A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

An exploration of testicular cancer survivors' experience of ejaculatory dysfunction following retroperitoneal lymph node dissection-a sub-study of the PREPARE clinical trial.

PURPOSE: Ejaculatory dysfunction secondary to retrograde ejaculation or anejaculation is a complication of retroperitoneal lymph node dissection (RPLND) for survivors of testicular cancer. We explored survivors' experiences of ejaculatory dysfunction following RPLND. METHODS: In a sub-study of a single-arm phase 2 clinical trial (ACTRN12622000537752/12622000542796), participants reporting ejaculatory dysfunction ≥ 6 months following RPLND were invited to complete semi-structured interviews. Purposive sampling was used. Interviews continued until thematic saturation occurred, and codebook thematic analysis of interviews was performed. RESULTS: Of 58 individuals recruited to the trial, 33 (57%) reported ejaculatory dysfunction. Of these, 32 (97%) agreed to interview and 15 participated. Participants interviewed had median age 34 years (range 24-66), 12 (80%) in a long-term relationship with median time from surgery 36 months (range 11-112). Three overarching themes were identified. The first reflected the value of RPLND despite ejaculatory dysfunction. The second illuminated the impact(s) of ejaculatory dysfunction closely mapped to life stage, with flow-on impacts to fertility, sex, psychological wellbeing and communication. The third reflected information needs. Fertility was a substantial source of concern for some participants. Ejaculatory dysfunction had no effect on sex for some, whilst for others, sex was less pleasurable. Some reported benefits. Few reported ejaculatory dysfunction challenged masculinity, confidence, or self-esteem. CONCLUSIONS: Future research should examine interventions to reduce distress related to fertility, challenged masculinity and body image. IMPLICATIONS FOR CANCER SURVIVORS: Whilst most participants considered ejaculatory dysfunction to have little impact on their sexual function and relationships, some reported significant difficulties varying by life stage and relationship status.

Order-disorder phase transition and elastic-to-plastic vortex creep crossover in a triclinic iron pnictide superconductor (Ca[Formula: see text]La[Formula: see text])[Formula: see text](Pt[Formula: see text]As[Formula: see text])(Fe[Formula: see text]As[Formula: see text])[Formula: see text].

Vortex matter in layered high-[Formula: see text] superconductors, including iron-pnictides, undergo several thermodynamic phase transitions due to the complex interplay of pinning energy, thermal energy and elastic energy. Moreover, the presence of anisotropy makes their vortex physics even more intriguing. Here, we report a detailed vortex dynamics study, using dc magnetization measurements, in a triclinic iron-pnictide superconductor (Ca[Formula: see text]La[Formula: see text])[Formula: see text](Pt[Formula: see text]As[Formula: see text])(Fe[Formula: see text]As[Formula: see text])[Formula: see text], with a superconducting transition temperature, T[Formula: see text] [Formula: see text] 31 K. A second magnetization peak (SMP) feature is observed for magnetic field perpendicular (H[Formula: see text]c) and parallel (H[Formula: see text]ab) to the crystal plane. However, its fundamental origin is quite different in both directions. For H[Formula: see text]c, the SMP can be well explained using an elastic-to-plastic vortex creep crossover, using collective creep theory. In addition, a possible rhombic-to-square vortex lattice phase transition is also observed for fields in between the onset-field and peak-field related to the SMP. On the other hand, for H[Formula: see text]ab, a clear signature of an order-disorder vortex phase transition is observed in the isothermal M(H) measurements at T [Formula: see text] 6 K. The disordered phase exhibits the characteristics of entangled pinned vortex-liquid. We construct a comprehensive vortex phase diagram by displaying characteristic temperatures and magnetic fields for both crystal geometries in this unique superconducting compound. Our study sheds light on the intricate vortex dynamics and pinning in an iron-pnictide superconductor with triclinic symmetry.

