.96% (41/108) of post-surgery cases showed retinal funnel-like unfold and posterior pole unfold, 69.57% (16/ 23) of which received second surgery for closure of pupil with good prognosis. At the last follow-up, 20% (60/300) were with vision above 20/200. CONCLUSION: LRP5 gene mutation was the most common mutation in FEVR patients. The severity of the clinical phenotype varied with different gene mutations. The main surgical methods for cases at Stage 4-5 were transcorneal vitrectomy with lensectomy or LSV. The earlier FEVR occurred, the worse prognosis would be. Active surgical intervention and lens sparing were necessary for cases at Stage 4-5.

Reprogramming adipose mesenchymal stem cells into islet ß-cells for the treatment of canine diabetes mellitus.

BACKGROUND: Islet transplantation is an excellent method for the treatment of type I diabetes mellitus. However, due to the limited number of donors, cumbersome isolation and purification procedures, and immune rejection, the clinical application is greatly limited. The development of a simple and efficient new method to obtain islet ß-cells is a key problem that urgently requires a solution for the treatment of type I diabetes mellitus. METHODS: In this study, Pbx1, Rfx3, Pdx1, Ngn3, Pax4 and MafA were used to form a six-gene combination to efficiently reprogram aMSCs (adipose mesenchymal stem cells) into ra-ßCs (reprogrammed aMSCs-derived islet ß-cells), and the characteristics and immunogenicity of ra-ßCs were detected. Feasibility of ra-ßCs transplantation for the treatment of diabetes mellitus in model dogs and clinical dogs was detected. RESULTS: In this study, aMSCs were efficiently reprogrammed into ra-ßCs using a six-gene combination. The ra-ßCs showed islet ß-cell characteristics. The immunogenicity of ra-ßCs was detected and remained low in vitro and increased after transplantation. The cotransplantation of ra-ßCs and aMSCs in the treatment of a model and clinical cases of canine diabetes mellitus achieved ideal therapeutic effects. CONCLUSIONS: The aMSCs were efficiently reprogrammed into ra-ßCs using a six-gene combination. The cotransplantation of ra-ßCs and aMSCs as a treatment for canine diabetes is feasible, which provides a theoretical basis and therapeutic method for the treatment of canine diabetes.

Intra-Arterial Chemotherapy as Primary Treatment for Advanced Unilateral Retinoblastoma in China.

Purpose: This study aimed to evaluate the efficacy and complications of intra-arterial chemotherapy (IAC) as a primary treatment for advanced unilateral retinoblastoma in Chinese patients. Methods: This study was a retrospective review of patients with advanced unilateral retinoblastoma treated with IAC as the primary treatment. The IAC procedures were performed using a balloon-assisted technique. The clinical status and treatment complications were recorded at each visit. Kaplan-Meier analysis was performed to estimate recurrence-free survival and ocular survival. Results: In total, 116 eyes of 116 patients with advanced unilateral retinoblastoma were enrolled, including 66 eyes (57%) in group D and 50 eyes (43%) in group E. All treated eyes received a mean of 3 cycles of IAC (range, 3-5), and 66% of the eyes were combined with local consolidation therapy. The median follow-up time was 39 months (range, 22-57 months). The 3-year recurrence-free survival and ocular survival rates were 68.8% (95% CI, 59.2-76.6%) and 88.5% (95% CI, 80.9-93.2%), respectively. Moreover, the 3-year ocular survival rate in group D was significantly higher than that in group E (96.9%, 76.3%; P < 0.01). The common ocular complication was vitreous hemorrhage (19.8%). No deaths or severe systemic complications occurred. Conclusion: Primary intra-arterial chemotherapy is effective for the treatment of advanced unilateral retinoblastoma, especially in group D, with acceptable toxicity.

The Value of the Antibody Detection in the Diagnosis of Ocular Toxocariasis and the Aqueous Cytokine Profile Associated With the Condition.

