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BACKGROUND In China, tuberculosis (TB) is still a major public health problem, and the incidence of TB has significant spatial heterogeneity. OBJECTIVE This study aimed to investigate the temporal trends and spatial patterns of pulmonary tuberculosis (PTB) in a low-epidemic area of eastern China, Wuxi city, from 2005 to 2020. METHODS The data of PTB cases from 2005 to 2020 were obtained from the Tuberculosis Information Management System. The joinpoint regression model was used to identify the changes in the secular temporal trend. Kernel density analysis and hot spot analysis were used to explore the spatial distribution characteristics and clusters of the PTB incidence rate. RESULTS A total of 37,592 cases were registered during 2005-2020, with an average annual incidence rate of 34.6 per 100,000 population. The population older than 60 years had the highest incidence rate of 59.0 per 100,000 population. In the study period, the incidence rate decreased from 50.4 to 23.9 per 100,000 population, with an average annual percent change of –4.9% (95% CI –6.8% to –2.9%). The incidence rate of pathogen-positive patients increased during 2017-2020, with an annual percent change of 13.4% (95% CI 4.3%-23.2%). The TB cases were mainly concentrated in the city center, and the incidence of hot spots areas gradually changed from rural areas to urban areas during the study period. CONCLUSIONS The PTB incidence rate in Wuxi city has been declining rapidly with the effective implementation of strategies and projects. The populated urban centers will become key areas of TB prevention and control, especially in the older population.

Introduction To report a family with severe ocular disorder caused by double gene variants in causative genes of autosomal dominant cataracts, GJA8 and CRYGC. Case presentation A 5-month-old boy with poor vision and enophthalmos was referred to our hospital. Further ocular examination showed horizontal nystagmus, iris abnormalities with pinpoint pupils, and extreme microphthalmia with axial right and left eye lengths of 13.48 mm and 13.75 mm, respectively. Digenic heterozygous variants (c.269T > G, p.Leu90Arg in CRYGC and c.151G > A, p.Asp51Asn in GJA8) have been detected based on the whole exome sequencing. His mother, who carried variant in CRYGC (c.269T > G, p.Leu90Arg), had nuclear cataract, microcornea and nystagmus, while his father, who carried variant in GJA8 (c.151G > A, p.Asp51Asn), showed bilateral membranous cataract, microphthalmia, sclerocornea, glaucoma, and nystagmus. Conclusions To our knowledge, this is the first report of a patient with variants in two cataract-related genes. Importantly, patient with double heterozygous variants in two dominantly inherited genes may suffer more serious phenotypes than those with heterozygous variant in a single dominantly inherited gene. Whole exome or genome sequencing is necessary for a genetic diagnosis in case of multiple gene variants.

Recurrence and metastasis after resection are still the main challenges in clinical treatment of breast cancer. Residual tumor and cancer stem-like cells are the primary culprits of recurrence and metastasis. Recent research studies indicate that autophagy is a cytoprotective mechanism of tumors, which maintains the stemness of cancer cells and promotes tumor proliferation and metastasis. Here, we constructed a "Trojan horse" using neutrophils as the carrier (PH-RL@NEs) to prevent the recurrence and metastasis of postoperative breast cancer. Neutrophils, as a "Trojan horse," can quickly respond to postoperative inflammation and accurately deliver drugs to the residual tumor site. The inflammation-triggered "Trojan horse" was then opened to release the liposomes containing the chemotherapeutic drug paclitaxel (PTX) and the autophagy inhibitor hydroxychloroquine (HCQ). We found that HCQ could effectively inhibit tumor cell autophagy, interfere with tumor epithelial-mesenchymal transition, and reduce the tumor stem cell-like population. In the orthotopic 4T1 postoperative recurrence models, PTX and HCQ synergistically killed tumors and regulated the stemness of tumor cells, thereby significantly inhibiting tumor recurrence and metastasis. Our work proved that the inhibition of autophagy to reduce tumor stemness is feasible and effective, which opens up a new prospect for postoperative tumor treatment. STATEMENT OF SIGNIFICANCE: The present study aimed to solve the issues of postoperative recurrence and metastasis of breast cancer and low efficiency of drug administration after surgery. For this purpose, we constructed neutrophils containing hydroxychloroquine (HCQ) and paclitaxel (PTX) co-loaded liposomes (PH-RL@NEs), which for the first time regulated the stemness of tumor cells by inhibiting autophagy, thereby inhibiting postoperative recurrence and metastasis of breast cancer cells. The results showed that PH-RL@NEs enhanced the targeted drug delivery efficiency, with the help of postoperative inflammation chemotaxis of neutrophils. HCQ effectively inhibited autophagy of tumor cells and reduced tumor stem cell-like cells, thus improving the therapeutic effect in the 4T1 in situ postoperative recurrence model.