Comparative evaluation of biased agonists Sarcosine1 , d-Alanine8 -Angiotensin (Ang) II (SD Ang II) and Sarcosine1 , Isoleucine8 -Ang II (SI Ang II) and their radioiodinated congeners binding to rat liver membrane AT1 receptors.

Angiotensin II analogue and ß-arrestin biased agonist TRV027 (Sarcosine1 , d-Alanine8 -Angiotensin (Ang) II; SD Ang II), developed by Trevena, Inc. in the early 2010s, brought hopes of a novel treatment for cardiovascular diseases, due to its ability to simultaneously cause signaling through the ß-arrestin signaling pathway, while antagonizing the pathophysiological effects of Ang II mediated by the AT1 receptor G protein signaling cascades. However, a phase II clinical trial of this agent revealed no significant benefit compared to placebo treatment. Using 125 I-Sarcosine1 , Isoleucine8 -Ang II (125 I-SI Ang II) radioligand receptor competition binding assays, we assessed the relative affinity of TRV027 compared to SI Ang II for liver AT1 receptors. We also compared radioiodinated TRV027 (125 I-SD Ang II) binding affinity for liver AT1 receptors with 125 I-SI Ang II. We found that despite its anticipated gain in metabolic stability, TRV027 and 125 I-SD Ang II had reduced affinity for the AT1 receptor compared with SI Ang II and 125 I-SI Ang II. Additionally, male-female comparisons showed that females have a higher AT1 receptor density, potentially attributed to tissue-dependent estrogen and progesterone effects. Peptide drugs have become more popular over the years due to their increased bioavailability, fast onset of action, high specificity, and low toxicity. Even though Trevena®'s biased agonist peptide TRV027 offered greater stability and potency compared to earlier AT1 R biased agonists, it failed its phase II clinical trial in 2016. Further refinements to AT1 R biased agonist peptides to improve affinity, as seen with SI Ang II, with better stability and bioavailability, has the potential to achieve the anticipated biased agonism.

Identification of 2-Aryl-Quinolone Inhibitors of Cytochrome bd and Chemical Validation of Combination Strategies for Respiratory Inhibitors against Mycobacterium tuberculosis.

Mycobacterium tuberculosis cytochrome bd quinol oxidase (cyt bd), the alternative terminal oxidase of the respiratory chain, has been identified as playing a key role during chronic infection and presents a putative target for the development of novel antitubercular agents. Here, we report confirmation of successful heterologous expression of M. tuberculosis cytochrome bd. The heterologous M. tuberculosis cytochrome bd expression system was used to identify a chemical series of inhibitors based on the 2-aryl-quinolone pharmacophore. Cytochrome bd inhibitors displayed modest efficacy in M. tuberculosis growth suppression assays together with a bacteriostatic phenotype in time-kill curve assays. Significantly, however, inhibitor combinations containing our front-runner cyt bd inhibitor CK-2-63 with either cyt bcc-aa3 inhibitors (e.g., Q203) and/or adenosine triphosphate (ATP) synthase inhibitors (e.g., bedaquiline) displayed enhanced efficacy with respect to the reduction of mycobacterium oxygen consumption, growth suppression, and in vitro sterilization kinetics. In vivo combinations of Q203 and CK-2-63 resulted in a modest lowering of lung burden compared to treatment with Q203 alone. The reduced efficacy in the in vivo experiments compared to in vitro experiments was shown to be a result of high plasma protein binding and a low unbound drug exposure at the target site. While further development is required to improve the tractability of cyt bd inhibitors for clinical evaluation, these data support the approach of using small-molecule inhibitors to target multiple components of the branched respiratory chain of M. tuberculosis as a combination strategy to improve therapeutic and pharmacokinetic/pharmacodynamic (PK/PD) indices related to efficacy.

Acyl-CoA thioesterase 9 promotes tumour growth and metastasis through reprogramming of fatty acid metabolism in hepatocellular carcinoma.