Introduction: To evaluate and compare the specificity of Toxocara canis-specific antibody detection in the serum and aqueous samples for the diagnosis of ocular toxocariasis (OT) and explore the cytokine profiles associated with the condition in children. Materials and Methods: This is a prospective cohort study. The inclusion criteria were the clinical presentations of OT, which included unilateral vision reduction, typical peripheral or posterior pole granuloma with variable degrees of vitritis, and exclusion of other diagnoses. The titer of antibody against the excretory-secretory antigen of Toxocara canis [T-immunoglobulin G (IgG)] was measured in serum and aqueous samples that were taken from the affected eyes. The diagnosis of OT was made upon positive detection of T-IgG either in the serum or aqueous. The rest with typical clinical presentations as described above but a positive serum or aqueous T-IgG could not be confirmed were diagnosed as suspected OT. Cytokines were measured using multiplexed cytometric bead array system. Results: Two hundred and eleven eyes of 211 patients had participated in the study. One hundred and twenty-eight eyes were diagnosed as OT. The median age of the cohort was 7.7 years with a male to female ratio of 2.5:1. Major initial symptoms were decreased vision (74%) and strabismus (22%). The percentages of eyes with peripheral granuloma, posterior granuloma, and endophthalmitis were 40, 18, and 41%, respectively. Vitritis (100%), vitreous strands (64%), retinal fibrotic bands (57%), and retinal detachment (42%) were the most common signs. T-IgG was positive in 66.7% of the aqueous and 57.2% of the serum samples. Forty-four patients were diagnosed T-IgG negative in both serum and aqueous of the affected eyes. Interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, IL-8, eosinophil chemotactic protein (Eotaxin), MCP-1ß, and vascular endothelial growth factor (VEGF) were higher in T-IgG negative eyes when compared to controls and further increased in T-IgG positive eyes. However, only T-IgG positive eyes showed increased IL-5, IL-13, and IL-10. IL-1ß, tumor necrosis factor-alpha (TNF-α), IL-12, IL-2, interferon-gamma (IFN-γ), and IL-4 were undetectable in all eyes. Conclusions: Pediatric OT is often present with severe retinal complications. Polarized intraocular Th2 response was only found in aqueous T-IgG positive eyes. Our results supported an aqueous sample-based antibody test for the more specific diagnosis of OT.

Facile Fabrication of Highly Hydrophobic Onion-like Candle Soot-Coated Mesh for Durable Oil/Water Separation.

Although sundry superhydrophobic filtrating materials have been extensively exploited for remediating water pollution arising from frequent oil spills and oily wastewater emission, the expensive reagents, rigorous reaction conditions, and poor durability severely restrict their water purification performance in practical applications. Herein, we present a facile and cost-effective method to fabricate highly hydrophobic onion-like candle soot (CS)-coated mesh for versatile oil/water separation with excellent reusability and durability. Benefiting from a superglue acting as a binder, the sub-micron CS coating composed of interconnected and intrinsic hydrophobic carbon nanoparticles stably anchors on the surface of porous substrates, which enables the mesh to be highly hydrophobic (146.8 ± 0.5°)/superoleophilic and resist the harsh environmental conditions, including acid, alkali, and salt solutions, and even ultrasonic wear. The as-prepared mesh can efficiently separate light or heavy oil/water mixtures with high separation efficiency (>99.95%), among which all the water content in filtrates is below 75 ppm. Besides, such mesh retains excellent separation performance and high hydrophobicity even after 20 cyclic tests, demonstrating its superior reusability and durability. Overall, this work not only makes the CS-coated mesh promising for durable oil/water separation, but also develops an eco-friendly approach to construct robust superhydrophobic surfaces.

Outcome of salvage intra-arterial chemotherapy for recurrent retinoblastoma.