Introduction: We report a novel phenotype of mandibular hypoplasia, deafness, and progeroid features with lipodystrophy (MDPL) syndrome with POLD1 mutation in a Chinese girl. Case description: Diabetic retinopathy was detected as the primary manifestation in a Chinese girl with MDPL syndrome carrying a known POLD1 mutation (c.1812_1814delCTC, p.Ser605del). Typical characteristics of the syndrome including mandibular hypoplasia, deafness, progeroid features, and diabetes were detected after comprehensive examinations. The patient suffered from blurred vision and eye pain due to the neovascularization of the retina (vitreous hemorrhage and retinal detachment) and iris (neovascular glaucoma). The literature review revealed that the prevalence of hepatomegaly and abnormal triglyceride levels were significantly higher in female than in male with MDPL syndrome carrying POLD1 mutations. Conclusion: These results expand our knowledge regarding the clinical phenotypes of MDPL syndrome with POLD1 mutations. Diabetic retinopathy is a non-negligible complication of MDPL syndrome. The phenotype varies among female and male patients with the syndrome. Hepatomegaly and abnormal triglyceride levels are more common in female patients with MDPL syndrome.

Background. Although hypothyroidism during pregnancy may develop grave outcomes for both mothers and offspring, management of which is still a challenge due to the insufficient understanding of this disease. The close correlation between hypothyroidism and preeclampsia is well documented, suggesting that preeclampsia is a potential risk factor for the development of maternal hypothyroidism. However, the exact role of preeclampsia in gestational hypothyroidism is still obscure. Objective. In this study, we explored the possible mechanisms of the effect of preeclampsia on thyroid function of maternal rats. Methods. Thirty pregnant rats were randomly divided into normal pregnancy control (NOP), preeclampsia (PE), and preeclampsia supplemented with amlodipine besylate (PEAml). NG-Nitro-L-arginine-methyl ester was used to induce preeclamptic symptoms. On gestational day 21, rats were sacrificed, and then, the ultrastructure of the thyroid gland, type 1 iodothyronine deiodinase (Dio1) expression, and serum-free thyroxine (FT4), free triiodothyronine (FT3), and thyroid stimulation hormones (TSH) were assessed. Results. Compared to NOP rats, results of PE rats showed that thyroid follicular cells’ ultrastructure was damaged; both hepatic Dio1 mRNA and protein levels were decreased. Interestingly, these changes were ameliorated in PEAml rats. Additionally, FT4, FT3, and TSH levels have no significant differences among groups. Conclusion. These findings indicated that preeclampsia could disrupt synthesis, secretion, and metabolism function of thyroid hormones by damaging thyroid follicular cells and interfering Dio1 expression.

Background: Tuberculin skin test (TST) has been the most commonly used test for diagnosis of tuberculosis (TB) infection in China for many years, because of well-established algorithms for test interpretation and a good cost-effectiveness. To our knowledge , there is no report or guideline on the influence of varicella vaccine on the sensitivity of TST in China. This paper aims to explore the effect of live attenuated varicella vaccine on the sensitivity of TST.Methods: A retrospective cohort study was carried out in a high school in Wuxi, Jiangsu province in 2020. TST and emergency varicella vaccine were administered to students in grade one of the high school which had both TB and varicella cases. The mean diameter of induration of TST were compared between 73d before varicella vaccine, 9d and 120d after varicella vaccine respectively. The retrospective cohort study was used to analyze the effect of live attenuated varicella vaccine on TST.Results: There were 45 students in the class of the high school had three TST, and 22 of them were vaccinated varicella. After 9 days of varicella vaccination, the mean diameter of induration was significantly smaller than that before the vaccination of 73 days and after the vaccination of 120 days (pConclusions: Live attenuated varicella vaccine may temporarily affect the sensitivity of tuberculin skin test.