Acyl-CoA thioesterase 9 (ACOT9) is a critical regulator of cellular utilization of fatty acids by catalysing the hydrolysis of acyl-CoA thioesters to non-esterified fatty acid and coenzyme A (CoA). Recently, ACOT9 was reported to participate in the pathogenesis of non-alcoholic liver disease (NAFLD), which arises from aberrant lipid metabolism and serves as a risk factor for hepatocellular carcinoma (HCC). However, the functions of ACOT9 in carcinogenesis and aberrant lipid metabolism in HCC remain unexplored. Here, we found that ACOT9 expression is significantly elevated in HCC at least partially due to the down-regulation of miR-449c-3p. Upregulation of ACOT9 is closely associated with poor prognosis for patients with HCC. Knockdown of ACOT9 expression in HCC cells significantly decreased cell proliferation, colony formation, migration and invasion, mainly through suppression of G1-to-S cell cycle transition and epithelial-to-mesenchymal transition (EMT). By contrast, forced ACOT9 expression promoted HCC growth and metastasis. In addition, we found that ACOT9 reprogrammed lipid metabolism in HCC cells by increasing de novo lipogenesis. Furthermore, we demonstrated that increased lipogenesis was involved in ACOT9-promoted HCC growth and metastasis. Altogether, we demonstrate that ACOT9 plays a critical oncogenic role in the promotion of tumour growth and metastasis by reprogramming lipid metabolism in HCC, indicating ACOT9 as a potential therapeutic target in treatment of HCC.

[Association of vitamin D nutritional status with calcaneal bone mineral density in school-age children: a prospective cohort study].

Objective: To investigate the relationships between vitamin D nutritional status and the calcaneal bone mineral density (BMD) in children. Methods: Data were obtained from School-based Cardiovascular and Bone Health Promotion Program. In 2017, a total of 15 391 children aged 6-16 years in Beijing selected through stratified cluster sampling were included in the baseline survey. A follow-up investigation was conducted in 2019. The questionnaire survey, detection of serum 25-hydroxyvitamin D [25(OH)D] level and ultrasound measurement of calcaneal BMD were conducted. Multivariable linear and logistic regression models were used to analyze the relationships between baseline vitamin D nutritional status and the follow-up calcaneal BMD. Results: A total of 10 914 children aged (11.5±3.3) years (boys accounting for 49.6%) were included in the analysis. The average 25(OH)D level was (35.4±12.0) nmol/L, and the deficiency rate was 36.1%. After the adjustment for age, gender, body mass index, smoking status, alcohol use status, dairy products intake, vitamin D supplement, calcium supplement, physical activity, pubertal development, and baseline calcaneal BMD Z-score, for per 10 nmol/L increase in 25(OH)D, the follow-up calcaneal BMD Z-score increased by 0.01(P=0.041), and the OR(95%CI) of decreased calcaneal BMD Z-score after 2 years was 0.96 (0.93-1.00)(P=0.030). Compared with vitamin D adequacy, the follow-up calcaneal BMD Z-score of children with vitamin D insufficiency and deficiency decreased by 0.03(P=0.307) and 0.06 (P=0.046), and the risk of decreased calcaneal BMD Z-score after 2 years increased by 15%(P=0.037) and 21%(P=0.006), respectively (P for trend<0.05). Conclusions: Vitamin D nutritional status was closely related to calcaneal BMD, and children with adequate vitamin D nutritional status tended to obtain higher BMD. Children and adolescents are encouraged to maintain sufficient vitamin D levels, strengthen nutrition and exercise to promote bone health.

A Novel Surgical Approach for Type 2 Mirizzi Syndrome: Based on a Decade of Clinical Experience at a Teaching Hospital.