PURPOSE: To examine the outcome of salvage intra-arterial chemotherapy (IAC) for patients with recurrent retinoblastoma after the initial course of IAC and determine the factors influencing clinical outcome. METHODS: A total of 73 eyes of 71 patients with recurrent retinoblastoma undergoing salvage IAC after initial successfully IAC between May 2014 and May 2019 were retrospectively reviewed for clinical outcomes. Ocular survival and progression-free survival were used to examine the efficacy of salvage IAC. The factors influencing clinical outcomes were determined using univariate and multivariate analyses. RESULTS: The salvage IAC was delivered at mean 9.4 months (median 7, range 2.1-38.3 months) following the last cycle of initial IAC. 86.5% (64/73) eyes relapsed 16 months after the initial IAC. After the salvage IAC, 57 eyes (78.1%) were salvaged, and no further-line therapies were required for 36 eyes (49.3%). The 2-year Kaplan-Meier ocular survival and progression-free survival estimates after salvage IAC were 66.4% (95% CI, 31.5-42.1%) and 38.2% (95% CI, 17.8-28.8%), respectively. Univariate and multivariate analyses showed that the ocular survival and progression-free survival after salvage IAC were significantly associated with the history of vitreous seeds (p = 0.02 and p = 0.03, respectively). CONCLUSION: Salvage IAC is effective for the management of recurrent retinoblastoma after the initial successful IAC. Eyes with a history of vitreous seeds in the course of the disease are more likely to relapse and with worse ocular survival. A close follow-up strategy is imperative to treat the recurrent tumour after salvage IAC.

Piezoelectric-Thermal Coupling Driven Biomimetic Stick-Slip Bidirectional Rotary Actuator for Nanomanipulation.

Substantial improvement of rotation driving accuracy is urgently needed and facing challenges. Miniature bidirectional rotary actuators with high-precision and controllable fallback rate require novel driving principles. Here, on the basis of a proposed biomimetic stick-slip motion principle, a novel piezoelectric-thermal coupling bidirectional rotary actuator was developed. The integrated mantis grasping leglike biomimetic claws and heating rods could realize the clockwise macroscopic rotation and anticlockwise macroscopic fallback of a cylindrical rotator, generated by piezoelectric stick-slip and thermal expansion, respectively. The rotation fallback was effectively inhibited at relatively lower frequencies and higher voltages, as a slight fallback rate of 0.095 was confirmed in term of 0.5 Hz and 80 V. An extraordinary piezoelectric-driven macroscopic rotation resolution of 0.2 µrad and thermal-induced microscopic resolution of 0.00073°/°C were experimentally revealed with the aid of real-time observation of the clockwise slow sticking and anticlockwise instantaneous slipping processes by using three-dimensional optical imaging.

Five novel copy number variations detected in patients with familial exudative vitreoretinopathy.

Purpose: Familial exudative vitreoretinopathy (FEVR) is an inherited retinal vascular disease genetically heterogeneous with multiple causative genes. The aim of this study is to report five novel copy number variation (CNV) regions in FEVR patients and to investigate the possible contributions of novel CNVs to FEVR. Methods: In this study, 824 FEVR families were collected. All cases were performed using the targeted next generation sequencing (NGS) assay, and families with no definite pathogenic mutations in FEVR genes were screened for CNVs according to the NGS results. Droplet digital polymerase chain reaction (ddPCR) testing was introduced to validate the screened CNV regions. We also reviewed the clinical presentations of the probands and affected family members associated with the novel CNVs and conducted segregation analysis. Results: Five CNVs in five patients were detected in this study: heterozygous deletions of kinesin family member 11 (KIF11) exons 2-4, KIF11 exon 11, KIF11 exons 1-10, tetraspanin-12 (TSPAN12) exons 1-3, and low-density lipoprotein receptor-related protein 5 (LRP5) exons 19-21. Among the five affected families, TSPAN12 exons 1-3 heterozygous deletion and LRP5 exons 19-21 heterozygous deletion originate from the mother and the father of the proband, respectively. No other family members manifested as FEVR except for the probands. The correlation between disease severity and CNV loci seems uncertain. Conclusions: Five novel CNV loci in FEVR patients were uncovered in this study, including one maternally-inherited and one paternally-inherited CNV region. Though there is no evidence of co-segregation between these CNVs and FEVR, our findings suggest novel genetic risk factors for FEVR.

Factors Affecting Voriconazole Trough Concentration and Optimal Maintenance Voriconazole Dose in Chinese Children.