The aim of this study was to analyse the clinical features, microbiology results, management and outcomes of patients with endogenous endophthalmitis caused by Klebsiella pneumoniae in western China.A retrospective review of medical records of 10 eyes in 10 subjects diagnosed with endogenous K. pneumoniae endophthalmitis from January 2008 to December 2018 was undertaken.The top 3 predisposing medical conditions included diabetes mellitus (50%), malignancy (20%) and cardiac stent implantation (10%). Extraocular infective foci were mainly found in the liver (40%), lungs (20%) and kidneys (10%). The positive culture rate was 85.71% (6/7) in vitreous samples, 83.33% (5/6) in blood samples and 100% (4/4) in body fluid samples. Only 20% of the patients, who had good initial visual acuity (VA) better than hand movement (HM), achieved a final VA better than 1.0 (log MAR). The mortality rate was 10%.Though the prognosis of endogenous K. pneumoniae endophthalmitis is often poor, patients with an initial VA better than HM may have a good prognosis under comprehensive treatments, including vitrectomy, systemic sensitive antibiotic injection and drainage of the primary infection loci.

Olive leaves were often extracted with methanol or ethanol at different proportions. In this study, ultrasound-assisted aqueous extraction was adopted for olive leaf extraction. The yields of total flavonoids (TF) and hydroxytyrosol (HT) were optimized by central composite experimental design. Two second-order polynomial equations were established to quantify the relationship between the responses and the processing parameters. Under the optimal condition of extracting at 60 °C for 60 min with the solvent-to-material ratio of 40, TF and HT amounted to 57.31 ± 0.35 and 1.80 ± 0.02 mg/g dry leaves (DL), respectively. The scavenging rate of all extracts against α, α-diphenyl-β-picrylhydrazyl (DPPH) and hydroxyl free radicals was screened. The integrated scores, representing both active ingredients and antioxidant capacity of the extracts, were calculated by principle component analysis (PCA). The optimal extract gained the highest score in PCA. In addition, compared to the extracts from 80% methanol to 44% ethanol, the ultrasound-assisted aqueous extract was richer in TF, HT, and polyphenols, while it also presented stronger ferric reducing antioxidant power (FRAP), but poorer strength to quench hydroxyl radicals. The study indicated that the aqueous extract of olive leaves may present broad potential opportunities in health-care sector.

A PEGylated multistimuli-responsive dendritic copolymer-doxorubicin (DOX) prodrug-based nanoscale system was developed as a delivery model for hydrophobic drugs. In this system, PEGylation did not only prolong circulation of the nanoscale system in the body (average half-life of 14.6 h, four times longer than that of the free drug), but also allowed the system to aggregate into nanoparticles (NPs) because of interactions between hydrophilic (polyethylene glycol) and hydrophobic (dendritic prodrug) moieties for better uptake through endocytosis (around 150 nm of particle size with a neutrally charged surface for the PEGylated dendritic prodrug with 12.1 wt % of DOX). The dendritic structure was built by bridging poly[ N-(2-hydroxypropyl)methacrylamide] segments with enzyme-responsive GFLG (Gly-Phe-Leu-Gly tetrapeptide) linkers. DOX was released by hydrolyzing the hydrazone bond between DOX and the copolymer framework in the acidic endosomes/lysosomes. In vitro studies on DOX released from the NPs induced mitochondrial dysfunction during apoptosis. By imaging the main organs and tumor tissues from mice treated with the NPs, boosted accumulation of this nanoscale medicine was found in tumor tissues, leading to a decrease in toxicity and side effects to normal tissues and enhancement in drug tolerance. In the 4T1 breast cancer model, these NPs exhibited a superior antitumor efficacy confirmed by inhibiting angiogenesis, proliferation of tumor tissues, and inducing procedural apoptosis of tumor cells. The highest tumor growth inhibition value mediated by the NPs was up to 86.5%. Therefore, this PEGylated multistimuli-responsive dendritic copolymer-DOX prodrug-based nanoscale system may be further explored as an alternative to traditional chemotherapy for breast cancer treatment.