Background. The Mirizzi syndrome (MS) is a rare complication of cholecystolithiasis that is often accompanied by severe inflammation and fibrosis around Calot's triangle. It is difficult to treat Type 2 MS surgically, and the treatment for this condition has not yet been standardized. The data on operative management are limited. The study aimed to review our institutional clinical experience regarding surgery and provide recommendations for treating Type 2 MS. Methods: We conducted a retrospective study on 6 patients with MS who were surgically treated at our institution between January 2010 and December 2019. The classification of MS by McSherry CK, Ferstenberg H, Virshup M. The Mirizzi syndrome: Suggested classification and surgical therapy. Surg Gastroenterol. 1982;1:219-225 was used. Mucosal approach was used to treat Type 2 MS. The parameters for comparison included patient demographics, operative procedures, operation time, blood loss, length of hospital stay, complications, and follow-up. Results: There were 23 patients with MS among 10 386 cholecystectomies in our area. Six patients with Type 2 MS had successful surgery, and the mucosal approach was used. The average operative time was 253.3 ± 32.5 minutes. The average blood loss was 70.0 ± 14.1 mL. The mean postoperative hospital stay was 9.5 ± 3.9 days. There was no postoperative mortality. The most frequent postoperative complications were bile leakage (16.7%), and postoperative intra-abdominal collection (16.7%). The mean postoperative follow-up was 10 months, and all patients are asymptomatic. The mucosal approach may decrease the risk of bile duct injury, biliary tract infection, and blood loss more than other surgical approaches. Conclusion: This study demonstrates that the mucosal approach is an effective surgical procedure for Type 2 MS.

E-Cigarettes and Cardiopulmonary Health.

E-cigarettes have surged in popularity over the last few years, particularly among youth and young adults. These battery-powered devices aerosolize e-liquids, comprised of propylene glycol and vegetable glycerin, typically with nicotine, flavors, and stabilizers/humectants. Although the use of combustible cigarettes is associated with several adverse health effects including multiple pulmonary and cardiovascular diseases, the effects of e-cigarettes on both short- and long-term health have only begun to be investigated. Given the recent increase in the popularity of e-cigarettes, there is an urgent need for studies to address their potential adverse health effects, particularly as many researchers have suggested that e-cigarettes may pose less of a health risk than traditional combustible cigarettes and should be used as nicotine replacements. This report is prepared for clinicians, researchers, and other health care providers to provide the current state of knowledge on how e-cigarette use might affect cardiopulmonary health, along with research gaps to be addressed in future studies.

The MUC5B-associated variant rs35705950 resides within an enhancer subject to lineage- and disease-dependent epigenetic remodeling.

The G/T transversion rs35705950, located approximately 3 kb upstream of the MUC5B start site, is the cardinal risk factor for idiopathic pulmonary fibrosis (IPF). Here, we investigate the function and chromatin structure of this -3 kb region and provide evidence that it functions as a classically defined enhancer subject to epigenetic programming. We use nascent transcript analysis to show that RNA polymerase II loads within 10 bp of the G/T transversion site, definitively establishing enhancer function for the region. By integrating Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analysis of fresh and cultured human airway epithelial cells with nuclease sensitivity data, we demonstrate that this region is in accessible chromatin that affects the expression of MUC5B. Through applying paired single-nucleus RNA- and ATAC-seq to frozen tissue from IPF lungs, we extend these findings directly to disease, with results indicating that epigenetic programming of the -3 kb enhancer in IPF occurs in both MUC5B-expressing and nonexpressing lineages. In aggregate, our results indicate that the MUC5B-associated variant rs35705950 resides within an enhancer that is subject to epigenetic remodeling and contributes to pathologic misexpression in IPF.

The value of interventional radiology in clinical trial teams: experience from the BATTLE lung cancer trials.