Voriconazole is a triazole antifungal agent commonly used for the treatment and prevention of invasive aspergillosis (IA). However, the study of voriconazole's use in children is limited. The present study was performed to explore maintenance dose to optimize voriconazole dosage in children and the factors affecting voriconazole trough concentration. This is a non-interventional retrospective clinical study conducted from 1 January 2016 to 31 December 2020. The study finally included 94 children with 145 voriconazole trough concentrations. The probability of achieving a targeted concentration of 1.0-5.5 µg/mL with empiric dosing increased from 43 (45.3%) to 78 (53.8%) after the TDM-guided adjustment. To achieve targeted concentration, the overall target maintenance dose for the age group of less than 2, 2 to 6, 6 to 12, and 12 to 18 years old was approximately 5.71, 6.67, 5.08 and 3.31 mg·kg-1/12 h, respectively (p < 0.001). Final multivariate analysis found that weight (p = 0.019), dose before sampling (p < 0.001), direct bilirubin (p < 0.001), urea nitrogen (p = 0.038) and phenotypes of CYP2C19 were influencing factors of voriconazole trough concentration. These factors can explain 36.2% of the variability in voriconazole trough concentration. Conclusion: In pediatric patients, voriconazole maintenance doses under the target concentration tend to be lower than the drug label recommended, but this still needs to be further studied. Age, body weight, dose, direct bilirubin, urea nitrogen and phenotypes of CYP2C19 were found to be influencing factors of voriconazole concentration in Chinese children. The influence of these factors should be taken into consideration during voriconazole use.

mTORC1 Activation in Chx10-Specific Tsc1 Knockout Mice Accelerates Retina Aging and Degeneration.

Age-associated decline in retina function is largely responsible for the irreversible vision deterioration in the elderly population. It is also an important risk factor for the development of degenerative and angiogenic diseases. However, the molecular mechanisms involved in the process of aging in the retina remain largely elusive. This study investigated the role of mTORC1 signaling in aging of the retina. We showed that mTORC1 was activated in old-aged retina, particularly in the ganglion cells. The role of mTORC1 activation was further investigated in Chx10-Cre;Tsc1fx/fx mouse (Tsc1-cKO). Activation of mTORC1 was found in bipolar and some of the ganglion and amacrine cells in the adult Tsc1-cKO retina. Bipolar cell hypertrophy and Müller gliosis were observed in Tsc1-cKO since 6 weeks of age. The abnormal endings of bipolar cell dendritic tips at the outer nuclear layer resembled that of the old-aged mice. Microglial cell activation became evident in 6-week-old Tsc1-cKO. At 5 months, the Tsc1-cKO mice exhibited advanced features of old-aged retina, including the expression of p16Ink4a and p21, expression of SA-ß-gal in ganglion cells, decreased photoreceptor cell numbers, decreased electroretinogram responses, increased oxidative stress, microglial cell activation, and increased expression of immune and inflammatory genes. Inhibition of microglial cells by minocycline partially prevented photoreceptor cell loss and restored the electroretinogram responses. Collectively, our study showed that the activation of mTORC1 signaling accelerated aging of the retina by both cell autonomous and nonautonomous mechanisms. Our study also highlighted the role of microglia cells in driving the decline in retina function.

Predictors of Voriconazole Trough Concentrations in Patients with Child-Pugh Class C Cirrhosis: A Prospective Study.

This prospective observational study aimed to clinically describe voriconazole administrations and trough concentrations in patients with Child-Pugh class C and to investigate the variability of trough concentration. A total of 144 voriconazole trough concentrations from 43 Child-Pugh class C patients were analyzed. The majority of patients (62.8%) received adjustments. The repeated measured trough concentration was higher than the first and final ones generally (median, 4.33 vs. 2.99, 3.90 mg/L). Eight patients with ideal initial concentrations later got supratherapeutic with no adjusted daily dose, implying accumulation. There was a significant difference in concentrations among the six groups by daily dose (p = 0.006). The bivariate correlation analysis showed that sex, CYP2C19 genotyping, daily dose, prothrombin time activity, international normalized ratio, platelet, and Model for end-stage liver disease score were significant factors for concentration. Subsequently, the first four factors mentioned above entered into a stepwise multiple linear regression model (variance inflation factor <5), implying that CYP2C19 testing makes sense for precision medicine of Child-Pugh class C cirrhosis patients. The equation fits well and explains the 34.8% variety of concentrations (R2 = 0.348). In conclusion, it needs more cautious administration clinically due to no recommendation for Child-Pugh class C patients in the medication label. The adjustment of the administration regimen should be mainly based on the results of repeated therapeutic drug monitoring.