Cell penetrating peptides (CPPs) were widely used as motifs for drug delivery to tumor. In former study, an RGD reverse sequence dGR was used to develop active-targeting liposome R8dGR-Lip, which showed well penetrating ability and treatment efficiency on glioma model. However, recurrence after tumor resection caused by post-operative residual cancer cells was a huge obstacle in tumor treatment. In consideration of the effective anti-cancer effect of PTX-R8dGR-Lip when treating glioma in former study, we decide to evaluate its pharmacodynamics on tumor resection models, which were more invasive and resistant. In vitro, the effectiveness of PTX-R8dGR-Lip in reducing tumor initiating cell (TIC) was investigated using mammosphere formation. In vivo, the inhibition efficiency of PTX-R8dGR-Lip on C6 glioma recurrence and 4 T1 breast cancer recurrence model were evaluated, including tumor bioluminescence imaging, survival rate and immumohistochemical staining, etc.. C6 mammosphere formation rate of PTX-R8dGR-Lip group was 48.06 ± 2.72%, and 4 T1 mammosphere formation rate of PTX-R8dGR-Lip group was 39.51 ± 4.02% when PBS group was set as 100%. C6 and 4 T1 bioluminescent tumor resected model were established, then effectiveness of different PTX-loaded preparations were evaluated on these two models. PTX-R8dGR-Lip could obviously inhibit tumor recurrence, prolong survival rate and reduce tumor tissue invasion. PTX-R8dGR-Lip could reduce post-operative recurrence rate, prolong survival time, and decrease the proliferation of residual cancer cells through regulating the expression of recurrence-related cytokines.

Therapeutic application of recombinant adeno-associated virus (AAV) has been limited by its small carrying capacity. To overcome this limitation trans-splicing vectors were developed recently. However, the transduction efficiency of trans-splicing vectors is considerably lower than that of a single intact vector in skeletal muscle. To improve trans-splicing vectors for skeletal muscle gene therapy, we examined whether coinfection efficiency is a rate-limiting factor in the mdx mouse, a model for Duchenne muscular dystrophy. Two different AAV viruses were delivered to the mdx muscle. Similar to previous reports in normal muscle, coinfection efficiency reached approximately 90% in the diseased muscle. This result suggests that coinfection is not a hurdle in dystrophic muscle. Another critical step in the trans-splicing method is the transcription and splicing across the inverted terminal repeat (ITR) junction in the reconstituted genome. To test whether this represented a significant obstacle, we systematically evaluated the transcription, pre-mRNA stability and splicing, and translation in a synthetic lacZ construct that mimicked the reconstituted genome. Although inserting an intron in the lacZ gene had no effect on its expression, inclusion of the ITR junction in the intron reduced expression by 50%. In construct containing the ITR junction, the mRNA transcript level was significantly reduced. This mRNA level reduction was associated with decreased pre-mRNA stability. These data suggest that the accumulation of mRNA is a rate-limiting factor in trans-splicing vector-mediated gene therapy.

Adeno-associated virus (AAV) is one of the smallest DNA viruses. Therapeutic application of recombinant AAV has been limited by its small carrying capacity. Many large genes, such as the 6 kb mini-dystrophin gene for Duchenne muscular dystrophy (DMD), are traditionally excluded from rAAV gene therapy. To overcome the size limitation, we have recently developed trans-splicing AAV vectors. This approach takes advantage of AAV inverted terminal repeat (ITR)-mediated intermolecular recombination and the eukaryotic splicing machinery. A large gene is split into two parts and engineered with splicing signals. Following packaging and co-infection, the transgene is expressed from the reconstituted genome. Despite the success of the proof-of-principle studies, the overall transduction efficiency of trans-splicing vectors is considerably lower than that of a single intact vector in skeletal muscle. To improve trans-splicing vectors for DMD gene therapy, we examined whether co-infection efficiency is a rate-limiting factor for skeletal muscle in a mouse model for DMD (mdx mouse). Two different AAV viruses carrying the gene either for alkaline phosphatase or nuclear-localized LacZ were delivered to mdx anterior tibialis muscle. Consistent with previous reports in normal muscle, co-infection efficiency reached 89.2±2.0% in the diseased muscle. This result suggests that co-infection efficiency is not a hurdle for trans-splicing vector-mediated gene therapy in dystrophic muscle.