AIM: To report on the multidisciplinary approach, focusing specifically on the role of the interventional radiologist (IR), used to support the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) and BATTLE-2 trials. MATERIALS AND METHODS: Patients who underwent percutaneous image-guided biopsy for the BATTLE and BATTLE-2 trials were reviewed. A radiology-based, three-point, lesion-scoring system was developed and used by two IRs. Lesions were given a score of 3 (most likely to yield sufficient material for biomarker analysis) if they met the following criteria: size >2 cm, solid mass, demonstrated imaging evidence of viability, and were technically easy to sample. Lesions not meeting all four criteria were scored 2 with the missing criteria noted as negative factors. Lesions considered to have risks that outweighed potential benefits receive a score of 1 and were not biopsied. Univariate and multivariate analyses were performed to evaluate the score's ability to predict successful yield for biomarker adequacy. RESULTS: A total of 555 biopsies were performed. The overall yield for analysis of the required biomarkers was 86.1% (478/555), and 84% (268/319) and 88.9% (210/236) for BATTLE and BATTLE-2, respectively (p=0.09). Lesions receiving a score of 3 were adequate for biomarker analysis in 89% of cases. Lesions receiving a score of 2 with more than two negative factors were adequate for molecular analysis in 69.2% (IR1, p=0.03) and 74% (IR2, p=0.04) of cases. The two IRs scored 78.4% of the lesions the same indicating moderate agreement (kappa=0.55; 95% confidence interval [CI]: 0.48, 0.61). CONCLUSIONS: IRs add value to clinical trial teams by optimising lesions selected for biopsy and biomarker analysis.

[Application of obesity indicators based on body fat in the screening of persistent dyslipidemia among school-aged children].

Objective: To explore the screening effect of obesity assessed by body fat indicators on persistent dyslipidemia among children. Methods: Data were obtained from the baseline and follow-up survey of 'School-based Cardiovascular and Bone Health Promotion Program.' BMI, fat mass index (FMI), and fat mass percentage (FMP) were used to define obesity. Dyslipidemia, diagnosed both in the baseline and a follow-up survey, was defined as persistent dyslipidemia. The area under the receiver operating characteristic curve (AUC) was used to compare the predictive capabilities of obesity defined by different indicators on persistent dyslipidemia. Results: A total of 10 783 children (boys accounted for 49.6%) were included in the analysis, with the average age as (10.9±3.3) years old. The detection rates of persistent high TC, high LDL-C, low HDL-C, high TG, and high non-HDL-C were 1.3%, 1.2%, 4.3%, 1.3%, and 0.8%, respectively. In boys, the capabilities of FMI- and FMP-defined obesity in the prediction of persistent high LDL-C [FMI: AUC=0.626 (95%CI: 0.558-0.694), P=0.024; FMP: AUC=0.642 (95%CI: 0.574-0.710), P=0.004] and high non-HDL-C [FMI: AUC=0.637 (95%CI: 0.584-0.689), P=0.017; FMP: AUC=0.641 (95%CI: 0.588- 0.693), P=0.018] were significantly higher than BMI-defined obesity. Besides, obese boys defined by FMI had the stronger capability in predicting persistent low HDL-C than that defined by BMI [AUC=0.784 (95%CI: 0.742-0.826) vs. 0.750 (95%CI: 0.726-0.773), P=0.047]. In girls, the capabilities of FMI- and FMP-defined obesity in the prediction of persistent dyslipidemia were not statistically different from BMI. Conclusions: The obesity assessed by body fat performed better in predicting persistent high LDL-C, low HDL-C, and high non-HDL-C than that assessed by BMI among boys, which can be further applied to cardiovascular disease prevention.

Surfactant Protein-A Protects against IL-13-Induced Inflammation in Asthma.

The lung surfactant proteins are recognized as critical not only for their role in lowering lung surface tension but also in innate host defense. Reports have shown that some asthmatic patients have decreased levels of one member of this protein family in particular, surfactant protein-A (SP-A). Our studies set out to determine the contribution of SP-A to the response of a key effector cytokine in asthma, IL-13. Our studies employ both animal models sufficient and deficient in SP-A challenged with IL-13 and primary epithelial cells from participants with asthma that are exogenously treated with SP-A in the context of IL-13 challenge. The inflammatory response and mucin production were assessed in both model systems. As compared with WT mice, we show that the activity of IL-13 is dramatically augmented in SP-A-/- mice, which have significantly increased neutrophil and eosinophil recruitment, mucin production and asthma-associated cytokines in the bronchoalveolar lavage fluid. In parallel, we show asthma-associated factors are attenuated in human cells from asthma subjects when exogenous SP-A is added during IL-13 challenge. Although many of these phenotypes have previously been associated with STAT6 signaling, SP-A inhibited IL-13-induced STAT3 phosphorylation in mice and in human epithelial cells while having little effect on STAT6 phosphorylation. In addition, when either STAT3 or IL-6 were inhibited in mice, the phenotypes observed in SP-A-/- mice were significantly attenuated. These studies suggest a novel mechanism for SP-A in asthma as a modulator of IL-13-induced inflammation via mediating downstream IL-6/STAT3 signaling.

[Advances in new type of biomolecular markers for liver fibrosis].

Liver fibrosis is a common pathological process of chronic liver disease, and the number of deaths from liver cirrhosis, liver failure and liver cancer is increasing year-by-year worldwide. Presently, the detection methods to evaluate hepatic fibrosis mainly include hepatic histological examination, imaging and serum markers, but all these have many limitations in clinical aspects. Recently, there have been more and more studies related to the development of non-coding RNA, exosomes and liver fibrosis that are considered as a new type of biomolecular markers with potential clinical application. Herein, we did a preliminary assessment in conjunction with relevant advances to provide a reference for the early diagnosis and treatment of liver fibrosis.

Marsupialisation for the treatment of unicystic ameloblastoma of the mandible: a long-term follow up of 116 cases.

Unicystic ameloblastoma is a unique histopathological type of ameloblastoma, and treatment is controversial. Marsupialisation is effective in reducing the size of cystic lesions and their complications. We have retrospectively analysed the clinical, histopathological, and prognostic data of affected patients who were treated by marsupialisation between 2003 and 2013 in three Chinese hospitals. Our aim was to evaluate the effects and prognosis, and the factors associated with outcome. A total of 116 patients with mandibular unicystic ameloblastomas were included, and 74, 26, and 16 patients were histopathologically classified as being luminal, intraluminal, and mural subtypes, respectively. Most responded well to marsupialisation, with an overall recurrence rate of 12%. Resorption of the root (p<0.001), perforation of the cortical bone (p=0.005), and histopathological subtype (p=0.013) were the main factors that predicted the outcome. Perforation of the cortical bone was the only reliable predictor of recurrence (p<0.001). Disease-free survival function curves indicated that patients with the mural subtype were at a higher risk of recurrence than patients with the other two subtypes (p=0.003). Poor outcomes of marsupialisation were treated surgically and, to date, no subsequent recurrences have been reported. Marsupialisation is effective for these patients, with a recurrence rate similar to that of radical treatment. The outcomes can be predicted using characteristics of the lesion such as resorption of the root, perforation of the cortical bone, and histopathological subtypes. However, additional studies are required to corroborate these findings.

Expression and characterization of the cyp19a gene and its responses to estradiol/letrozole exposure in Chinese soft-shelled turtle (Pelodiscus sinensis).

Cytochrome P450 aromatase (CYP19) catalyzes the conversion of androgens to estrogens and is critical in sex differentiation. CYP19 exists as the ovarian type and brain type. Herein, we cloned the full-length ovarian cyp19a gene from the Chinese soft-shelled turtle, Pelodiscus sinensis (pscyp19a). We determined the distribution of pscyp19a in adult tissue and evaluated its expression during embryonic development, following treatment with 17ß-estradiol (E2) or letrozole (LE). The pscyp19a complementary DNA is 2,285 bp in length and comprises a 1,512 bp open reading frame that encodes a protein of 503 AA. The nucleotide sequence and amino acid of pscyp19a shared significant identity with other vertebrate sequences. Expression of pscyp19a was high in the ovary (p < 0.01), and exhibited modest expression in the female brain and intestine. Expression of pscyp19a displayed significant differences between sexes during early embryo development stages; expression increased gradually during embryonic development in females, but the opposite trend was observed in males. Female embryos treated with different concentrations of E2 and LE displayed altered pscyp19a expression compared with untreated individuals, and E2 clearly induced pscyp19a expression. These results indicate that pscyp19a gene plays important roles in early developmental stages in Chinese soft-shelled turtle, and may assist future studies on sex differentiation and sex control in this and similar species.

Estradiol modulation of the renin-angiotensin system and the regulation of fear extinction.

Post-traumatic stress disorder (PTSD) is more prevalent in women than men, yet much remains to be determined regarding the mechanism underlying this sex difference. Clinical and preclinical studies have shown that low estradiol levels during extinction of fear conditioning in rodents (i.e., cue exposure therapy in humans) leads to poor extinction consolidation and increased fear during extinction recall. The renin-angiotensin system (RAS) is also associated with stress-related pathologies, and RAS antagonists can enhance extinction consolidation in males. However, less is known about how estradiol and the RAS converge to alter fear extinction consolidation in females. Since estradiol downregulates the RAS, we determined the role of surgically (via ovariectomy [OVX]) and pharmacologically (via the hormonal contraceptive [HC], levonorgestrel) clamping estradiol at low levels in female rats on fear-related behavior, serum estradiol and angiotensin II (Ang II) levels, and angiotensin II type I receptor (AT1R) binding in the brain. We then tested whether the AT1R antagonist losartan would alter fear-related behavior in an estradiol-dependent manner. We found that both OVX and HC treatment produced extinction consolidation deficits relative to intact female rats in proestrus (when estradiol levels are high), and that losartan treatment mitigated these deficits and reduced freezing. OVX, but not HC, altered AT1R ligand binding, though HC reduced estradiol and increased Ang II levels in plasma. These findings have significant clinical implications, indicating that administration of an AT1R antagonist, especially if estradiol levels are low, prior to an exposure therapy session may improve treatment outcomes in females.

Comparison of changes in refractive error and corneal curvature following small-incision lenticule extraction and femtosecond laser-assisted in situ keratomileusis surgery.

PURPOSE: To compare visual acuity, refractive error, corneal curvature, and the stability of these parameters during the early postoperative period following small-incision lenticule extraction (SMILE) and femtosecond laser-assisted in situ keratomileusis (FS-LASIK) surgery. METHODS: One hundred and five eyes and 110 eyes were enrolled in SMILE and FS-LASIK group, respectively. Uncorrected and best-corrected distance visual acuity (UCVA and BCVA), manifest refraction, corneal curvature, intraocular pressure, and slit-lamp examinations were performed preoperatively, 1 day, 1 week, 1 month, and 3 months postoperatively. RESULTS: No significant differences in postoperative UCVA or BCVA were observed between the SMILE and FS-LASIK groups at any time point. SMILE group had significant better postoperative spherical equivalent (SE) values than FS-LASIK group at 1 day, 1 week, and 1-month follow-up. However, there was no significant difference in postoperative SE values at 3-month follow-up. Significant differences in mean postoperative corneal curvature were observed during all follow-up examinations. CONCLUSION: SMILE surgery was associated with more accurate postoperative refractive correction up to 1 month following surgery. SMILE surgery also resulted in less significant corneal curvature changes than FS-LASIK. Furthermore, FS-LASIK was associated with decreased stability of postoperative refractive error and corneal curvature relative to SMILE.

[A comparison of fine needle nonaspiration cytology versus fine needle aspiration for thyroid nodules: a Meta-analysis].

Objective:To evaluate the differences of smear quality and diagnostic accuracy between thyroid nodules and fine needle nonaspiration cytology (FNNAC) and fine needle aspiration cytology (FNAC).Method:Databases were used to search the literature on FNNAC and FNAC. All statistical analyses were performed using Review Manager 5.3 Software.Result:A total of 10 studies were included in the study. Meta-analysis showed no significant difference in FNNAC and FNAC between low, middle and high quality smears. There was no significant difference in diagnostic accuracy.Conclusion:There were no difference in obtaining the smear quality and diagnostic accuracy, the person doing the piercing can freely choose which way according to the habit.